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Pharmacology > Penicillins > Flashcards

Penicillins Flashcards

1
Q

What is the shared structure of penicillins?

A

All penicillins share the basic structure of a 5-membered thiazolidine ring connected to a ß-lactam ring, with attached acyl side chains.

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2
Q

What is modified in penicillins to create drugs of different properties?

A

Manipulations of the side chain have led to agents with differing antibacterial spectrums, greater ß-lactamase stability, and pharmacokinetic properties.

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3
Q

What is the mechanism of action of all penicillins?

A

Penicillins interfere with bacterial cell wall synthesis by binding to and inhibiting enzymes called penicillin-binding proteins (PBPs) that are located in the cell wall of bacteria.

PBPs are enzymes (transpeptidases, carboxypeptidases, and endopeptidases) that regulate the synthesis, assembly, and maintenance of peptidoglycan (cross-linking of the cell wall).

Inhibition of PBPs by ß-lactam antibiotics leads to inhibition of the final transpeptidation step of peptidoglycan synthesis, exposing a less osmotically stable cell membrane that leads to decreased bacterial growth, bacterial cell lysis, and death.

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4
Q

Are penicillins bactericidal or bacteriostatic?

A

Bactericidal, except against Enterococcus spp. where they display bacteriostatic activity.

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5
Q

What are the 3 mechanisms that bacteria use to resist penicillin antibiotics?

A
  1. Production of ß-lactamase enzymes
  2. Alteration in the structure of the PBPs, which leads to decreased binding affinity of penicillins to the PBPs (MRSA)
  3. Inability of the antibiotic to reach the PBP target due to poor penetration through the outer membrane of the bacteria (Gram-negative)
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6
Q

What is the most important of the 3 penicillin resistance mechanisms and why?

A
  1. Production of ß-lactamase enzymes

The most important and most common mechanism of bacterial resistance where the bacteria produces a ß-lactamase enzyme that hydrolyzes the cyclic amide bond of the ß-lactam ring, inactivating the antibiotic.

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7
Q

What bacteria mainly produce the ß-lactamase enzymes as a means of resistance?

A

Gram-negative bacteria will produce them mainly and have them in the periplasm.

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8
Q

Natural Penicillins

A

The first penicillin agents used clinically

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9
Q

Natural Penicillins Examples

A

Penicillin G
Benzathine penicillin G
Procaine penicillin G
Penicillin VK.

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10
Q

Natural Penicillins activity against Gram Positive

A

Gram-Positive: excellent activity against non-ß-lactamase-producing gram- positive cocci and bacilli

˚ Very little activity against Staphylococcus spp.- due to penicillinase production

 Group Streptococci (groups A, B, C, F, G)
 Viridans streptococci
 Some Enterococcus spp.
 Some Streptococcus pneumoniae (high level resistance ~ 15 to 20%)
 Bacillus spp. (including B. anthracis)
 Corynebacterium spp.

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11
Q

Natural Penicillins Drug of Choice for…

A

Penicillin G is still considered to be a DRUG OF CHOICE for the treatment of infections due to:

 Treponema pallidum (syphilis) 
 Neisseria meningitidis
 Corynebacterium diphtheriae 
 Bacillus anthracis (anthrax)
 Clostridium perfringens and tetani
 Viridans
 Group Streptococci.
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12
Q

Natural Penicillins activity against Gram Negative

A

Gram-Negative: only against some gram-negative cocci

 Neisseria meningitidis
Non-ß-lactamase-producing Neisseria gonorrhoeae,
Pasteurella multocida

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13
Q

Natural Penicillins activity against Anerobes

A

Anaerobes: good activity against gram-positive anaerobes

 Mouth anaerobes (gram-positive cocci, “above the diaphragm”) – such as Peptococcus spp, Peptostreptococcus spp., Actinomyces spp.
 Clostridium spp. (gram-positive bacilli, “below the diaphragm”), with the exception of C. difficile

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14
Q

Penicillinase Resistant Penicillins

A

Developed to address the emergence of penicillinase-producing staphylococci that rendered the natural penicillins inactive. They contain an acyl side chain that sterically inhibits the action of penicillinase by preventing opening of the ß-lactam ring.

