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Antimicrobial Therapy Part Two (Ch 30-31) Protein Synthesis Inhibitors / Quinolones / Folic acid Antagonists / Urinary Antiseptics Protein Synthesis Inhibitors
- Many antibiotic families target bacterial ribosomes to inhibit protein synthesis acting as bacteriostatic agents -prevents growth instead of just killing them directly which is bactericidal.
- Bacterial ribosomes (cell components crucial for protein synthesis) have 30S and 50S subunits, distinct from mammalian 40S and 60S subunits, allowing for selective targeting. *Being selective for bacterial ribosomes decreases potential AEs from disrupting protein synthesis in the host
- High doses of some protein synthesis inhibitors can be toxic due to interaction with mitochondrial ribosomes, which structurally resemble bacterial ones. Types: • Tetracyclines • Glycylcyclines • Aminoglycosides • Macrolide/Ketolides
- Macrocyclics • Lincosamides • Oxazolidinones • Others 1.Tetracyclines (oldies but goodies)
- including Tetracycline (prototype), Doxycycline, and Minocycline, MOA: enter susceptible bacteria via passive diffusion and an energy-dependent transport mechanism. àOnce inside they concentrate intracellularly in bacterial cells àThey bind reversibly to the 30S ribosomal subunit, preventing tRNA binding to the mRNA- ribosome complex and inhibiting protein synthesis.
- Tetracyclines have a broad antibacterial spectrum, covering:
Gram + / - bacteria, protozoa, spirochetes, mycobacteria, and atypical species
(ex.chlamydia) Ex. MRSA, think abx for the great outdoors (ex tick diseases, Q fever and plague)
- Common resistance mechanisms : pt not necessarily resistant to all drugs in class if resistant to one drug. o Efflux pumps that expel the drug from the cell preventing intracellular accumulation o Enzyme inactivation of the drug o Production of bacterial proteins that prevent drug from binding to ribosome *** Absorption is decreased by dairy, antacids, calcium, magnesium, and iron** due to chelate formation. Tetracycline always given on empty stomach.
- Tetracyclines concentrate in bile, liver, kidney, gingival fluid, and skin, and bind to calcified tissues like teeth and bones. àMainly eliminated in urine
** Doxycycline is preferred in renal disease as it's eliminated via bile into feces**.
- Liver Toxicity can occur at high doses in pregnant women and pts w/ preexisting liver or kidney dx
- Adverse effects : GI discomfort (take with food except dairy products), deposition in bones and teeth (tooth discoloration) ( contraindicated in children). Sun sensitivity, dizziness (with Minocycline), and pseudotumor cerebri (benign intracranial hypertension) Contraindications: not used in pregnancy breastfeeding or children < 8 yo Sarecycline is a newer tetracycline approved for acne vulgaris, with a long half-life and potential for pseudotumor cerebri. Need baseline ophthalmologic exam- can cause blurred vision and change in green/blue color perception Le Tour de Cyclines
2. Glycylcyclines
- ** Tigecycline is the prototype** glycylcycline, a derivative of minocycline, used for -complicated soft tissue, intra-abdominal infections, and community- acquired pneumonia
- It inhibits bacterial protein synthesis by binding to the 30S ribosome subunit.
- Glycylcyclines have a broad spectrum MRSA, VRE, and extended-spectrum beta-lactamase-producing Gram-negative pathogens NOT: Morganella, Proteus, Providencia, or Pseudomonas species.
- This class was developed to overcome tetracycline resistance mechanisms like efflux pumps.
- Tigecycline is given IV and has a large volume of distribution but poor plasma levels à **making it a poor option for bloodstream infections. *** Eliminated via bile and feces- need dose reduction for liver disease (no changes for renal disease)
* Adverse effects: nausea, vomiting, diarrhea, acute pancreatitis, increased LFTs and
creatinine Other ADE’s similar to tetracylcines-photosensitivity, pseudotumor cerebri discolored teeth (d/t and harmful to fetus b lack box warning for increased mortality. - only use if no other options
- Tigecycline decreases the clearance of Warfarin.
