MOA_ANTIBIOTICS Flashcards
-See ppt for 1st 8 slides not included -For each of the major classes (penicillins, cephalosporins, glucopeptids, macrolide, tetracyclines, fluoroquinolones, amino glycosides, sulfonamides, trimethoprim) know the MOA and whether the agent is cidal or static
Inhibitors of Cell-Wall Synthesis
-Beta Lactams
+Penicillins, Cephalosporins, Monobactams Carbapenems
-Glycopeptides
+Vancomycin (Gram+ only)
-Fosfomycin
+UTIs only
-Daptomycin
+Gram+ Only
+4 MRSA, VISA, VRSA, VRE
Beta Lactams
Share Beta Lactam Ring
Bactericidal
Nontoxic= Can be administered at high doses
Organic Acids + Most Soluble in H2O
Class of Cell-Wall Inhibitors?
Share Beta Lactam Ring
Bactericidal
Nontoxic= Can be administered at high doses
Organic Acids + Most Soluble in H2O
Beta Lactams
PBPs
Tranpeptidases that help in peptidoglycan synthesis by catalyzing the final cross-linking reactions of peptidoglycan synthesis
-Two Types: Low and High Molecular Weight
High: involved in different activities during peptidoglycan synthesis
Low MW PBP : D-alanine carboxypeptidases
*Inactivation of Low MW PBPs not thought to affect viability of (bacterial?) cell —-> implications for drug resistance
Beta Lactam Cell Wall Agents
Penicillins
6 Different Classes
Cephalosporins
4 different “generations”
Newer class w/ activity against MRSA
Carbapenems
Monobactams (Aztronam)
Describe how beta lactams work.
What are the beta lactams? What class of antibiotics are they?
Since beta lactams structurally analogous to D-Ala-D-Ala, PBPs react with these antibiotics (“thinking they are D-Ala-D-Ala) by cleaving the beta lactam bond and forming a stable intermediate that does not react further
+So Beta Lactams acetylate the PBPs and inactivate them
Name specific Penicillin Beta Lactams
Natural Penicillins
Pen G
Penicillinase(Beta-Lactamase)-Resistant Penicillins
+resists the bacterial enzyme
Oxacillin, (methicillin, nafcillin + isoxazolyl penicillins)
Extended-spectrum Penicillins
+Aminopenicillins: (ampicillin + amoxicillin)
+Carboxypenicillins (carbenicillin + tiracillin)
+Ureidopenicillins (azlocillin, mezlocillin, piperacillin)
Co-Drugs (Beta-lactam + beta-lactamase inhibitor)
What are some examples of the different generations of Cephalosporin Beta-Lactams?
Generations they belong to?
1st generation (narrow spectrum)
Cephalothin, Cefazolin
-most active against streptococci and staphlococci
2nd generation
Cefuroxime, Cefotetan, Cefoxitin
(Haemoph. Influezae)
3rd generation (extended spectrum) Ceftiaxone, Ceftoxime, Ceftazidime \+activity against most Gram- including pseudomonas
4th Generation cephalosporin (extended spectrum)
Cefepime
+activity against most Gram- including pseudomonas
1st gen= better activity against Gram+ and less against Gram-
3rd gen = better gram- negative activity and less gram+ activity
Only 4th agent : broad spectrum both gram + and - activity
3rd and 4th = Extended-Spectrum Penicillin
Example of Cephalosporins that preferentially target Gram+ over Gram- bacteria
1st Generation
What are the drugs in 1st Gen Cephs?
Cephalothin and Cefazolin
So patient came in hospital with __Ecoli?___(gram - infection). Which generation of cephlosporin would you use to treat?
Third Generation Cephalosporin Treats Gram -
Examples of 3rd Gen Agents:
Ceftiaxone, Ceftoxime, Ceftazidime
Carbepenem Beta Lactams
Beta Lactas w/ Broad Spectrum (the Cepime of Cephalosporins)
+active against essentially all pathgenic (and nonpathogenic?) organisms
Effective on Gram+, Except MRSA
Broad Activity agianst Gram-, P. aeruginosa (except Ertapenem) and anaerobes
Slightly diff structure than the other beta lactams
+much more resistant to beta-lactamsse hydrolysis such as ESBL producers
Wide diffusion in the body, esp. in cerebrospinal fluid (CSF)
Examples: imipenem, meropenem, etrapenem, doripenem
Glycopeptides and Lipoglycopeptides
Glycopepitde = another class of cell-wall inhibitors \+Vancomycin
Lipoglycopeptides:
Use for Vancomycin-Resistnat Strains
RX gram+ complicated skin and soft tissue infections
Structurally related to Vancomycin - activity against vancomycin-resistant strains
+Dalbacanicin not FDA approved
+Oritavacin not FDA approved
+Telavancin Not yet FDA Approved
+Teicoplanin: Not FDA Approved in USA but widespread in Europe
Glyco and Lipo = Effective against GRAM+ only. The drugs enter without any problem because peptidoglycan does not act as barrier for the diffusion of these molecules.
