Beta-Lactam Antibiotics: Penicillins.Lecture1 Flashcards
Beta Lactam structure
Penicillin-house and garage
other beta lactams: cephalosporin, monobactams, carbapenems
SIX GENERAL Beta Lactam Characteristics
- Same MOA-inhibit cell wall synthesis
- Same MOR-beta lactamase degradation, PBP alteration, decreased penetration
- PD properties: bactericidal in a time-dependent manner (**except against Enterococcus spp).
- short elimination half-life of
Penicillin Basics
-all share a beta-lactam ring attached to a 5 membered thiazolidine ring
What is changed in the Penicillin structure to enhance activity?
The R group (acyl side chain) at the site of the amidase action can be substituted to produce new penicillin
Info on Penicillin G (benzylpenicillin)
- high activity against gram POSITIVE bacteria
- low activity against gram NEGATIVE bacteria
- acid-labile
- destroyed by beta-lactamase
- 60% protein-bound
Penicillins MOA
- 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)
Bacterial Cell Wall Structure
PBPs are located in the cell membrane
- gram positive has a thick peptidoglycan
- gram negative also has an outer membrane
Transpeptidase
causes cross-linking in the membrane
Penicillins MOR 1/3
__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
Penicillins MOR 2/3
Alteration in structure of PBPs leading to decreased binding affinity-methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae (PRSP)
Penicillins MOR 3/3
Alteration of (G-) outer membrane porin proteins leading to decreased penetration-inability of the antibiotic to reach the PBP target
PBP who and what
PBPs are enzymes (trans/carboxy/endopeptidases) that regulate synthesis, assembly, maintenance of peptidoglycan (cross-linking of the cell wall)
Penicillins-SOA
- 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
Natural Penicillins
- 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)
Natural Penicillins (penicillin G, penicillin K)
G+: group streptococci, viridans streptococci
G-: neisseria spp
Anaerobes: Clostridium spp
Other: Treponema pallidum (syphilis)
Penicillinase-Resistant Penicillins
- 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
What are the penicillinase-resistant penicillins?
What were they developed to overcome?
What is the G+ target organism for penicillinase-resistant penicillins?
Nafcillin, Oxacillin Methicillin, Dicloxacillin
To overcome the penicillinase enzyme of S. aueus which inactivated natural (naked) penicillin
**methicillin-susceptible S. aureus (MSSA)=TARGET ORGANISM
Antibiotic resistance in S. aureus in 1941?
Penicillin available
Antibiotic resistance in S. aureus in 1942?
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)
Antibiotic resistance in S. aureus in 1959?
Methicillin available
Antibiotic resistance in S. aureus late 60s?
80% of S. aureus pcn-resistant
Antibiotic resistance in S. aureus in 1968?
First report of MRSA caused by PBP alteration mediated by mecA gene which confers resistant to ALL beta-lactams (except ceftaroline)
Antibiotic resistance in S. aureus in 2015?
99% of S. aureus pcn-resistant and ~50% MRSA (varies)
Why were aminopenicillins developed?
What is their relationship to natural penicillin?
What are examples parenteral and oral agents?
- in response to the need for agents with G- activity
- semisynthetic derivative of natural penicillin via an addition of amino group (duh, look at the name)
- PE: Ampicillin (iv), PO: Ampicillin (not clinically oral, used iv) and Amoxicillin
What are some G- targets of aminopenicillins?
What are some side G+ that are also targeted?
- proteus mirabilis, some E coli, Salmonella, Shigella, betaL-H influenzae
- Enterococcus spp (**better activity than natural penicillin) and Listeria monocytogenes (niche)
Why were carboxypenicillins developed?
What is their relationship to natural penicillin?
What are PE and PO examples?
- In response to the need for agents with enhanced activity against G- (just like reasoing for aminopenicillins)
- semisynthetic derivative of natural penicillin-addition of carboxyl group (duh, look at the name)
- PE: Ticarcillin (not available), PO: None
What are the target G- aerobes that respond to ________ (Carboxypenicillins)
[Ticarcillin]…G-: enterobacter spp., Pseudomonas aeruginosa (**target)
________ are semisynthetic derivative of the amino-penicillins with acyl side chain adaptations.
________were developed also for EVEN MORE enhanced activity against _______
PE/PO examples?
- Ureidopenicillins
- Ureidopenicillins
- G-
- PE: Piperacillin (in combo with Tazobacpam..but no longer available), PO: none
G- targets of Ureidopenicillins
- enterobacter sp, Pseudomonas aeruginosa**, serratia marcescens, some Klebsiella spp.
- **Anaerobes-fairly good activity
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)
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)
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
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
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
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
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 (
Where does sodium pop up?
Who must use these types of penicillins with caution?
What is the sodium content of:
- S______ ______ __
- T_____
- P_____
- Sodium is contained in some preperations of parenterally-administered penicillins
- must be used with caution in patients with CHF or renal insufficiency
- Sodium content:
Sodium Penicillin G: 2.0 mEq per 1 million units
Ticarcillin: 5.2 mEq per gram
Piperacillin: 1.85 mEq per gram
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
What are the clinical uses for penicillinase-resistant penicillins?
Infections due to MSSA, such as:
- SSTI
- septic arthritis
- osteomyelitis
- bacteremia
- endocarditis
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
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)
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)
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
Penicillins-Adverse Effects: Neurologic
direct toxic effect
- especially in patients receiving high IV doses in the presence of renal insufficiency
- irritability, jerking, confusion, seizures
Penicillins-Adverse Effects: Hematologic
-leukopenia, neutropenia, thrombocytopenia
»usually during prolonged (transplant patients) therapy (>2 weeks)
»reversible upon discontinuation
What are the five main categories of penicillin adverse effects?
- Hypersensitivity
- Neurologic
- Hematologic
- GI
- Interstitial Nephritis
* other: phlebitis, hypokalemia, Na overload
Penicillins-Adverse Effects: GI
-increased LFTs, nausea, vomiting, diarrhea, pseudomembranous colitis (Clostridium difficile diarrhea)
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