3. Aminoglycosides
- Gentamicin (prototype), Amikacin, Neomycin, Streptomycin, and Tobramycin,
à treat serious infections from aerobic Gram-negative bacilli
but have significant toxicities. MOA: They diffuse through porin channels and an oxygen-dependent system to reach
the cytoplasm, where they bind irreversibly to the 30S ribosomal subunit ,
interfering with ribosome assembly or causing misreading of genetic code- killing the cell (bacterialcidal agents)
- Aminoglycosides are concentration-dependent bactericidal agents Efficacy depends on Max conc. (Cmax) of the drug above the MIC of pathogen- target 8-10x theMIC
* postantibiotic effect (PAE), allowing for high-dose, extended-interval dosing to
reduce renal damage.
- Their spectrum covers most aerobic Gram-negative bugs psuedomonas aeruginosa, kleb PNA & Enterobacter species *often combined with beta-lactams for synergistic effects (help getting thru cell wall) against Enterococcus species -enterococcus faecalis & enterococcus faecium infective endocardititis
- Resistance occurs via efflux pumps, decreased uptake or enzymatic inactivation- each enzyme specific to one aminoglycoside NO cross resistance ☑️
- Aminoglycosides are polar and poorly absorbed orally, requiring IM or IV administration except Neomycin- causes renal damage if given IV ** at least 1/3 of people are sensitive to the neomycin topically and will develop a dermatitis, that takes the appearance of cellulitis-not suggested 1st line as topical therapy--- Avoid TAOs!
- They have variable tissue penetration, inadequate CSF levels, and cross the placental barrier.
- Neomycin is excreted unchanged in feces-good for bowel prep** while others are renally excreted and require dose adjustment in renal disease.
Feudal Assassins [glycoSIdes- SAI (dagger)]
Sketchy Lesson Summary Aminoglycosides are bactericidal antibiotics that inhibit protein synthesis by binding to the 30s ribosomal subunit and disrupting the formation of the initiation complex. This leads to the misreading of mRNA, which ultimately causes cell death. The most common clinical application of the aminoglycosides is in the treatment of serious infections caused by aerobic gram-negative bacilli, usually in combination with a beta-lactam antibiotic or vancomycin, which are cell wall active drugs. These drugs enhance the ability of aminoglycosides to penetrate cells. There are different types of aminoglycosides: neomycin (useful in bowel preparation before colorectal surgery) streptomycin (effective against tularemia and plague) gentamicin and tobramycin (used for severe systemic infections c/b gram-negative bacteria) amikacin (for resistant gram-negative bacteria)-most expensive Two major adverse effects of aminoglycosides are ototoxicity and nephrotoxicity, and as such, it is important to monitor serum concentrations to prevent toxicity. Contraindications to aminoglycoside use include: pregnancy (can cause deafness in newborn) myasthenia gravis (due to the risk of neuromuscular blockade).
o Azithromycin concentrates in neutrophils, macrophages and fibroblasts, but serum levels are LOW—it has the highest volume of distribution of all macrolides Erythromycin and Telithromycin are metabolized in liver—they inhibit oxidation of many drugs through their interact Clarithromycin interferes with metabolism of theophylline, statins and many AEDs
- Erythromycin** and Telithromycin are metabolized in the liver and inhibit CYP 450, while Azithromycin is concentrated and excreted in bile as active drug. *** Common adverse effects:** o GI upset, and high doses of Erythromycin can cause smooth muscle contractions in Gi tract Used to treat gastroparesis and post-op ileus o Cholestatic Jaundice- Occurs most commonly with estolate form of Erythromycin [no longer available in the US o Ototoxicity- transient deafness w/ high dose Erythromycin. Arythromycin assc w/ irreversible sensorineural hearing loss o QTc prolongation-caution with pts on antiarrhythmics o Liver toxicity (especially with Telithromycin) Erythromycin, especially Telithromycin and Clarithromycin can interfere with liver metabolism of many drugs which can result in toxic levels of these agents
à chose Azithromycin if pt on any of these drugs:
Alfuzosin [Uroxatrol] Atorvastatin [Lipitor] Carbamazepine [Tegretol] PIs Sildenafil [Viagra] Simvastatin [Zocor] Valproate [Depakote] Warfarin Change in gut flora from these antibiotics can lead to digoxin toxicity 30 Sketchy Lesson Summary The macrolide class of antibiotics--- which includes erythromycin, azithromycin, clarithromycin, and fidaxomicin--- exerts its bacteriostatic action by binding to the 50S ribosomal subunit within bacterial cells. This binding obstructs protein synthesis, which effectively halts bacterial replication and growth. Along with their antimicrobial applications, macrolides exhibit strong anti- inflammatory properties in the lungs, making them suitable for managing chronic lung diseases. Additionally, these antibiotics enhance smooth muscle
motility in the gut, imparting a prokinetic effect that aids gastrointestinal movement. Macrolides, owing to their broad bacterial coverage, find utility in an array of clinical scenarios. These include treating community-acquired pneumonias, atypical pneumonias, pertussis (100 day cough), mycobacterial infections like mycobacterium avium complex (MAC), sexually transmitted infections, neonatal eye infections, and H. pylori-related ulcers. Additionally, macrolides are unique for their use against Mycoplasma, Babesia, and Bartonella infections. Different types of macrolides offer distinct advantages; for instance, fidaxomicin is ideal for C. difficile colitis due to its bactericidal nature and high retention in the gut. While effective, however, macrolides use is not without its drawbacks. Potential adverse effects include hepatotoxicity, potentially fatal cardiac dysrhythmias, heightened risks in patients with coronary artery disease, and skin rashes. Drug interaction is also an important consideration for patients on macrolides due to their inhibitory effect on cytochrome P450 and P-glycoprotein The Crow (Macrolides)
5. Fidaxomicin (Dificid)
- Fidaxomicin is a macrocyclic drug with a unique mechanism of action, targeting the sigma subunit of RNA polymerase to disrupt transcription and cause cell death.
- has a narrow spectrum, primarily active against Gram + aerobes and anaerobes mainly used for Clostridium difficile infections.
- Due to its unique target site, cross-resistance has not been observed.
- given orally with minimal systemic absorption, making it ideal for GI tract infections.
- Adverse effects : nausea, vomiting, and abdominal pain; anemia and neutropenia are rare. Hypersensitivity, angioedema, SOB and itching have occurred
- Use with caution in those allergy to a macrolide
- Despite its efficacy, its high cost is a significant barrier
6. Chloramphenicol
- broad-spectrum antibiotic reserved for life-threatening infections where no alternatives exist, considered salvage therapy in the US (used in 3rd^ world countries for meningitis epidemics)
- It binds reversibly to the 50S ribosomal subunit, inhibiting protein synthesis *some of host mitochondria ribosomes closely resemble those of pathogen, so it can also impair mitochondrial protein and ATP production in host cells at high levels à bone marrow toxicity Last resort for life threatening infections when no other issues
- used for meningitis - Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis
- alternate agent in Rickettsial infections- rocky mountain spotted fever or tick bourne diseases
- The oral form was removed from the US market due to toxicity.
- It is active against many pathogens: Chlamydia Rickettsia spirochetes anaerobes. *** Bacteriostatic, but can be bactericidal — depending on dose and organism**
- It is widely distributed throughout the body, including the CSF, and primarily undergoes hepatic metabolism. -reduce dose in liver disease Avoid in breastfeeding mothers *** Adverse effects:** rdose-related anemia (reversible) bone marrow suppression (irreversible) hemolytic anemia in G6PD deficiency rare but fatal aplastic anemia (which can occur after drug cessation). Gray Baby Syndrome is a severe, potentially fatal reaction in infants due to impaired glucuronidation and excretion d/t their renal system not being fully developed. Drug builds up and interferes w/ mitochondrial ribosomes- poor feeding & resp. depression -can occur in adults as well
- Chloramphenicol interferes with the metabolism of Warfarin and Phenytoin, potentiating their effects. Sketchy Lesson Summary Chloramphenicol is a potent broad-spectrum antibiotic renowned for its effectiveness against a wide range of bacterial infections; however, there are potential adverse effects and hematologic risks that should be taken into account before use.