Not effective against GRAM NEGATIVES - molecule cannot pass through porins
What are the classes of drugs that are inhibitors of protein synthesis?
-Tetracyclines
\+Glycyclines a new class of antibiotics derived from tetracycline
- Aminoglycosides (gentamycin, tobramycin)
- Macrolides (erythromycim, azithromycin, clarithromycin)
- Lincosamines (clindamycin)
- Phenicols (chloramphenicol)
- Ansamycins (rifampin)
- Oxazolidiones (Linezolid)
Tetracyclines
- Bacteriostatic
- Broad Spectrum but Limited Use b/c Resistance Common
- Primary Treatment for Chlamydiae, Rickettsiae and Mycoplasm
- Not recommended for children <2yrs and Pregnant women b/c toxicity to bones and teeth of fetus
Why was Glycycline developed?
-Developed to Overcome some of the more common tetracycyline resistance mechanisms
-Like Tetracyclne, Bacteriostatic, Broadspectrum
Example: Tigcycle
New Class (of Inhibitior of Protein Synthesis)
Structure Classification and Groups of Tetracyclines
Structure: 4 fused 6-membered ring forms the basic structure from which various tetracyclines are made
Classification: Based on Length of Activity in Body and Absorption From GI
Groups:
1: short-actinf (tetracycline, oxytetracycline)
2: intermediate (demeclocycline)
3: long-acting (doxycycline, minocycline)
What class of Antibiotics are Aminoglycosides?
Protein Synthesis Inhibitors, Just Like Tetrcyclines (+ Glycyclines)
Aminoglycosides _ MOA?
Toxicity?
They are Protein Synthesis Inhibitors
Work By Binding to RNA of the 30S RNA subunit that affects all stages of normal protein synthesis - bactericidal activity
Renal and Ototoxicity; need to monitor blood levels
Examples of Aminoglycosides. How do they work?
+Gentamycin, Tobramycin, Amikacin, Streptomycin
They are Protein Synthesis Inhibitors
Work By Binding to RNA of the 30S RNA subunit that affects all stages of normal protein synthesis - bactericidal activity
Macrolides, Lincosamides, Streptogramins, Ketolides
Bacteriostatic
Not Broad Spectrum : limited to Gram+ Cocci such as Staphylococci & Streptococci
Also active against anaerobes
Bacteriostatic
Not Broad Spectrum : limited to Gram+ Cocci such as Staphylococci & Streptococci
Also active against anaerobes
Macrolides, Lincosamides, Streptogramins, Ketolides
Macrolides
Class? Examples? Uses?
Protein Synthesis Inhibitors
Erythomycin, Zithromax Z-Pak (azithromycin)
-respiratory infections due to S. pneumonia and S. pyogenes, Mycoplasms
Lincosamides
Class? Examples? Uses
Protein Synthesis Inhibitors
Clindamycin - Gram+ skin Infections
Streptogramins
Class? Examples? Uses?
Quinupristin/Dalfopristin (Synercid) Used for E faecalis (VRE) and MRSA
Phenicols: Chloramphenicol
Class?
Use?
Restricted Use?
Toxicity?
Protein Synthesis Inhibitors
Broad Spectrum::: Very active against many Gram+ and Gram- bacteria, Chlamydia, Mycoplasma and Rickettsiae
Restricted Use (why?) for extra-intestinal severe salmonella infection
High toxicity, causes Bone Marrow Aplasia and other hematological abnormalities
Oxazolidinones: Linezpid
Class? Use? MOA?
Protein Synthesis Inhibitor
Relatively New
Gram+ Infections; Effective For E. Faecium, VRE, MRSA, and multi drug resistant strp pneumoniae
Trade name Zyvox
Linezolid disrupts bacterial growth by inhibiting initiation in protein synthesis
Inhibitors not yet reported?
Gram- bacteria appear to be naturally resistant
Ansamycins>Rifamycins>Rifampin (Rifamipicin)
Class?
Spectrum?
Uses?
Prophlaxsis for?
