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

Beta-Lactam Antibiotics: Penicillins.Lecture1 Flashcards

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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?

Study These Flashcards
A

Methicillin available

21
Q

Antibiotic resistance in S. aureus late 60s?

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A

80% of S. aureus pcn-resistant

22
Q

Antibiotic resistance in S. aureus in 1968?

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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?

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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?

Study These Flashcards
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
What are some G- targets of aminopenicillins? What are some side G+ that are also targeted?
1. proteus mirabilis, some E coli, Salmonella, Shigella, betaL-H influenzae 2. Enterococcus spp (**better activity than natural penicillin) and Listeria monocytogenes (niche)
26
Why were carboxypenicillins developed? What is their relationship to natural penicillin? What are PE and PO examples?
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
What are the target G- aerobes that respond to ________ (Carboxypenicillins)
[Ticarcillin]...G-: enterobacter spp., Pseudomonas aeruginosa (**target)
28
________ are semisynthetic derivative of the amino-penicillins with acyl side chain adaptations. ________were developed also for EVEN MORE enhanced activity against _______ PE/PO examples?
1. Ureidopenicillins 2. Ureidopenicillins 3. G- 4. PE: Piperacillin (in combo with Tazobacpam..but no longer available), PO: none
29
G- targets of Ureidopenicillins
- enterobacter sp, Pseudomonas aeruginosa**, serratia marcescens, some Klebsiella spp. - **Anaerobes-fairly good activity
30
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
- 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
Beta-Lactamase Inhibitor Combinations were developed to ______ of the ______ against _______ bacteria. In what format are they available? PE/PO examples?
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
Beta-Lactamas Inhibitor Combos PE: Ampicillin-sulbactam (Unasyn), Ticarcillin-clavulanate (Timentin, not available), Piperacillin-tazobactam (Zosyn) and PO: Amoxicillin-clavulanate (Augmentin) attack
G+: S. aureus (NOT MRSA) G-: H. influenza, Moraxella catarrhalis Anerobes**(target organism): Bacteroides spp
33
Penicillins Pharmacology
- 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
Absorption of Penicillins
-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
Distribution of Penicillins
- 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
Elimination of Penicillins
- 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
Where does sodium pop up? Who must use these types of penicillins with caution? What is the sodium content of: - S______ ______ __ - T_____ - P_____
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
What are the clinical uses for natural penicillins?
-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
What are the clinical uses for penicillinase-resistant penicillins?
Infections due to MSSA, such as: - SSTI - septic arthritis - osteomyelitis - bacteremia - endocarditis
40
What are the clinical uses for aminopenicillins?
- 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
What are the clinical uses for carboxypenicillins and ureidopenicillins?
- 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
What are the clinical uses for Beta-Lactamase Inhibitor Combinations?
- 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
Penicillins-Adverse Effects: Hypersensitivity
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
Penicillins-Adverse Effects: Neurologic
direct toxic effect - especially in patients receiving high IV doses in the presence of renal insufficiency - irritability, jerking, confusion, seizures
45
Penicillins-Adverse Effects: Hematologic
-leukopenia, neutropenia, thrombocytopenia >>usually during prolonged (transplant patients) therapy (>2 weeks) >>reversible upon discontinuation
46
What are the five main categories of penicillin adverse effects?
1. Hypersensitivity 2. Neurologic 3. Hematologic 4. GI 5. Interstitial Nephritis * other: phlebitis, hypokalemia, Na overload
47
Penicillins-Adverse Effects: GI
-increased LFTs, nausea, vomiting, diarrhea, pseudomembranous colitis (Clostridium difficile diarrhea)
48
Penicillins-Adverse Effects: Interstitial Nephritis
- immune-mediated damage to renal tubules characterized by an abrupt increase in serum creatinine, eosinophilia, eosinophiluria - can lead to renal failure - especially with nafcillin

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