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E3.PHARM > Beta-Lactam Antibiotics: Penicillins.Lecture1 > Flashcards

Beta-Lactam Antibiotics: Penicillins.Lecture1 Flashcards

1
Q

Beta Lactam structure

A

Penicillin-house and garage

other beta lactams: cephalosporin, monobactams, carbapenems

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2
Q

SIX GENERAL Beta Lactam Characteristics

A
  1. Same MOA-inhibit cell wall synthesis
  2. Same MOR-beta lactamase degradation, PBP alteration, decreased penetration
  3. PD properties: bactericidal in a time-dependent manner (**except against Enterococcus spp).
  4. short elimination half-life of
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3
Q

Penicillin Basics

A

-all share a beta-lactam ring attached to a 5 membered thiazolidine ring

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4
Q

What is changed in the Penicillin structure to enhance activity?

A

The R group (acyl side chain) at the site of the amidase action can be substituted to produce new penicillin

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5
Q

Info on Penicillin G (benzylpenicillin)

A
  • high activity against gram POSITIVE bacteria
  • low activity against gram NEGATIVE bacteria
  • acid-labile
  • destroyed by beta-lactamase
  • 60% protein-bound
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6
Q

Penicillins MOA

A
  • interfere with cell wall synthesis by binding to and inhibiting PBPs located in bacterial cell membranes
  • number, type, and location of PBPs vary between bacteria, PBPs are only expressed during cell division
  • Inhibition of PBPs leads to inhibition of final transpeptidation step of peptidoglycan synthesis=less osmotically stable cell membrane=decreased bacterial growth, bacterial cell lysis, death
  • are bactericidal (except against enterococcus)
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7
Q

Bacterial Cell Wall Structure

A

PBPs are located in the cell membrane

  • gram positive has a thick peptidoglycan
  • gram negative also has an outer membrane
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8
Q

Transpeptidase

A

causes cross-linking in the membrane

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9
Q

Penicillins MOR 1/3

A

__production of beta-lactamase enzyme__

  • most important and most common mechanism where the enzyme hydrolyzes the beta-lactam ring inactivating the antibiotic
  • over 200 beta-lactamase enzymes have been identified
  • produced by: G+: penicillin-resistant Staphylococcus aureus.
  • produced by: G-**: Haemophilus influenzae, moraxella catarrhalis, neisseri gonorrhoeae, E. coli, Klebsiella pneumoniae, enterobacter spp. etc
  • produced by: G- anaerobes: Bacteriodes fragilis
  • Beta-lactamase inhibitors have been developed
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10
Q

Penicillins MOR 2/3

A

Alteration in structure of PBPs leading to decreased binding affinity-methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae (PRSP)

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11
Q

Penicillins MOR 3/3

A

Alteration of (G-) outer membrane porin proteins leading to decreased penetration-inability of the antibiotic to reach the PBP target

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12
Q

PBP who and what

A

PBPs are enzymes (trans/carboxy/endopeptidases) that regulate synthesis, assembly, maintenance of peptidoglycan (cross-linking of the cell wall)

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13
Q

Penicillins-SOA

A
  • natural and semisynthetic penicillins display different antibacterial activity
  • semisynthetic penicillins developed to provide enhanced activity
  • know the story behind the development of each group to understand the spectrum of activity of each group
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14
Q

Natural Penicillins

A
  • first group of penicilins to be discovered and used clinically
  • other groups of penicillins are semi-synthetically derived from natural penicillin
  • naturally derived from penicillium notatum
  • examples: parenteral agents [aqueous penicillin G (iv), benzathine penicillin G (im, long-acting), procaine penicillin G (im)]. oral agent: Penicillin K (more bioavailable and readily absorbed)
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15
Q

Natural Penicillins (penicillin G, penicillin K)

A

G+: group streptococci, viridans streptococci
G-: neisseria spp
Anaerobes: Clostridium spp
Other: Treponema pallidum (syphilis)

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16
Q

Penicillinase-Resistant Penicillins

A
  • developed in response to the emergence of penicillinase-producing Staphylococcus
  • semi-synthetic derivatives of natural penicillin-contain an acyl side chain (improves staphylococcal activity)
  • Examples: Parenteral agents [Nafcillin (which you test for with), Oxacillin, and Methicillin (not available)]. Oral agent: Dicloxacillin
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17
Q

What are the penicillinase-resistant penicillins?

What were they developed to overcome?

What is the G+ target organism for penicillinase-resistant penicillins?

A

Nafcillin, Oxacillin Methicillin, Dicloxacillin

To overcome the penicillinase enzyme of S. aueus which inactivated natural (naked) penicillin

**methicillin-susceptible S. aureus (MSSA)=TARGET ORGANISM

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18
Q

Antibiotic resistance in S. aureus in 1941?