Protein Synthesis Inhibitors
Mostly Gram+, Some Gram -
- Used in Combination w/ Other Drugs to Treat TB
- Prophlaxsis in N. Meningitidis Carriers
- Combo w/ other antibiotics to treat severe Staphylococcal infections (including MRSA)
Inhibitors of Membrane Function?
Lipopeptides: Polymyxins and
Cyclic Lipopeptides: Daptomycin
Class of Antibiotics?
Lipopeptides: Polymyxins and
Cyclic Lipopeptides: Daptomycin
Inhibitors of Membrane Function
What class are Liptopeptides? Examples?
Inhibitors of Membrane Function
-Polymyxin B
High Toxicity - neuro and nephrotoxic (NS and Kidneys)
-Colistin
Narrow Spectrum, For Gram-
Recent Use, Treats Multidrug Resistant Acinetobacter infections
High nephro and neurotoxicity
What class are cyclic lipopeptides: Daptomycin
FDA approved for? By what microorganisms?
Inhibitors of Membrane Function
FDA approved for Skin/Skin Structure Infections
+S. aureus (MRSA and MSSA)
+Beta-hemolytic Streptococci (A, B, C, G)
+E. Faecalis (Vanco Sensitive)
FDA approved for Skin/Skin Structure Infections
+S. aureus (MRSA and MSSA)
+Beta-hemolytic Streptococci (A, B, C, G)
+E. Faecalis (Vanco Sensitive)
Daptomycin (Inhibitor of Cell Membrane Function)
Antimetabolities:Which Pathway do they Inhibit?
Why is the PWAY Impt? Folate essential for synthesis of which bases?
Why is this Pway a good selective target?
Examples of Antimetabolites?
Folate Pathway
Makes Adenine and Thymine
Humans do not make folic acid. Good selective target.
Examples: Sulfonamides and Trimethoprim/Sulfamethoxazole
The ff are examples of what class of Antibiotics?
Sulfonamides and Trimethoprim/Sulfamethoxazole
Antimetabolites
Sulfonamides
Class?
Cidal or Static?
Treats?
Antimetabolites
Bacteriostatic
1st effective systemic antimicrobial agent
Used to treat acute, uncomplicated UTIs
Trimethoprim/Sulfamethoxazole
Class of Antibiotic?
Antimetabolite
TMP/SXT bactericidal (Bactrim)
Broad Spectrum
Synergistic Action
Sulfonamides
Pharmacokinetics
Clinical Uses
Adverse Reaction
An Antimetabolite
Pharmacokinetics: Good Urine Solubility, high levels in urine
Uses:
Acute UTIs (a la sulfonamides)
Patient Allergic to Penicillins
Otitis Media
Adverse Reactions:
-Allergies: may lead to Steven-Johnson syndrome
+An immune-complex-hypersensitivity (allergic) condition that affects the skin and mucous membranes
+Incidence of sulfa allergy similar to penicillin (3% of population)
-Ker nicterus
-Hemolytic Anemia
Antimetabolite that causes the following Adverse Reactions:
Adverse Reactions:
-Allergies: may lead to Steven-Johnson syndrome
+An immune-complex-hypersensitivity (allergic) condition that affects the skin and mucous membranes
+Incidence of sulfa allergy similar to penicillin (3% of population)
-Ker nicterus
-Hemolytic Anemia
Sulfonamides
TMX/SXT
Class of Antibiotics?
MOA?
Antimetabolite
Resembles a microbial substrate and competes with the substrate for limited microbial enzyme
-Drug ties up the substrate and blocks a step in metabolism
Classes and Drug Examples of Inhibitors of Nucleic Acid Synthesis
MOA?
Quinolones - 1st Generation - Narrow Spectrum
+Nalidixic Acid, Cinoxacin
Flouroquinolones
+Ciprofloaxin, Levofloaxcin, Norfloxacin, Ofloxacin, Moxifloxacin
MOA: Target Topoisomerases e.g. DNA-syrase, which is responsible for cutting one of the chromosomal DNA strands at the beginning of the supercoiling process
Furanes
Class of Drug?
Target Topoisomerases e.g. DNA-syrase, which is responsible for cutting one of the chromosomal DNA strands at the beginning of the supercoiling process
Inhibitors of Nucleic Acid Synthesis
Difference between Antimetabolites and Inhibitors of Nucleic Acid Synthesis?
?
Class and Subclass of the following Drugs:
+Ciprofloaxin, Levofloaxcin, Norfloxacin, Ofloxacin, Moxifloxacin
Inhibitors of Nucleic Acid Synthesis, Fluroquinolones
Furanes
Class?
Spectrum?
Cidal or Static?
Route of Administration?
MOA?