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15
Q

Penicillinase Resistant Penicillins Examples

A

Nafcillin
Methacillin
Oxacillin
Dicloxacillin

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16
Q

Penicillinase Resistant Penicillins activity against Gram Positive

A

˚ Methicillin Susceptible Staphylococcus aureus (MSSA) - NOT ACTIVE AGAINST MRSA

 Viridans and Group streptococci (less activity than Pen G)
 No activity against Enterococcus spp. or S. pneumoniae

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17
Q

Penicillinase Resistant Penicillins activity against Gram Negative

A

No activity

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18
Q

Penicillinase Resistant Penicillins activity against Anerobes

A

Limited

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19
Q

Aminopenicillins

A

Developed to address the need for penicillins with extended activity against gram-negative aerobic bacilli. Aminopenicillins were formulated by the addition of an amino group to the basic penicillin molecule.

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20
Q

Aminopenicillins Examples

A

Amoxicillin

Ampicillin

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21
Q

Aminopenicillins activity against Gram Positive

A

Gram-Positive: similar activity to the natural penicillins (also ineffective against Staphylococcus aureus because destroyed by penicillinase)

 Better activity than natural penicillin against Enterococcus spp.
 Excellent against Listeria monocytogenes, a gram positive bacillus

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22
Q

Aminopenicillins activity against Gram Negative

A

Gram-Negative: better activity than natural penicillins

 H. influenzae (only ß-lactamase negative strains  70%)
 E.coli (45 to 50% of strains are resistant)
 Proteus mirabilis
 Salmonella spp., Shigella spp.

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23
Q

Aminopenicillins activity against Anerobes

A

Similar activity to Penicillin G

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24
Q

Aminopenicillins Drug of Choice for…

A

Drug of Choice for infections due to Listeria monocytogenes, Enterococcus

25
Q

Carboxypenicillins

A

Developed to address the emergence of more resistant gram-negative bacteria and the increasing frequency of Pseudomonas aeruginosa as a nosocomial pathogen. These agents were formulated by adding a carboxyl group to the basic penicillin molecule.

26
Q

Carboxypenicillins Examples

A

Ticarcicillin (only one available but discontinued 2004)

27
Q

Carboxypenicillins activity against Gram Positive

A

Gram-Positive: generally weak activity

 Less active against Streptococcus spp.
 Not active against. Enterococcus or Staphylococcus spp.

28
Q

Carboxypenicillins activity against Gram Negative

A

Gram-Negative: enhanced activity

˚ Pseudomonas aeruginosa

 Same gram-negative bacteria as aminopenicillins (including indole-positive
Proteus mirabilis)
 Enterobacter spp.
 Providencia spp.
 Morganella spp.

NOT active against Klebsiella spp., Serratia spp., or Actinobacter spp.

29
Q

Ureidopenicillins

A

Developed to further enhance activity against gram-negative bacteria. These agents are derived from the ampicillin molecule with acyl side chain adaptations that allow for greater cell wall penetration and increased PBP affinity. The ureidopenicillins are the broadest-spectrum penicillins available without ß-lactamase inhibitors.

30
Q

Ureidopenicillins Examples

A

Piperacillin

31
Q

Ureidopenicillins activity against Gram Positive

A

˚ No activity against Staphylococcus spp.

 Good activity against viridans and Group Streptococci
 Some activity against Enterococcus spp.

32
Q

Ureidopenicillins activity against Gram Negative

A

˚ Pseudomonas aeruginosa (piperacillin is the most active penicillin)

 Displays activity against most Enterobacteriaceae
 Active against Klebsiella spp. and Serratia marcescens

33
Q

Ureidopenicillins activity against Anerobes

A

 Activity similar to Pen G against Clostridium and Peptostreptococcus

34
Q

ß-lactamase Inhibitor Combinations

A

Available as a combination product containing a penicillin and a ß-lactamase inhibitor. The ß-lactamase inhibitor irreversibly binds to the catalytic site of the -lactamase enzyme, preventing the hydrolytic action on the penicillin. The ß-lactamase inhibitors enhance the antibacterial activity of their companion penicillin in situations where the resistance is primarily the result of ß-lactamase production.

35
Q

ß-lactamase Inhibitor Combinations Examples

A

Amoxicillin / Clavulanate (Augmentin®) – PO
Ampicillin / Sulbactam (Unasyn®) – IV
Ticarcillin / Clavulanate (Timentin®) – IV (discontinued 2014)
Piperacillin / Tazobactam (Zosyn®) – IV

36
Q

ß-lactamase Inhibitor Combinations activity against Gram Positive

A

Provide activity against ß-lactamase producing strains of Staphylococcus aureus (they have activity against MSSA)

37
Q

ß-lactamase Inhibitor Combinations activity against Gram Negative

A

˚ Ticarcillin/clavulanate is active against Stenotrophomonas maltophilia

Enhanced activity against ß-lactamase producing strains of E. coli, Proteus spp., Klebsiella spp., H. influenzae, M. catarrhalis, and N. gonorrhoeae.

