B&B: Penicillins Flashcards
Beta lactam rings are found in
Penicillins
Carbapenems
Aztreonam
Cephalosporins
3 components of penicillin
- Beta lactam ring
- Thiazolide Ring
- Side Chain (variable component)
Thiazolide rings are found
only in penicillins
Penicillin MOA is same as
MOA of all Beta lactam antibiotics
Bacteria are
constantly breaking down/remaking cell wall
Bacterial transpeptidases
Cross-link peptidoglycan in cell walls by binding to alanine residues
Transpeptidases are also called
Penicillin binding proteins
Transpeptidase MOA
Bind ala-ala residues
Link lysine-alanine residues to cross-link cell wall
Configuration of alanine in bacteria vs humans
Human: L-ala
Bacteria: D-ala
Peniciliin mimics
alanine residues (D-analyl-D-alanine)
- inactivates transpeptidase
- rate of cell wall breakdown becomes greater than rate of cell wall proliferation
- result is autolysis of cell: enzymes that hydrolyze cell wall continue to work so bacteria kills itself
What are the two natural penicillins?
Penicillin G (IM and IV) Penicillin VK (oral)
Why are Penicillin G and Penicillin VK co-administered with Probenicid (gout drug)?
Probenicid inhibits renal secretion of penicillin so they can be co-administered to increase penicillin levels
Natural penicillins (Penicillin G and Penicillin VK) have a very low spectrum of activity due to
common bacterial resistance mechanisms
Modified penicillin binding proteins
Bacterial resistance mechanism modified by genetic mutations
-Often produced by Strep Pneumonia
Reduced Bacterial Cell Penetration
Bacterial resistance mechanism
-Bacteria decreases the number of porins they have to decrease drug penetration
Gram Negative Bacteria
Very poor bacterial cell penetration (higher resistance to penicillins)
Porins
Gram negative proteins that transport nutrients/waste
Beta Lactamase enzyme
Bacterial resistance mechanism that degrades beta lactam compounds. Used by many gram-negative bacteria and staphylococcus aureus.
Beta Lactamase
Family of bacterial enzymes that degrade beta lactam compounds:
- Penicillin G and VK
- Some other penicillins
- Some cephalosporins
Beta Lactamase =
Penicillinase
Beta lactamase in gram negative bacteria is found in
Cytoplasm
Beta lactamase in gram positive bacteria (eg. S. Aureus)
There is no periplasm, so beta lactamase secreted into EC space. Generally produces more enzymes than gram negative.
Beta-lactamase inhibitors
Clavulanic Acid, Sulbactam, Tazobactum
Beta-lactamase inhibitors
Little/no effect if used alone
Added to some penicillins to expand coverage
-Aminopenicillins
-Antistaphylcoccal penicillins
Clinical uses of Penicillin G and VK
Narrow spectrum: few specific modern uses Gram positives: -Strep pyrogenes (strep throat) -Actinomyces Treponema Pallidum (syphilis) Rare uses (only in susceptible isolates) -Neisseria Meningitides -Strep Pneumonia
Penicillin Adverse Effects
Hypersensitivity (allergic reaction)
1st exposure: Sensitization
2nd exposure: Hypersensitivity reaction
Symptoms resolve on stopping drug
Penicillin Hypersensitivity (allergic) reactions
Acute (immediate)
- Type I, IgE-mediated
- Usually within 1 hour of taking drug
- Histamine release
- Itching, urticarial
- Bronchospasm
- Anaphylaxis
Penicillin Adverse Effects
Maculopapullar rash
- Non-immediate reaction
- Most common with aminopenicillins
- Maculopapules
- Itchy or non-pruritic
- Absence of fever, wheezing, joint pain
- Days or weeks after starting drug
- Type IV (T-cell mediated) mechanism
Penicillin Maculopapular Rash
More common with viral infection
- EBV pharyngitis
- Amoxicillin given for pharyngitis leads to maculopapular rash
- MOA unknown
Penicillin Adverse Effects: SJS
SJS: -Fever, necrosis -Sloughing of skin -Dermal-epidermal junction -Vesicles, blisters Toxic epidermal necrolysis -Severe form SJS (>30% skin) Mortality: SJS 1-5%; TEN 25-35%
Penicillin Adverse Effects: SJS and TEN
Immune mediated drug reaction -CD8 T cells -Re-challenge with same drug can cause recurrence Antibiotic associations: -Sulfonamides (TMP-SMX) -Aminopenicillins -Cephalosporins
Penicillin Adverse Effects: Interstitial Nephritis
Drug acts as hapten (triggers immune response in kidneys)
Hypersensitivity (allergic) reaction with complex mechanism
Considered a Type IV hypersensitivity reaction
T-cells, Mast cells
Classic Presentation of Interstitial Nephritis
Fever Oliguria Increased BUN/Cr Eosinophils in urine White cells and WBC casts (sterile pyuria)
High dose of Penicillin can lead to
Extrinsic hemolytic anemia
Penicillin binds to RBC and leads to immune response (drug acts as hapten)
Antibodies against penicillin are bound to RBCs
Direct Coombs test: positive
Type II Hypersensitivity
Penicillin Adverse Effects: Serum Sickness
Immune complex disorder related to IgG antibodies
Days/Weeks after exposure
Antigen-antibody complex made of Penicillin-IgG molecules will deposit in tissues and lead to complement activation
Type III hypersensitivity reaction
Urticaria, fever, arthritis, lymphadenopathy
Penicillin Type I Reaction
Acute
IgE
Anaphylaxis
Penicillin Type II Reaction
Hemolysis, IgG
Penicillin Type III Reaction
Serum Sickness IgG Fever Urticaria Arthritis
Penicillin Type IV Reaction
T cells, Skin, Nephritis
Penicillin Adverse Effect: C. Difficile Infection
C. difficile growth leads to pseudomembranous colitis
May occur with any antibiotic
What are some common antibiotics associat3ed with C. Difficile Infection?