A

Penicillin available

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19
Q

Antibiotic resistance in S. aureus in 1942?

A

Penicillin-resistanct S. aureus (beta-lactamase (penicillinase) which can be overcome with penicillinase-resistant penicillins, beta-lactamases inhibitors, or changing to cephalosporin core (cefazolin); called MSSA)

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20
Q

Antibiotic resistance in S. aureus in 1959?

A

Methicillin available

21
Q

Antibiotic resistance in S. aureus late 60s?

A

80% of S. aureus pcn-resistant

22
Q

Antibiotic resistance in S. aureus in 1968?

A

First report of MRSA caused by PBP alteration mediated by mecA gene which confers resistant to ALL beta-lactams (except ceftaroline)

23
Q

Antibiotic resistance in S. aureus in 2015?

A

99% of S. aureus pcn-resistant and ~50% MRSA (varies)

24
Q

Why were aminopenicillins developed?

What is their relationship to natural penicillin?

What are examples parenteral and oral agents?

A
  1. in response to the need for agents with G- activity
  2. semisynthetic derivative of natural penicillin via an addition of amino group (duh, look at the name)
  3. PE: Ampicillin (iv), PO: Ampicillin (not clinically oral, used iv) and Amoxicillin
25
Q

What are some G- targets of aminopenicillins?

What are some side G+ that are also targeted?

A
  1. proteus mirabilis, some E coli, Salmonella, Shigella, betaL-H influenzae
  2. Enterococcus spp (**better activity than natural penicillin) and Listeria monocytogenes (niche)
26
Q

Why were carboxypenicillins developed?

What is their relationship to natural penicillin?

What are PE and PO examples?

A
  1. In response to the need for agents with enhanced activity against G- (just like reasoing for aminopenicillins)
  2. semisynthetic derivative of natural penicillin-addition of carboxyl group (duh, look at the name)
  3. PE: Ticarcillin (not available), PO: None
27
Q

What are the target G- aerobes that respond to ________ (Carboxypenicillins)

A

[Ticarcillin]…G-: enterobacter spp., Pseudomonas aeruginosa (**target)

28
Q

________ are semisynthetic derivative of the amino-penicillins with acyl side chain adaptations.

________were developed also for EVEN MORE enhanced activity against _______

PE/PO examples?

A
  1. Ureidopenicillins
  2. Ureidopenicillins
  3. G-
  4. PE: Piperacillin (in combo with Tazobacpam..but no longer available), PO: none
29
Q

G- targets of Ureidopenicillins

A
  • enterobacter sp, Pseudomonas aeruginosa**, serratia marcescens, some Klebsiella spp.
  • **Anaerobes-fairly good activity
30
Q

Beta-Lactamase Inhibitors are _______ of many _______. They protect ______ from being ______ by some ______ by ______ binding the _______ of the ______ enzyme

What are examples of Beta-lactamase Inhibitors

A
  • potent inhibitors of many bacterial beta-lactamases
  • protect penicillins from being hydrolyzed by some beta-lactamases by irreversibly binding the catalytic site of beta-lactamase enzyme.
  • very weak to no antibacterial activity

Examples: Clavulanate, sulbactam, Tazobactam, avibactam (used in combo with cephalosporins)

31
Q

Beta-Lactamase Inhibitor Combinations were developed to ______ of the ______ against _______ bacteria.

In what format are they available?

PE/PO examples?

A

enhance activity of the penicillins against Beta-Lactamase-producing bacteria

Available only in fixed-dose combinations with specific penicillins.

PE: Ampicillin-sulbactam (Unasyn), Ticarcillin-clavulanate (Timentin, not available), Piperacillin-tazobactam (Zosyn)

PO: Amoxicillin-clavulanate (Augmentin)

32
Q

Beta-Lactamas Inhibitor Combos
PE: Ampicillin-sulbactam (Unasyn), Ticarcillin-clavulanate (Timentin, not available), Piperacillin-tazobactam (Zosyn)

and PO: Amoxicillin-clavulanate (Augmentin)

attack

A

G+: S. aureus (NOT MRSA)

G-: H. influenza, Moraxella catarrhalis

Anerobes**(target organism): Bacteroides spp

33
Q

Penicillins Pharmacology

A
  • Time dependent bacterial killing; time above MIC correlated with efficacy {no PAE for G(-) bacteria, post-AB effect}
  • synergy with aminoglycosides against Enterococcus spp., Staphylococcus spp., viridans strep, and G(-) bacteria
34
Q

