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What is the primary mechanism of action for clindamycin?
Which of the following organisms is clindamycin particularly effective against?
What is a common adverse effect associated with clindamycin use?
In which scenario should dosage adjustment be made when prescribing clindamycin?
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What is clindamycin's spectrum of activity primarily against?
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What type of infections is clindamycin commonly used to treat?
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Which of the following describes a mechanism of resistance to clindamycin?
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Which formulations of clindamycin are available for administration?
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What is a primary mechanism of action for aminoglycosides?
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Which of the following aminoglycosides is known for its broad spectrum activity against gram-negative enteric bacteria?
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What is the significance of the trough level of aminoglycosides?
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Which factors contribute to the ototoxicity associated with aminoglycosides?
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How do aminoglycosides affect mRNA during protein synthesis?
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Which of the following is a notable adverse effect of aminoglycosides?
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What is the primary mechanism by which organisms resist streptomycin?
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What condition is associated with a trough level of tobramycin exceeding 4 ug/mL?
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What is a common route of administration for most aminoglycosides?
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Which two types of bacteria are generally targeted by aminoglycosides?
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Which adverse effect is specifically related to Neomycin?
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What is the common route of administration for aminoglycosides like Neomycin due to their toxicity?
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Which of the following is a typical clinical use for streptomycin?
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Which adverse effect is closely linked to the use of tobramycin?
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What occurs as a result of high trough levels of aminoglycosides?
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Which of the following describes the pharmacokinetics of Streptomycin?
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What is the mechanism of action of streptogramins?
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Which of the following is a characteristic of linezolid?
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Which adverse effect is associated with linezolid?
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What is the recommended adjustment for streptogramins in patients with liver failure?
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Which type of bacteria are streptogramins particularly effective against?
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What potential issue arises from the use of streptogramins with other medications?
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In the case study, which antibiotic was indicated for empiric treatment of the patient?
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Which type of clearance would be necessary to monitor when administering tobramycin to the patient?
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What is a significant concern associated with prolonged use of clindamycin?
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Which condition requires no dosage adjustment when using clindamycin?
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What is the primary structure of aminoglycosides?
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Which of the following actions is NOT a mechanism of aminoglycosides?
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Which pharmacokinetic property is true for most aminoglycosides?
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Which group of bacteria are aminoglycosides primarily effective against?
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What type of adverse effect is commonly associated with the use of aminoglycosides?
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What happens when the trough level of aminoglycosides exceeds 2 ug/mL?
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What is the mechanism of action of streptogramins?
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Which of the following is a key pharmacokinetic characteristic of linezolid?
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For which condition are streptogramins primarily approved for treatment?
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What is the common adverse effect associated with linezolid?
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Which of the following describes the mechanism of resistance for streptogramins?
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What is a critical pharmacokinetic adjustment required for patients with liver failure when using streptogramins?
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In treating the case study patient, which method is advisable to monitor for toxicity of tobramycin?
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What is a common adverse effect associated with tobramycin use?
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What type of toxicity correlates with increased trough levels of aminoglycosides?
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What is the preferred method of administration for neomycin due to its toxicity?
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Which of the following describes the primary clinical use for streptomycin?
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What is a common action of aminoglycosides like tobramycin and streptomycin?
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How does nephrotoxicity manifest in patients using aminoglycosides?
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Which bacterial infections may still respond to streptomycin despite resistance to other aminoglycosides?
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Study Notes
Lincosamides
- Clindamycin is the only drug in this class, derived from Streptomyces lincolnensis.
- It acts by binding to the 50S ribosomal subunit, similar to erythromycin and other macrolides.
- Clindamycin is available orally or intravenously, possesses a high volume of distribution, and penetrates most tissues.
- No dosage adjustment is needed for renal failure.
- Clindamycin is effective against Gram-positive and Gram-negative bacteria, including Streptococci, Staphylococci, and Pneumococci.
- It is commonly prescribed for severe anaerobic infections caused by Bacteroides and other anaerobic bacteria.
- Skin rashes, impaired liver function, and antibiotic-associated colitis due to Clostridium difficile (often fatal) are potential adverse effects.
- Metronidazole is used to treat Clostridium difficile associated colitis.
- Most frequently reported adverse effect is diarrhea, which typically resolves after drug discontinuation.
- Standard dosage is 600-900 mg every 8 hours intravenously or intramuscularly, or 150-300 mg three times daily orally.
- Dosage adjustment is not necessary for reduced creatinine clearance as the drug is primarily eliminated by the liver.