Inhibitors of Nucleic Acid Synthesis
Spectrum of Action: UTIs caused by both Gram+ and Gram- Organisms
Broad Spectrum, Bactericidal, Oral
MOA: Damage bacterial DNA. In bacterial cell, nirtofurantoin is reduced by flavoproteins (nitrofuran reductase)
+these reduced products are highly active and attack ribosomal proteins, DNA, respiration, pyruvate metabolism and other macromolecules w/in cell
Class of Drugs?
- Lincosamines (clindamycin)
- Phenicols (chloramphenicol)
- Ansamycins (rifampin)
- Oxazolidiones (Linezolid)
Protein Synthesis Inhibitors
Class of Drugs?
-Aminoglycosides (gentamycin, tobramycin)
-Macrolides (erythromycim, azithromycin, clarithromycin)
Tetracyclines
Protein Synthesis Inhibitors
Ker nicterus
Sulfonomides (Antimetabolite)
causes this adverse reaction
Name 5 features of the ideal antibiotic.
slective target cidal narrow spectrum - does not kill normal flora high therapeutic index - why? few adverse runs many routes of admins. (iv, im, oral) good absorption good distribution to site of infection emergence of resistance slow
MIC
minimum conc of antibiotic which prevents the organism from multiplying (doesn’t necessarily kill the organism)
MBC
lowest concentration of drug which KILLs the organism
T or F
There is a much closer relation ship between the MIC and MBC values for bactericidal drugs that for bacteriostatic drugs
True
Why?
Depends on Host’s Immune System to eliminate the microorganism
Bacteriostatic - describes most antibiotics
-Extended Spectrum Beta Lactamases
-Inducible Ampc C Beta-LActamases
-Carbapenase Producing Gram-
-HA and CA MRSA
-Inducible Clindamycin Resistance in Staplococci and Streplococci
-Staphlococci w/ Vancomycin Resistance or Reduced Suceptibility
VRE (Old- But a Resevoir)
Multi Drug Resistant S. Pneumonia (including vancomycin-tolerant strains)
Current Challenges
Name 5 Current Challenges w/ Antibiotics. Be Specific.
-Extended Spectrum Beta Lactamases
-Inducible Ampc C Beta-LActamases
-Carbapenase Producing Gram-
-HA and CA MRSA
-Inducible Clindamycin Resistance in Staplococci and Streplococci
-Staphlococci w/ Vancomycin Resistance or Reduced Suceptibility
VRE (Old- But a Resevoir)
Multi Drug Resistant S. Pneumonia (including vancomycin-tolerant strains)
Explain the relationship w/ Toxicity and Effectiveness as it relates to Natural vs. Synthetic Antimicrobial Agents
Inverse Relationship between Toxicity and Effectiveness as you move from natural to synthetic antibiotics
Synthetic Antibiotics More Effective and Less Toxic
Natural Antibiotics Less Effective and More Toxic
Where do most of out natural Antibacterial Agents come from?
Example of semisynthetic and synthetic antibacterial agents?
Fungal Sources
+Ex: Benzypenicillin and Gentamycin
Semisynthetic chemically altered compound:
Ampicillin and Amikacin
Synthetic: Lab
Moxifloacin and Norfloaxin
Newer Classes of Antibiotics?
Lipoglycopeptides (Telavancin)
Cycliclipopeptides (Daptomycin)
Glycylcyclines (Tigcycline)
Oxazolidinones (Linezolid)
Oxa: Rx MRSA and VRE, Inhibs. Microbial Protein Synthesis
Glycyclines: Rx Gram+ (Incl MRSA), gram -
Similar MOA as tetracycline antibiotics
Cycliclipopeptides (Daptomycin)
Rx Gram+ Infections - including MRSA
MOA: Binds to bacterial membrane and causes rapid depolarization of the cell membrane ; loss of membrane potential leads to inhibition of DNA, RNA and Protein Synthesis
Lipoglycopeptids
Rx Gram+ complicated skin and soft tissue infections
Structurally related to vancomycin - activity against vancomycin-resistant strains
MOA? Uses?
