Cushman Flashcards
What are the differences between Gram-(+) and Gram-(–) bacteria regarding drug penetration?
Molecules penetrate Gram+ readily, while Gram- requires porins for polar molecules
Gram+ has a thicker peptidoglycan layer compared to Gram-.
How do beta-lactamases distribute in Gram+ and Gram- bacteria?
In Gram+, beta-lactamases are excreted into the solvent; in Gram-, they are confined to the periplasmic space
This affects the quantity needed for effectiveness.
What is the peptidoglycan layer composition difference between Gram+ and Gram- bacteria?
Gram+ contains lysine residues; Gram- contains diaminopimelic acid (DAP) residues
This difference contributes to their structural integrity.
What is the role of transpeptidase in bacterial cell walls?
Transpeptidase cross-links peptidoglycan strands, forming a stable structure
It is essential for maintaining cell wall integrity.
How do beta-lactams affect transpeptidases?
Beta-lactams inhibit transpeptidases by forming a stable acyl-enzyme complex
This leads to weakened cell walls and bacterial death.
What are the mechanisms of bacterial resistance to penicillins?
Resistance mechanisms include:
* Decreased cellular uptake
* Mutation of penicillin binding proteins
* Efflux pumps
* Beta-lactamase hydrolysis
How does penicillin act as an allergen?
Penicillin acts as a hapten, acylating host proteins and raising antibodies
This can lead to allergic reactions in sensitive individuals.
What conditions affect penicillin stability?
Penicillin is less stable under acidic conditions due to nucleophilic attacks on the carbonyl
This results in hydrolysis and loss of antibiotic activity.
What chemical feature of penicillins confers resistance to acid degradation?
An electronegative side chain increases stability under acidic conditions
This affects the drug’s bioavailability.
How does serum protein binding affect penicillin bioavailability?
Higher protein binding reduces bioavailability by lowering effective drug concentration
More lipophilic penicillins tend to bind more to serum proteins.
What are the major penicillin excretion mechanisms?
Penicillin is primarily excreted through:
* 90% tubular secretion
* 10% glomerular secretion
How does renal disease affect the half-life of penicillins?
Half-lives of penicillins are increased in patients with renal failure
This necessitates dosage adjustments in such patients.
What is the effect of probenecid on penicillin half-life?
Probenecid prolongs penicillin half-life by competing for tubular secretion
This can enhance penicillin’s therapeutic effects.
What characterizes beta-lactam nomenclature?
Beta-lactam nomenclature involves classifying antibiotics based on their structure and resistance profiles.
What chemical features stabilize penicillins against beta-lactamase hydrolysis?
Two ortho methoxy groups create steric hindrance, conferring stability
This makes certain penicillins more resistant to breakdown.
Characterize penicillin G in terms of antimicrobial spectrum and precautions.
Antimicrobial spectrum: Gram+
Beta-lactamase sensitivity: Yes
Administration: Parenteral
Toxicity: Acute allergic reactions
Precautions: Caution in individuals with allergies/asthma
What distinguishes penicillin V from penicillin G?
Penicillin V has an electronegative oxygen, making it more stable in acid and suitable for oral administration
This enhances its bioavailability.
Classify major penicillins based on their beta-lactamase resistance.
Beta-lactamase resistant parenteral: Methicillin, Nafcillin
Beta-lactamase resistant oral: Oxacillin, Cloxacillin, Dicloxacillin
Beta-lactamase sensitive broad-spectrum oral: Ampicillin, Amoxicillin
Beta-lactamase sensitive broad-spectrum parenteral: Piperacillin
What feature of methicillin confers resistance to beta-lactamases?
Methicillin’s two ortho methoxy groups create steric hindrance
This structure makes it resistant to hydrolysis.
Explain why methicillin is unstable in acidic conditions.
Methicillin’s amide carbonyl oxygen becomes more nucleophilic due to electron donation from ortho methoxy groups
This instability leads to hydrolysis in stomach acid.
Characterize methicillin with respect to its antibiotic spectrum.
Spectrum: Narrow
Many bacteria are resistant, leading to its discontinuation
MecA mutation in Staphylococcus aureus confers resistance
Characterize nafcillin regarding beta-lactamase sensitivity and acid stability.
Beta-lactamase sensitivity: Not sensitive
Acid stability: Slightly more stable than methicillin
Identify structural similarities among oxacillin, cloxacillin, and dicloxacillin.