- Dosage adjustment is required for patients with hepatic failure.
- Resistance to lincosamides can develop through various mechanisms:
- Mutations in the ribosomal binding site.
- Enzymatic drug inactivation.
- Receptor modification by induced methylase.
- Clindamycin is clinically used for lower extremity infections (Staph in penicillin-allergic patients), mild diabetic ulcerations (oral therapy), and osteomyelitis due to Staph (good bone penetration).
- In severe diabetic ulcerations, it is combined with a Gram-negative antibiotic.
- Lincosamides are cross-resistant to macrolides.
Aminoglycosides
- Aminoglycosides are a class of antibiotics produced by various species of Streptomyces and Micromonospora.
- They are water-soluble hexose rings with amino sugars linked through glycosidic bonds.
- Aminoglycosides irreversibly inhibit protein synthesis, demonstrating bactericidal effects.
- They enter bacteria through porins in the outer membrane and accumulate inside through an oxygen-dependent proton pump, subsequently binding to ribosomes (streptomycin binds to the 30S subunit).
- Mechanisms of action include:
- Blocking peptide formation during initiation.
- Causing misreading of mRNA, leading to the insertion of incorrect amino acids and production of non-functional proteins.
- Breaking down polysomes into non-functional monosomes.
- Most aminoglycosides are administered intravenously or intramuscularly (except neomycin and kanamycin, which are given orally and topically).
- Usual dosing is once daily intravenously.
- Toxic levels are associated with plasma concentrations exceeding 2 µg/mL (trough level) before the next intravenous dose.
- Dosage adjustments are essential for patients with impaired renal function to prevent toxicity.
- Aminoglycosides are primarily effective against Gram-negative enteric bacteria.
- They have broad-spectrum activity, but many anaerobes are resistant.
Clinical Uses of Aminoglycosides
- Used to treat most Gram-negative enteric bacteria.
- Effective in sepsis.
- Often combined with beta-lactam antibiotics to achieve broad-spectrum coverage, including Gram-positive bacteria.
- Synergistic with beta-lactams, as penicillins cause cell wall abnormalities which facilitate entry of aminoglycosides into bacteria.
Adverse Effects and ADRs of Aminoglycosides
- Ototoxicity: auditory damage (tinnitus, high-frequency hearing loss) and vestibular damage (vertigo, ataxia, loss of balance).
- Nephrotoxicity: elevated creatinine clearance, serum creatinine, and trough levels.
- Neuromuscular toxicity: curare-like effect at the neuromuscular junction, leading to respiratory paralysis. Can be reversed with neostigmine.
- Aminoglycosides have a narrow therapeutic index, requiring careful monitoring.
- Tobramycin trough levels of 2-4 µg/mL are considered therapeutic, while levels exceeding 4 µg/mL are toxic.
Mechanisms of Resistance to Aminoglycosides
- Bacteria can produce transferase enzymes that inactivate the drug through adenylylation, acetylation, or phosphorylation.
- Mutation or deletion of porins, or a non-functional oxygen-dependent transport process, can hinder drug entry.
- Mutation or alteration of the 30S ribosomal protein receptor.
Streptomycin
- Derived from Streptomyces griseus.
- Binds to the 30S ribosomal protein.
- Administered intravenously or intramuscularly.
- Second-line treatment for tuberculosis (TB).
- Typically used as an adjunct drug in TB treatment.
- Hypersensitivity reactions (rash, fever) in patients and those handling the drug.
- Vestibular toxicity (vertigo, loss of balance).
- Toxicity correlates with plasma concentration and creatinine clearance.
- Resistance primarily arises from mutations in the 30S ribosomal protein, rendering streptomycin ineffective for TB.
- Streptomycin can be helpful for some enterococcal infections resistant to other aminoglycosides (approximately 15% of isolates).
Other Aminoglycosides
- Similar to streptomycin in terms of mechanisms of action, pharmacokinetics, and mechanisms of resistance.
- Includes: gentamicin, amikacin, tobramycin, and neomycin.
Neomycin
- Derived from Streptomyces.
- Mechanism of action similar to other aminoglycosides.
- Too toxic for intravenous use, but used orally and topically.
- Poor oral absorption.
- Effective against Gram-positive and Gram-negative bacteria, as well as some mycobacteria.
- Pseudomonas and Streptococci are resistant.
- Clinically used for injection into infected joints, pleural cavities, infected surfaces, and abscess cavities.