Not very active against the inducible ß-lactamase enzymes produced by Serratia marcescens, P. aeruginosa, indole-positive Proteus spp., Citrobacter spp., and Enterobacter spp. (SPICE bacteria).

38
Q

ß-lactamase Inhibitor Combinations activity against Anerobes

A

Enhanced activity against ß-lactamase producing strains of B. fragilis and B. fragilis group (DOT) organisms.

39
Q

What is the activity of penicillins dependent upon?

A

Time-dependent bactericidal activity

40
Q

What correlates with penicillin activity?

A

Time above the MIC

41
Q

Does penicillin have a PAE?

A

PAE for gram-positive bacteria; no significant PAE for gram-negatives.

42
Q

Are penicillins suitable for oral administration?

A

Many penicillins are degraded by gastric acid and are unsuitable for oral administration, so they must be administered parenterally.

43
Q

Does penicillin penetrate the CSF?

A

Yes and no. Adequate concentrations of penicillins in the cerebrospinal fluid (CSF) are attainable only in the presence of inflamed meninges when high doses of parenteral penicillins are used.

44
Q

Where do penicillins NOT distribute?

A

Eye and prostate

45
Q

What is the main route of elimination for most penicillins?

A

Most penicillins are eliminated primarily by the kidneys unchanged via glomerular filtration and tubular secretion, and require dosage adjustment in the presence of renal insufficiency.

46
Q

What are the exceptions to the main route of elimination of penicillins?

A

Exceptions include nafcillin and oxacillin, which are eliminated primarily by the liver, and piperacillin which undergoes dual elimination.

47
Q

How does probenecid interact with penicillins?

A

Probenecid blocks the tubular secretion of renally-eliminated penicillins and can increase their serum concentrations.

48
Q

What is the half life of penicillins like?

A

All are relatively SHORT

49
Q

Sodium Load

A

Sodium Load – several parenterally-administered penicillins (especially the carboxy- and ureidopenicillins) contain sodium in their parenteral preparations, which must be considered in patients with cardiac or renal dysfunction.

50
Q

What is the main clinical use of natural penicillins?

A

Intravenous aqueous penicillin G is often used for serious infections in hospitalized patients due to its rapid effect and high serum concentrations.

It is also used for Endocarditis prophylaxis in patients with valvular heart disease undergoing dental procedures at high risk for inducing bacteremia

51
Q

What are the main clinical uses of penicillinase resistant penicillins?

A

Used for S. aureus like MSSA and other skin infections

52
Q

What are the main clinical uses of aminopenicillin?

A

Ampicillin is used for respiratory tract, urinary tract and Enterococcal infections

53
Q

What are the main clinical uses of carboxypenicillins and ureidopenicillinl?

A

Largely used against Gram Negative like in hospital acquired infections and piperacillin is used against P. aeruginosa in particular.

54
Q

Amoxicillin-clavulanate Clinical Use

A

Otitis media, sinusitis, bronchitis, lower respiratory tract infections, and human or animal bites

55
Q

Ampicillin-sulbactam Clinical Use

A

Mixed aerobic/anaerobic infections (limited gram-negative coverage).

56
Q

Ticarcillin-clavulanate Clinical Use

A

Infections caused by Stenotrophomonas maltophilia. It has similarly broad coverage to piperacillin-tazobactam but the latter is preferred due to tolerability

57
Q

Piperacillin-tazobactam Clinical Use

A

Polymicrobial infections or other infections involving gram-negative bacteria including hospital- acquired pneumonia, bacteremia, complicated urinary tract infections, complicated skin and soft tissue infections, intraabdominal infections, and empiric therapy for febrile neutropenia.

58
Q

What is the most common adverse effect of penicillins?

A

Hypersensitivity

59
Q

What are some of the other possible SE of penicillins?

A

Neurotoxicity with large IV doses - seizures
GI toxicity
Leukopenia
Neutropenia
Thrombopenia
Can cause immune mediated damage to the renal tubules

Pharmacology (74 decks)

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