They are all isoxazoles with a NO ring connected to a benzene ring
This structure contributes to their beta-lactamase resistance.
Characterize the antibacterial spectrum of ampicillin.
Ampicillin is sensitive to Gram-negative organisms.
Explain why ampicillin is stable in acid.
The primary amino group is protonated at physiological pH, making it less nucleophilic and more electronegative
This enhances oral absorption.
What is the main difference between amoxicillin and ampicillin regarding absorption?
Amoxicillin is better absorbed orally.
Describe the mechanism of action of beta-lactamase inhibitors like clavulanic acid.
Inhibitors acylate the serine group of beta-lactamase, inactivating it.
What structural feature of acylureidopenicillins enhances their antibacterial activity?
The urea moiety resembles a longer section of the peptidoglycan chain, increasing potency
This allows for activity against both Gram+ and Gram- bacteria.
Describe the mechanism of action of cephalosporins.
Cephalosporins react with transpeptidases, inhibiting peptidoglycan cross-linking
They have a six-membered ring structure.
How are cephalosporins affected by beta-lactamase?
Cephalosporins are hydrolyzed by beta-lactamase.
How do cephalosporins compare with penicillins in terms of allergenicity?
Cephalosporins are less likely to cause allergic reactions than penicillins.
Outline the main classification scheme for cephalosporins.
Cephalosporins are classified from 1st to 5th generation, with higher generations showing more Gram-negative activity and less Gram-positive activity.
What distinguishes orally active cephalosporins from parenteral ones?
Orally active cephalosporins have non-reactive side chains; parenteral agents have good leaving groups
Example: Cefazolin (parenteral) vs. Cephalexin (oral).
What C-3 side chain feature confers acid stability to cephalosporins?
Bad leaving groups enhance acid stability.
How do syn and anti oxime ethers on C-7 side chains differ in hydrolysis by beta-lactamases?
Syn ethers are more resistant to hydrolysis; anti ethers are less resistant.
Describe how acetate vs. carbamate side chains at C-3 differ in enzymatic hydrolysis.
Carbamates are not good leaving groups, making them less susceptible to hydrolysis.
What is the effect of the large oxime ether functionality of ceftazidime on stability?
It enhances stability against beta-lactamases due to steric hindrance.
How does the charged pyridinium ring of ceftazidime affect its reactivity?
It increases solubility and facilitates treatment of Gram-negative bacteria.
What effect does the charged N-methylpyrrolidine moiety of cefepime have on reactivity?
It increases activity against Gram-negative bacteria.
How does the syn methoximino group on cefepime affect stability?
It stabilizes cefepime against beta-lactamases due to steric hindrance.
Why can’t thienamycin be used as a drug?
It interacts with the beta-lactam ring of another molecule, making it unstable
This interaction has limited its clinical use.
What is the main caution when using cephamycin drugs?
Do not drink alcohol
Cephamycin drugs release N-methylthiotetrazole, which can cause adverse reactions with alcohol.
What structural feature of cephamycin contributes to its broad spectrum activity?
OH group on far left side is negatively charged at physiological pH
This charge allows interaction with a wider range of bacteria.
How does the 7 alpha methoxy group affect cephamycin?
Causes stability against beta lactamases
Why can’t thienamycin be used as a drug?
Primary amino group NH2 interacts with the beta lactam ring of another molecule, making it too unstable.
What is imipenem and how does it overcome the instability of thienamycin?
Imipenem is an N-formiminoyl derivative that lacks a primary amino group.
What effect does replacing the sulfur atom with a methylene group have on carbapenems?
Increases the reactivity of the beta-lactam ring.
What unique feature does imipenem have regarding beta lactamases?
Imipenem inhibits beta lactamases.
What is the role of renal enzyme dehydropeptidase-1 on imipenem?
It hydrolyzes imipenem, but this is overcome by cilastatin sodium.
What is the antibiotic spectrum of imipenem?
Broad spectrum activity including serious infections of gut, GI, bone, skin, and endocardium.
How is imipenem administered?
Parenterally.
How do monobactams differ in origin from penicillins and cephalosporins?
Monobactams are synthetic agents inspired by monocyclic beta-lactam natural products.
What structural feature allows monobactams to be biologically active despite lacking a carboxylic acid group?
Sulfamic acid group that is electronegative and reacts.
What is the antibiotic spectrum of monobactams?