- Oral administration is used to reduce normal flora before bowel surgery.
- Adverse effects include renal and ototoxicity, similar to other aminoglycosides.
- Neosporin® is a topical formulation.
Streptogramins
- Combination of streptogramin A (dalfopristin) and streptogramin B (quinupristin), produced by various Streptomyces species.
- FDA-approved in 1999 (Synercid®).
- Inhibits peptide bond formation in the 50S ribosome.
- Administered intravenously only.
- Less than 20% excreted by the kidneys, no dosage adjustment required for renal failure.
- Requires dose reduction for patients with liver failure.
- Active against Gram-positive cocci, including multi-drug resistant strains of Streptococci and penicillin-resistant Staph.
- Approved for use in vancomycin-resistant strains of some Gram-negative bacteria.
- Significantly inhibits CYP3A3, requiring dosage reduction of drugs metabolized by this enzyme (e.g., warfarin, cyclosporine).
- Resistance mainly arises from modification of the binding site on the ribosome.
Oxazolidinones
- Synthetic class of antibiotics, with linezolid (Zyvox®) being the main representative.
- A new class of protein synthesis inhibitors.
Linezolid
- Binds to the 23S rRNA on the 50S ribosomal subunit, preventing ribosomal binding to mRNA.
- Available orally or intravenously.
- Does not induce or inhibit CYP450 enzymes.
- Active against many Gram-positive bacteria.
- Used for vancomycin-resistant infections, nosocomial pneumonia, community-acquired pneumonia, and skin infections.
- Reserved for the treatment of multi-drug-resistant Gram-positive bacteria.
- Potential adverse effects include thrombocytopenia (in 3% of patients) and neutropenia.
Case Study
- A 45-year old male with 3rd degree burns covering 40% of his body, presents with fever (39.5 °C) and a white blood cell count of 20,000/µL on day 10 after admission.
- Blood cultures are pending, and empirical treatment for Pseudomonas is indicated.
- Tobramycin is chosen, with a creatinine clearance of 90 mL/min and a body weight of 70 kg.
- Dosage regimen and toxicity monitoring are required.
Lincosamides
- Structure/Source: Clindamycin is the only lincosamide, derived from Streptomyces lincolnensis
- Mechanism of Action: Clindamycin binds to the 50S subunit of ribosomes, similar to erythromycin and other macrolides
- Pharmacokinetics: Administered orally or intravenously, reaches high volume of distribution, penetrates most tissues, and no dosage adjustment is needed for renal failure.
- Antimicrobial Activity: Active against Gram-positive and Gram-negative bacteria, including streptococci, staphylococci, and pneumococci.
- Clinical Uses: Used for severe anaerobic infections caused by Bacteroides and other anaerobic bacteria.
- Adverse Effects & ADRs: Skin rashes, impaired liver function, antibiotic-associated colitis due to Clostridium difficile (often fatal), treat with metronidazole.
- Most Common ADR: Diarrhea (up to 20% of patients) resolves after stopping the drug.
- Dosage: 600-900 mg every 8 hours intravenously or intramuscularly, or 150-300 mg three times a day orally. No dosage adjustment needed for decreased creatinine clearance as the drug is cleared by the liver. Dosage adjustment is needed for liver failure.
- Resistance Mechanism: Develops cross-resistance to macrolides through mutation in ribosomal receptor binding site, enzymatic inactivation of drug, or mutation altering the receptor by induced methylase.
- Clinical Uses: Used for lower extremity infections: Staph infection in penicillin-allergic patients, oral therapy for mild diabetic ulcerations, combination with a Gram-negative antibiotic for severe diabetic ulcerations, and osteomyelitis due to Staph due to good bone penetration.
Aminoglycosides
- Source: Various Streptomyces species, produce gentamicin, streptomycin, netilmicin, neomycin, and tobramycin.
- Micromonospora produces amikacin.
- Structure: Water-soluble hexose rings with amino sugars attached via glycosidic linkages.
- Mechanism of Action: Irreversibly inhibits protein synthesis, bactericidal effect. They enter bacteria through porins in the outer membrane and concentrate inside through an oxygen-dependent proton pump. They bind to ribosomes: streptomycin binds to the 30S subunit.
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Mechanism of Action details:
- Block peptide formation during initiation.
- Cause misreading of mRNA, resulting in incorrect amino acid insertion and non-functional protein production.
- Cause breakup of polysomes into non-functional monosomes.
- Pharmacokinetics: Mostly administered intravenously or intramuscularly, except neomycin and kanamycin which are given orally and topically.