Absorption of Penicillins

A

-many penicillins are degraded by gastric acid
-oral penicillins are variably absorbed
»Pen VK (oral as well) absorbed better than oral Pen G
»Amoxicillin absorbed better than ampicillin
»Dicloxacillin is absorbed the best of the PRPs

35
Q

Distribution of Penicillins

A
  • widely distributed into tissues and fluids
  • adequate CSF concentration achieved ONLY IN THE PRESENCE OF INFLAMED MENINGES with high-dose parenteral administration
  • variable protein binding
36
Q

Elimination of Penicillins

A
  • most are eliminated unchanged by the kidney so that dosage adjustment is required in the presence of renal insufficiency; probenecid blocks tubular secretion
  • Nafcillin and Oxacillin are eliminated primarily by the liver-DO NOT REQUIRE ADJUSTMENT IN RENAL INSUFFICIENCY
  • ALL PENICILLINS HAVE SHORT ELIMINATION HALF LIVES (
37
Q

Where does sodium pop up?

Who must use these types of penicillins with caution?

What is the sodium content of:

  • S______ ______ __
  • T_____
  • P_____
A
  1. Sodium is contained in some preperations of parenterally-administered penicillins
  2. must be used with caution in patients with CHF or renal insufficiency
  3. Sodium content:
    Sodium Penicillin G: 2.0 mEq per 1 million units
    Ticarcillin: 5.2 mEq per gram
    Piperacillin: 1.85 mEq per gram
38
Q

What are the clinical uses for natural penicillins?

A

-penicillin-susceptible S. pneumoniae
-infections due to other streptococci
-Neisseria meningitidis
-syphilis**
-Clostridium perfringens or tetani
(-actinomyces, bacillus anthracis-anthrax)
-endocarditis prophylaxis; prevention of rheumatic fever

39
Q

What are the clinical uses for penicillinase-resistant penicillins?

A

Infections due to MSSA, such as:

  • SSTI
  • septic arthritis
  • osteomyelitis
  • bacteremia
  • endocarditis
40
Q

What are the clinical uses for aminopenicillins?

A
  • respiratory tract infections: pharyngitis, sinusitis, otitis media, bronchitis, UTI
  • **enterococcal infections (often with aminoglycoside) and infections due to Listeria monocytogenes
  • enocarditis prophylaxis in selected patients with valvular disease
41
Q

What are the clinical uses for carboxypenicillins and ureidopenicillins?

A
  • serious infections due to G(-) aerobic bacteria: pneumonia, bacteremia, complicated UTI, SSTI, peritonitis, etc
  • emperic therapy for hospital-acquired infections
  • infections due to Pseudomonas aeruginosa (esp piperacillin)
42
Q

What are the clinical uses for Beta-Lactamase Inhibitor Combinations?

A
  • Augmention (oral): sinusitis, otitis media, upper and lower respiratory tract infections, humsm or animal bite wounds
  • Unasyn, Zosyn, Timentin (iv)-used for polymicrobial infections such as polymicrobial pneumonia (aspiration), intra-abdominal infections, gynecologic infections, diabetic foot infections
  • emperic therapy for febrile neutropenia or hospital-acquired infections (Zosyn)
43
Q

Penicillins-Adverse Effects: Hypersensitivity

A

Hypersensitivity: 3-10%

  • higher incidence with parenteral administration
  • mild to severe allergic reactions ranging from rash to anaphylaxis and death
  • antibodies produced against metabolic by-products (penicillin degradation products) or penicillin itself
  • cross-reactivity exists among all penicillins and even some other beta-lactams
  • desensitization is possible
44
Q

Penicillins-Adverse Effects: Neurologic

A

direct toxic effect

  • especially in patients receiving high IV doses in the presence of renal insufficiency
  • irritability, jerking, confusion, seizures
45
Q

Penicillins-Adverse Effects: Hematologic

A

-leukopenia, neutropenia, thrombocytopenia
»usually during prolonged (transplant patients) therapy (>2 weeks)
»reversible upon discontinuation

46
Q

What are the five main categories of penicillin adverse effects?

A
  1. Hypersensitivity
  2. Neurologic
  3. Hematologic
  4. GI
  5. Interstitial Nephritis
    * other: phlebitis, hypokalemia, Na overload
47
Q

Penicillins-Adverse Effects: GI

A

-increased LFTs, nausea, vomiting, diarrhea, pseudomembranous colitis (Clostridium difficile diarrhea)

48
Q

Penicillins-Adverse Effects: Interstitial Nephritis

A
  • immune-mediated damage to renal tubules characterized by an abrupt increase in serum creatinine, eosinophilia, eosinophiluria
  • can lead to renal failure
  • especially with nafcillin

E3.PHARM (1 decks)

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