Almost completely gram negative; used for penicillin-resistant organisms.
How do monobactams react with penicillin-binding proteins?
Sulfamic acid activates the beta lactam ring towards hydrolysis and reaction with transpeptidases.
What is the cross allergenicity of monobactams with penicillins and cephalosporins?
No cross allergenicity except for ceftazidime.
What effect does the sulfamic acid moiety have on the reactivity of the beta-lactam ring in monobactams?
Makes it more reactive and resistant to beta lactamases due to the oxime ether side chain.
What is the mechanism of action of vancomycin?
Inhibits transpeptidation by binding to D-Ala-D-Ala.
What is the antibiotic spectrum of vancomycin?
Gram positive organisms only.
What is the mechanism of bacterial resistance to vancomycin?
Mutation of D-Ala-D-Ala to D-Ala-D-Lactate.
What is the main route of administration for vancomycin?
IV administered.
What are the main therapeutic uses of vancomycin?
C. diff pseudomembranous colitis, methicillin-resistant Staph aureus.
What are the main toxic effects of vancomycin?
Hypersensitivity reaction, red man syndrome, nephrotoxicity, ototoxicity.
What is the half-life of vancomycin?
4-11 hours.
What distinguishes lipoglycopeptides like Oritavancin from vancomycin?
They have lipid side chains.
What is the mechanism of action of Oritavancin?
Inhibits transpeptidation and transglycosylation, disrupts membrane of gram positive bacteria.
What is the half-life of Dalbavancin?
204 hours.
What is the route of administration for streptogramin?
Parenterally.
What is the mechanism of action of Dalfopristin?
Inhibits peptidyl transferase and alters ribosome structure.
What are the therapeutic uses of Synercid?
Vancomycin resistant Enterococcus faecium infections, MRSA skin infections.
What is the main side effect of Synercid?
Pain at injection site, nausea, diarrhea.
What is the mechanism of action of linezolid?
Inhibits formation of the 70S complex by interacting with the 50S subunit.
What are the main therapeutic uses of linezolid?
Vancomycin resistant Enterococcus faecium, MRSA skin infections.
What are the main side effects of linezolid?
GI issues, tongue discoloration, thrombocytopenia.
What is the potential for drug interactions with linezolid?
Reversible nonselective inhibitor of monoamine oxidase.
How does tedizolid phosphate compare to linezolid?
More potent against MRSA, same mechanism of action.
What is the mechanism of action of aminoglycosides?
Bind to the 16S rRNA and 30S ribosomal subunit to block formation of the initiation complex
Also elicit premature termination and impair proofreading function of the ribosome.
How do aminoglycosides affect translation?
Block further translation and cause premature termination
This leads to the formation of nonsense proteins that impair the bacterial cell wall.
What occurs as a result of aminoglycoside action on the ribosome?
Leakage of ions and disruption of the cytoplasmic membrane resulting in cell death
What is the mechanism of aminoglycoside uptake?
Positively charged aminoglycosides displace Mg+ and Ca+ ions in the membrane, allowing entry through active transport
This process requires energy.
What are the main bacterial metabolic pathways of aminoglycosides?
Acetylation, adenylation, phosphorylation
How do bacteria develop resistance to aminoglycosides?
Through metabolism (acetylation, adenylation, phosphorylation), altered ribosome, and altered aminoglycoside uptake
What are the toxicities associated with aminoglycosides?
Ototoxic (irreversible), nephrotoxic (reversible)
Respiratory paralysis can be reversed by neostigmine or calcium gluconate.
What are the symptoms of aminoglycoside ototoxicity?
Tinnitus, high frequency hearing loss, vertigo, loss of balance, ataxia
Which aminoglycoside toxicities are reversible?
Nephrotoxicity, respiratory paralysis
Which drugs can potentiate nephrotoxicity of aminoglycosides?
Loop diuretics, vancomycin, amphotericin
What is the potential toxic effect of aminoglycosides on respiration?
Respiratory paralysis, which can be reversed by neostigmine or calcium gluconate
What are the risk factors for aminoglycoside toxicity?
Elderly, renal impairment, treatment duration of 5 days or more, higher doses
How can aminoglycoside toxicity be minimized?
Use sparingly for specific indications, minimize duration of therapy, monitor serum concentrations
What are the main clinical uses of aminoglycosides?