- Dosage: Once daily dosing for IV administration.
- Toxicity: Correlates with plasma concentration, trough level (just before the next IV dose) of >2 ug/mL is considered toxic. Dosing adjustments required for impaired renal function to avoid toxicity.
- Antimicrobial activity: Primarily used against Gram-negative enteric bacteria, broad spectrum (but many anaerobes are resistant, see Mechanisms of Resistance).
- Clinical Uses: Used for most Gram-negative enterics, useful in sepsis, often combined with a beta-lactam to obtain coverage of Gram-positive bacteria - they are synergistic with beta-lactams because penicillins cause cell wall abnormalities, promoting aminoglycoside entry into bacteria.
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Adverse Effects & ADRs: Ototoxicity, nephrotoxicity, and neuromuscular toxicity - low safety margin.
- Ototoxicity: Auditory damage (tinnitus, high-frequency hearing loss) and vestibular damage (vertigo, ataxia, loss of balance).
- Nephrotoxicity: Rise in creatinine clearance, serum creatinine, and trough levels.
- Neuromuscular Toxicity: Curare-like effect at neuromuscular junction leading to respiratory paralysis. Can be reversed with neostigmine.
-
Resistance Mechanism:
- Organism produces a transferase enzyme inactivating the drug through adenylylation, acetylation, or phosphorylation.
- Mutation deleting a porin or phenotypic induced by oxygen-dependent transport process becomes non-functional.
- Mutation deleting or altering the 30S protein receptor on the ribosome.
- Streptomycin: Mostly due to mutations in the 30S ribosomal protein, leading to frequent resistance. Streptomycin is not used alone for TB and has limited other uses. Can be useful for some enterococcal infections resistant to other aminoglycosides.
- Gentamicin, Amikacin, Tobramycin, Neomycin: Similar traits to those of streptomycin.
- Neomycin: Too toxic for intravenous administration, used orally and topically, but poor oral absorption.
- Neomycin Antimicrobial activity: Effective against Gram-positive and Gram-negative bacteria, including some mycobacteria. Resistant to Pseudomonas and streptococci.
- Neomycin Clinical Uses: Injected into infected joints, pleural cavity, infected surfaces, and abscess cavities. Orally to reduce normal flora prior to bowel surgery.
- Neomycin Adverse Effects & ADR: Renal and ototoxicity, similar to other aminoglycosides.
- Topical Neomycin: Found in Neosporin® product.
Streptogramins
- Structure/Source: Combination of streptogramin A (dalfopristin) and streptogramin B (quinupristin), produced by various Streptomyces species.
- FDA Approval: 1999, marketed as Synercid®.
- Mechanism of Action: Inhibits peptide bond formation at the 50S ribosome.
- Pharmacokinetics: Administered intravenously only, less than 20% excretion by the kidney. Dose adjustment not required for renal failure; dose reduction required for liver failure.
- Antimicrobial Activity: Active against Gram-positive cocci, including multi-drug resistant strains of streptococci and penicillin-resistant strains of staphylococci.
- Clinical Uses: Approved for use in vancomycin-resistant strains of some Gram-negative bacteria.
- Adverse Effects & ADRs: Significantly inhibits CYP 3A4, requiring dose reduction for drugs metabolized by this enzyme (from warfarin to cyclosporin).
- Resistance Mechanism: Mostly due to modification of the binding site on the ribosome.
Oxazolidinones
- Structure/Source: Synthetic compound, linezolid (Zyvox®).
- Class: New class of antibiotic with a protein synthesis inhibitor mechanism.
- Mechanism of Action: Binds to the 23S ribosomal RNA unit on the 50S subunit, preventing ribosome binding to mRNA.
- Pharmacokinetics: Administered orally or intravenously, doesn't induce or inhibit CYP 450.
- Antimicrobial Activity: Active against many Gram-positive bacteria.
- Clinical Uses: Used for vancomycin-resistant infections, nosocomial pneumonia, community-acquired pneumonia, and skin infections. Reserved for treatment of multi-drug resistant Gram-positive bacteria.
- Adverse Effects & ADRs: Thrombocytopenia in 3% of patients, neutropenia.
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Description
This quiz provides an overview of lincosamides, focusing on clindamycin, its pharmacological properties, and its clinical applications. Learn how clindamycin works, its efficacy against various bacteria, potential adverse effects, and necessary precautions. Ideal for students and professionals in medicine and pharmacology.