7. Clindamycin
*** MOA:** is similar to macrolides Binds to 50S subunits ribosomes of bacteria inhibiting translocation-inhibiting protein synthesis- bacteriostatic
- primarily treating Gram + bacteria: MRSA, streptococcus skin infx
Anaerobes-
Actively transported in macrophages-excellent penetration into abscesses (ex lungs; asp PNA)
- Resistance mechanisms are like Erythromycin, and cross-resistance has been described.
C.Diff is resistant to Clindamycin
- It is available orally and IV but has limited oral use due to GI side effects.
- Clindamycin distributes well into body fluids but has poor entry into the CSF. Treats serious infections of female genital tract infx Garderella vaginitis Safest to treat MRSA in pregnancy
- It undergoes extensive metabolism and is excreted into bile and urine. **Low urinary excretion of active drug- don’t use for UTI’s Accumulates in body of renal and/or liver disease
- Adverse effects** : rash diarrhea (which may be an overgrowth of C. difficile) Oral Vancomycin or Metronidazole is usually effective to treat C. difficile from Clindamycin Sketchy Lesson Summary Clindamycin is an antibiotic that functions similar to a macrolide, in that it inhibits bacterial protein synthesis through binding to the 50S ribosomal subunit, thereby halting bacterial growth. This antibiotic demonstrates activity against gram-positive organisms, such as Streptococci, Staphylococci, and Bacteroides fragilis, and also gives coverage against Methicillin-resistant Staphylococcus aureus (MRSA). It also has activity against anaerobic bacteria and can penetrate abscesses, and thus is useful for lung abscesses caused by anaerobes. It's also effective in handling oral
infections caused by anaerobes like Fusobacterium, Bacteroides, and Clostridium (e.g. Clostridium perfringens). Apart from these, it addresses skin problems like inflammatory acne caused by skin anaerobes, and genital tract infections like bacterial vaginosis caused by Gardnerella. Adverse effects of clindamycin include gastrointestinal symptoms such as nausea, vomiting, and diarrhea. A severe complication, Clostridioides difficile-associated diarrhea (CDAD), can also arise, and warrants prompt intervention.
10. Oxazolidinones
- Linezolid (prototype)** and Tedizolid, were developed to treat Gram + organisms , includes resistant bugs like MRSA (not 1st^ line), VRE (vanco resistant enterococcus, and PCN resistant streptococci Nosocomial PNA, complicated skin and soft tissue infx
- MOA : bind to the 23S ribosomal RNA of the 50S subunit , inhibiting the formation of the 70S initiation complex and bacterial protein translation.
- Their main action is against Gram + pathogens, and they are generally bacteriostatic though Linezolid is bactericidal against Streptococcus
- Resistance occurs from reduced binding at target sites. Seen in S. aureus and Enterococci species (vanco resistant organisms) Cross sensitivities to other protein synthesis inhibitors does not occur
- They are well absorbed orally and IV and distribute widely throughout the body.
- Common adverse effects : o GI issues, headache, and rash. o Thrombocytopenia** can occur with use longer than 10 days. o They possess nonselective MAO activity, potentially causing serotonin syndrome with tyramine-rich foods or certain antidepressants (SSRIs, SNRIs, MAO inhibitors and bupropion o Irreversible peripheral neuropathy** and optic neuritis can occur with use longer than 28 days. Lesson Summary Linezolid is an antibiotic known for its activity against serious infections caused by gram- positive organisms, specifically by Staphylococci, Streptococci, and Enterococci 🟣. It hinders bacterial protein synthesis by binding to the 50S ribosomal subunit which effectively prevents protein synthesis and therefore, bacterial growth. Linezolid is effective against a number of serious infections, notably nosocomial pneumonia and complicated skin and soft tissue infections due to Methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin-resistant Enterococcus (VRE). The primary toxicity associated with linezolid, however, is hematologic, with thrombocytopenia as the most common manifestation, followed by anemia and neutropenia. Other adverse effects include optic neuropathy and peripheral neuropathy.
Additionally, linezolid is a weak inhibitor of monoamine oxidase and can precipitate serotonin syndrome; it should be used with caution in patients taking serotonergic agents (e.g. SSRIs, SNRIs, MAO inhibitors, or bupropion.)