Treatment of gram-negative bacteria, administered with penicillins for bacterial endocarditis
Why should aminoglycosides and penicillins not be administered together?
Penicillin beta-lactam reacts with aminoglycoside amino groups, inactivating both drugs
What is an aminoglycoside-induced frameshift?
Affects the 30S subunit, causing formation of altered proteins due to a different anticodon
What are the clinical uses of streptomycin?
Tuberculosis, bubonic plague
What are the clinical uses of gentamicin?
UTIs, burns, pneumonia, joint and bone infections caused by gram-negative bacteria
What makes amikacin less susceptible to bacterial metabolism than kanamycin?
Amikacin has a side chain that inhibits bacterial metabolism
What are the features of gentamicin that contribute to its widespread use?
Low cost and reliability against most gram-negative organisms
What is the polyketide biosynthesis pathway?
Sequential addition of propionate groups to a growing chain results in methyl groups on alternate carbon atoms in the macrolide ring
What structural feature is characteristic of macrolide antibiotics?
14 membered lactone rings with desosamine sugar important for activity
What happens to the biological activity of macrolide antibiotics when carbohydrate residues are removed?
Activity is decreased
How do macrolide antibiotics work?
Inhibit peptide bond formation by binding reversibly to the P site of the ribosome, preventing translocation
Mainly bacteriostatic but can be bacteriocidal in high concentrations.
What are the mechanisms of bacterial resistance to macrolide antibiotics?
Lactone ester hydrolase degradation, RNA methylase production, adenine to guanine mutation, efflux pump activation
How can macrolide resistance be minimized?
Careful stewardship of antibiotics
Why is resistance to macrolides by Pseudomonas spp. and Enterobacter spp. unavoidable?
Intrinsic resistance due to inability to allow drug entry
How do acidic conditions inactivate erythromycin?
6-OH and 12-OH groups can form ketals that inactivate the drug
What modifications in newer macrolide antibiotics prevent erythromycin inactivation in acid?
Methyl group added to 6-OH group in clarithromycin; methyleneamino added at C9 in azithromycin
What is the metabolism of erythromycin?
Demethylation in the liver, half-life of 1.5 hours
Which macrolides are more likely to cause drug interactions?
Erythromycin and clarithromycin, as they inhibit CYP3A4
What is the antibiotic spectrum of macrolides?
Effective against skin and soft tissues Gram-positive bacteria, Mycoplasma pneumoniae, Legionella, Campylobacter
Clinical uses include bacterial bronchitis, otitis media, acne, and prophylaxis for endocarditis.
What are the main side effects of macrolide antibiotics?
GI activity (vomiting, cramps), skin reactions (urticaria, hives), cholestatic hepatitis
Why are erythromycin dosage forms for oral administration enteric coated?
To protect from inactivation by gastric acids
How do phagocytes deliver erythromycin to the site of action?
Erythromycin diffuses into phagocytes, which release it at the site of infection
What makes clarithromycin stable under acidic conditions?
Methyl group at 6-OH position prevents ketal ring formation
How does clindamycin’s mechanism of action compare to erythromycin?
Clindamycin binds to the 50S ribosome’s peptidyl transferase center, while erythromycin binds the P site
What are the main clinical uses of clindamycin?
Aerobic gram-positive cocci, anaerobic gram-negative bacilli, treats bone infections, severe acne, bacterial vaginosis, lung abscesses
What is the main side effect of clindamycin that limits its use?
Pseudomembranous colitis and diarrhea
How are clindamycin and its metabolites processed in the body?
Metabolized by CYP450 in the liver to inactive sulfoxide and demethylated derivatives
What is the absorption and elimination profile of clindamycin?
90% absorbed orally, penetrates CNS, half-life 1.5-5 hours, excreted in urine and bile
What are the main adverse effects of clindamycin?
Diarrhea, pseudomembranous colitis, nausea/vomiting, rash
What is pseudomembranous colitis?
Potentially lethal condition due to C. diff overgrowth, treated with metronidazole or vancomycin
How do tetracyclines bind to heavy metals?
They chelate and form a cyclic derivative at the bottom of structure 10 position OH
Why should tetracyclines not be taken with calcium-rich foods?
Calcium chelates prevent absorption from the GI tract
What is the preferred route of tetracycline administration?
Oral
Why should children avoid tetracycline during teeth formation?
It chelates calcium and can stain teeth gray or brown
What is tetracycline epimerization?