Lipoglycopeptides (Telavancin)
Cycliclipopeptides (Daptomycin)
Glycylcyclines (Tigcycline)
Oxazolidinones (Linezolid)
Oxa: Rx MRSA and VRE, Inhibs. Microbial Protein Synthesis
Glycyclines: Rx Gram+ (Incl MRSA), gram -
Similar MOA as tetracycline antibiotics
Cycliclipopeptides (Daptomycin)
Rx Gram+ Infections - including MRSA
MOA: Binds to bacterial membrane and causes rapid depolarization of the cell membrane ; loss of membrane potential leads to inhibition of DNA, RNA and Protein Synthesis
Lipoglycopeptids
Rx Gram+ complicated skin and soft tissue infections
Structurally related to vancomycin - activity against vancomycin-resistant strains
Static Antibiotics
Macrolids (erythromycin), clinadamycin, Sulfsmethoxazole, Trimethoprim, Tetracyclines, Chloramphenicol
Cidal Antibiotics
Betal Lactams, Vancomycin, Aminoglycosides (gentamycin), Flouroquins (ciprofloxacin)
When would you want to use broad spectrum antibiotics?
- Use empirically prior to identifying the causative bacteria when there is a wide differential and
- Potentially serious illness would result in delay of treatment
Broad Spectrum Antibiotics
Carbepenems
Extended -Spectrum Cephalosporins
beta-lactm/beta-lactam inhibitor combination
Newer fluroquinolones
Broad Spectrum might kill normal flora?
Narrow Spectrum (selective)
Older Penicillin Gs, the Macrolides. Vancomycin (only Gram +)
-Narrow spectrum does not kill normal dlora
Most Agents In This Class Interfere w/ Murein Assembly and Peptidoglycan Synthesis
Cell Wall Synthesis Inhibitors
Carbapenams
Cidal, Broad Spect, Cell Wall Inhibitor
Monobactams
Class?
Organism?
Beta Lactam Antibiotics - cell wall synthesis inhibitors
Aztronam
Aerobic Gram- Bacilli
How is action of Vancomycin unique w/ respect to beta lactams?
Binds D-Ala - D-Ala instead of the PBP —same effect of preventing crosslinking of the peptidoglycan sheets (Cidal)
Inhibits phosphoenel pyruvate halting muramic acid synthesis. Indicated in treatment of UTIs, where it is usually administered in a single megadose
Fosfomycin, Cell Wall Synthesis Inhibitor
Cidal
Interferes w/ Initiation of Protein Synthesis
by binding to 30S Ribosome and Changing its shape so that it inhibits proteins synthesis by causing misreading of RNA
Amnoglycosides
Cidal
Used to treat SEVERE infections caused by Gram+ bacteria that are resistant to other antibiotics
Linezolid (Class?)
-should not be used against bacteria that are sensitive to drugs with a narrower spectrum of activity, such as penicillins and cephlosporins
Blocks Formation of Translation initiation complex by binding the 23S portion of the 50S subunit
Static
Blocks Exit of Growing Peptide chain by binding 23S rRNA
Macrolids
Static
Similar Action as Macrolids
Clindamycin
Blocks Exit of Growing Peptide chain by binding 23S rRNA
Static
Chloremphenicol
Static
Binds Residues in the 23S rRNA of the 50S ribosomal subunit preventing peptide bond formation (substrate binding)
Interference w/ Cytoplasmic Membrane Function
Polymixins (topical) - cationic detergent-like activity
BAcitracin (topical) - disrupt cytoplasmic membranes
Antifungals: Polyenes (eg amphotericin), Azoles (eg fluconazole), Allyamines (eg terbinafine) - alteration of sterol (ergosterol) structure and function
Tetracyclines
static
Inhibits bacterial protein synthesis by blocking the attachment of the tRNA-aa to the ribosome 30S subunit (inhibit codon-anticodon interaction)
Inhibits Nucleic Acid Synthesis
DNA:
cidal:
Quin and Flouroqunolones (ciprofloxacin, levofloxacin, norflxacin); Inhibit DNA gyrases or topoisomerases required for DNA supercoiling
Metronidazole (metabolic cytotoxic products disrupt DNA)
RNA:
cidal:
Rifampin -Binds RNA polymerase and prevent RNA transcription/RNA synthesis
and Bacitracin (topical) - Inhibits RNA transcription
Nucleoside Analogs: Acyclovir (viruses), Zidovudine (retroviruses)
Interference w/ Metabolic Activity/Pathways
Sulfonamides (static) and Dapsone (cidal): Compete w. PABA, preventing synthesis of folic acid
Trimethoprim (cidal): Inhibit DHFR preventing synthesis of folic acid
Used in ratio 1:5
Trimethoprim and Sulfamethoxazole (Bactrim)
- Synergistic Activity
- UTIs, Otitis Media, Bronchitis, Traveller’s Diarrhea, Shigellosis (bacillary dysentry)
Static
Inhibit bacterial protein synthesis by blocking attachment of the transfer RNA-amino acid to ribosome 30S
Inhibitors of Codon-Anticodon Interactions
Tetracyclines