Penicillin
Cephalosporins
Clindamycin
Fluoroquinolones
Jerisch-Herxheimer Reaction
Occurs with penicillin therapy for spirochete infections
- Classically occurs in syphilis
- Fever, chills, flushing, hyperventilation
- Usually 2 hours after starting therapy
- Not a hypersensitivity (allergic) reaction: Caused by immune response to bacterial cell death.
Oxacillin, Nafcillin, Dicloxacillin
Antistaphylococcal Penicillins
How do Antistaphylococall Penicillins work
Have side chain that prevents beta-lactam from staph penicillinase
Prototype: Methicillin no longer used b/c high frequency of adverse effects (interstitial nephritis)
Antistaphylococal Penicillins are effect for
Staph Aureus (Non-MRSA) Most strep
What is the advantage of Antisphylococcal Penicillins
Cover same infections as Penicillin but have advanced effectiveness for staph aureus
-Side chain to protect beta-lactam results in staph penicillinase resistance
Antistaphylococcal Penicillins
Oxacillin, Nafcillin, Dicloxacillin Commonly used for -Community acquired cellulitis -Impetigo Staph endocarditis based on culture data S/E similar to penicillin
Amoxicillin and Ampicillin are
Aminopenicillins
Amoxicillin is administered
orally
Ampicillin is administered
IV due to poor bioavailability with oral administration
How do Aminopenicillins work?
Penetrate porin channels of gram-negative bacteria
All penicillins are sensitive to beta lactamase enzymes except
Antistaphylococcal Penicillins (can resist staph penicillinase)
What is advantage of Aminopenicillins
Cover same infections as Penicillin and some gram negatives that express low amounts of beta-lactamase enzymes.
Aminopenicillins are effective for which bacteria?
H. Influenza (gram negative bacteria) E. Coli Proteus Salmonella Shigella Listeria (gram positive bacteria) -Aminopenicillins are administered with Listeria to prevent comorbid infections by gram negative bacteria
Main clinical uses of Aminopenicillin
Situations where there are both gram positives and some gram negatives that are potential causes of infection
- Otitis Media and bacterial sinusitis are often caused by strep as well as H. flu
- Meningitis in newborns and elderly (at risk for Listeria)
Maculopapular rash is most common with which type of penicillin?
Aminopenicillin
-Note: Maculopapular rash is more common in viral infections
Maculopapular Rash Classic Case
EBV infection w/ sore throat
Amoxicillin given for presumed bacterial pharyngitis
Maculopapular rash
Which type of penicillin are SJS and TEN classically associated with?
Aminopenicillins
Beta-Lactamase inhibitors are often administered with aminopenicillins
Clavulanic Acid, Sulbactam, Tazobactam
Augmentin =
Amoxicillin + Beta-Lactamase Inhibitor
Unasyn =
Ampicillin + Beta-Lactamase Inhibitor
What does adding a beta-lactamase inhibitor to an amiinopenicillin do?
Increase activity of aminopenicillins against staph aureus and H. flu.
Also increases activity against anaerobes (B. fragilis)
Common uses for aminopenicillin/beta-lactase inhibitor drugs
Otitis media/sinusitis (broad spectrum) Bite wounds (Polymicrobial with anaerobes)
Antipseudomonal Penicillins
Ticarcillin: Carboxypenicillin
Piperacillin: Piperazine penicillin
Advantage of antipseudomonal penicillins
Have greater porin channel penetration than aminopenicillins (more gram (-) coverage)
Effective against pseudomonas aeruginosa
Even through antipseudomonal penicillin have significant porin channel penetration, they remain susceptible to
Beta-lactamase
Administer with beta-lactamase inhibitor
All penicillin drugs are susceptible to Beta-lactamase except
Anti-staphylococcal drugs
Have resistance to staph penicillinase enzyme
Timentin =
Ticarcillin + beta-lactamase inhibitor (clavulanic acid)
Zosyn =
Piperacillin + taxobactam (beta-lactamase inhibitor)
Antipseudomonal Penicillins (Ticarcillin, Piperacillin)
Broad-spectrum antibiotics
- Most gram (+) but not MRSA
- More gram (-) eg. pseudomonas
- Most anaerobic bacteria