Creates an inactive product by changing the position of a proton on the 4 position
At what pH is tetracycline epimerization most rapid?
pH 4
What occurs during tetracycline dehydration?
Hydroxyl group at C6 is protonated and undergoes dehydration, forming a double bond
What is the toxicity of epianhydrotetracycline?
Toxic to kidneys and can produce fatal reabsorption syndrome
Why do minocycline and doxycycline lack renal toxicity?
They do not have the 6-OH group, preventing dehydration
What is the mechanism of action of tetracyclines?
Bind to the 30S ribosomal subunit and block attachment of aminoacyl-tRNA to the A site, inhibiting protein synthesis
What is the basis for selective toxicity of tetracyclines to bacteria?
The host does not have the same ribosomal structure as bacteria
What occurs to tetracyclines under basic conditions (pH 8.5 or above)?
Cleavage of a ring which is inactive
What is the mechanism of action of the tetracyclines?
Bind the 30S site of the ribosomal subunit and block attachment of the aminoacyl-tRNA to the A site of the ribosome
What is the basis for selective toxicity of tetracyclines to bacteria?
The host does not have an uptake mechanism for tetracyclines
List the main therapeutic uses of tetracyclines.
- Broad spectrum
- Acne
- Chlamydia
- Rickettsia
- Rocky Mountain spotted fever
- Lyme Disease
What are the advantages of using tetracycline itself rather than other antibiotics in the tetracycline class?
Generic and inexpensive
Why is demeclocycline more stable to dehydration than tetracycline?
Secondary hydroxyl group at C6 instead of a tertiary
Why do minocycline and doxycycline not undergo dehydration?
Lacks a C6 hydroxyl group
What are the unique toxicities of minocycline compared to other tetracyclines?
- Vestibular toxicities
- Vertigo
- Ataxia
- Nausea
How does doxycycline compare with other tetracyclines in terms of toxicity?
No potential for toxicity and fewer GI symptoms
Why is doxycycline considered the tetracycline of choice?
No potential for toxicity and fewer GI side effects
Why does tigecycline have no potential for 4-epianhydrotetracycline-mediated toxicity?
Lacks a C6 hydroxyl group
What are the potential toxic effects of tigecycline?
- Hepatotoxicity
- Pancreatitis
- Anaphylactoid reactions
What are the main therapeutic uses of sarecycline and omadacycline?
- Moderate to severe acne
Why should sarecycline and omadacycline not be administered to pregnant women?
Can cause fetal harm
What is the mechanism of action of chloramphenicol?
Binds reversibly to the 50S ribosomal subunit to inhibit peptidyl transferase activity
What is chloramphenicol sodium succinate?
A prodrug hydrolyzed to chloramphenicol in the liver
What are the main therapeutic uses of chloramphenicol?
- Bacterial meningitis
- Typhoid fever
- Rickettsial infections
- Intraocular infections
What are the main bacterial resistance mechanisms to chloramphenicol?
- Acetylation on either of the OH groups
- Reduced membrane permeability
- Mutation of the 50S ribosomal subunit
What is the most serious potential toxicity of chloramphenicol?
Aplastic anemia
Is chloramphenicol bone marrow suppression a predictor of aplastic anemia?
No
What is the relationship between chloramphenicol bone marrow suppression and cumulative dose?
Occurs when a cumulative dose of 20 g has been given
What is the risk of drug interactions with chloramphenicol?
CYP450 interactions
How does inflammation of the meninges affect brain concentrations of chloramphenicol?
Inflammation can raise concentration to 89% in the brain and CSF
What are the characteristics of first generation quinolone antibiotics?
- Gram - activity
- Lower UTIs
What defines second generation quinolone antibiotics?
- Fluorine at C6
- Piperazine ring at C7
- Gram + and - activity
What is the function of topoisomerases and gyrases?
Untangle DNA by cutting one or two of the strands
What is the mechanism of action of the quinolones?
Quinolones bind to the cleavage complex and inhibit DNA religation
What are the therapeutic uses of ciprofloxacin?
- UTI
- Prostatitis
- STIs
- Shigellosis
- Diabetic foot infections
What are the main adverse effects of the quinolone antibiotics?
- Tendonitis
- Tendon rupture
- Peripheral neuropathy
- CNS effects
- N/V diarrhea
What should quinolone antibiotics not be administered with?
Foods that have heavy metals
