Antibiotics and Tetracyclines

• Many antibiotics target bacterial ribosomes to inhibit bacterial protein synthesis, generally resulting in bacteriostatic activity.
• Bacterial ribosomes (30S and 50S subunits) differ structurally from mammalian cytoplasmic ribosomes (40S and 60S subunits), allowing for selective targeting.
• High concentrations of some drugs like chloramphenicol and tetracyclines can affect mammalian mitochondrial ribosomes, which resemble bacterial ribosomes, leading to toxic effects.

Tetracyclines

• Mechanism: Enter bacteria via passive diffusion and energy-dependent transport, bind reversibly to the 30S ribosomal subunit, and prevent tRNA binding, thus inhibiting protein synthesis.
• Spectrum: Effective against a broad range of organisms, including gram-positive and gram-negative bacteria, protozoa, spirochetes, mycobacteria, and atypical species; commonly used for acne and Chlamydia infections.
• Resistance: Primarily via efflux pumps, enzymatic inactivation, or production of proteins that prevent tetracycline binding to ribosomes.
• Pharmacokinetics include:
  • Adequate oral absorption, but decreased by divalent and trivalent cations (e.g., in dairy products, antacids).
  • Doxycycline and minocycline available in oral and IV forms.
  • Concentrates in bile, liver, kidney, gingival fluid, and skin, as well as calcifying tissues and tumors with high calcium content.
  • Minocycline and doxycycline can reach therapeutic levels in CSF; minocycline also in saliva and tears.
  • Tetracycline primarily eliminated unchanged in urine.
  • Minocycline undergoes hepatic metabolism.
  • Doxycycline is eliminated via bile into feces, making it suitable for patients with renal dysfunction.
• Adverse effects:
  • Gastric discomfort is common.
  • Deposition in calcifying tissues can cause tooth discoloration, hypoplasia, and temporary stunting of growth in children.
  • Hepatotoxicity may occur at high doses, especially in pregnant women and those with liver or kidney issues.
  • Phototoxicity can cause severe sunburn with sun exposure.
  • Vestibular dysfunction (dizziness, vertigo, tinnitus) is more common with minocycline.
  • Pseudotumor cerebri (benign intracranial hypertension) may occur rarely in adults.
  • Avoid use in pregnant or breastfeeding women and children under 8 years old.

Glycylcyclines

• Tigecycline is a derivative of minocycline used for complicated skin and soft tissue infections, intra-abdominal infections, and community-acquired pneumonia.
• Mechanism: Bacteriostatic, it reversibly binds to the 30S ribosomal subunit, inhibiting bacterial protein synthesis.
• Spectrum: Broad-spectrum, including MRSA, multidrug-resistant streptococci, VRE, extended-spectrum β-lactamase-producing gram-negative bacteria, Acinetobacter baumannii, and many anaerobic organisms.
  • Inactive against Morganella, Proteus, Providencia, and Pseudomonas species.
• Resistance: Primarily due to overexpression of efflux pumps.
• Pharmacokinetics:
  • Large volume of distribution but low plasma concentrations, making it unsuitable for bloodstream infections.
  • Primarily eliminated via biliary/fecal route.
  • Dose reduction recommended in severe hepatic dysfunction; no adjustment needed for renal impairment.
• Adverse effects:
  • Significant nausea and vomiting.
  • Acute pancreatitis (potentially fatal) reported.
  • Elevations in liver enzymes and serum creatinine may occur.
  • Higher all-cause mortality compared to other agents.
  • Other effects similar to tetracyclines: photosensitivity, pseudotumor cerebri, tooth discoloration, fetal harm.
  • May decrease warfarin clearance, requiring close monitoring of INR.
  • Should be reserved for situations where alternative treatments are unsuitable.

Aminoglycosides

• Mechanism: Diffuse through porin channels, transported across the cytoplasmic membrane (oxygen-dependent), bind to the 30S ribosomal subunit, interfering with ribosomal assembly or causing misreading of the genetic code.
• Exhibit concentration-dependent bactericidal activity and a postantibiotic effect (PAE).
• High-dose, extended-interval dosing is commonly used.
• Spectrum: Effective against most aerobic gram-negative bacilli, including multidrug-resistant strains like Pseudomonas aeruginosa, Klebsiella pneumoniae, and Enterobacter sp.
  • Often combined with a β-lactam antibiotic for synergistic effect, especially against Enterococcus faecalis and Enterococcus faecium endocarditis.
• Resistance: Via efflux pumps, decreased uptake, or enzymatic modification and inactivation.
  • Amikacin is less vulnerable to enzymatic inactivation.
• Pharmacokinetics:
  • Poor oral absorption, requiring parenteral administration (except for neomycin).
  • Neomycin is not given parenterally due to nephrotoxicity; used topically or orally for GI decontamination.
  • Tissue concentrations may be subtherapeutic; variable penetration into body fluids.
  • CSF concentrations are inadequate, requiring intrathecal or intraventricular administration for CNS infections.
  • Crosses the placental barrier.
  • Primarily excreted unchanged in urine, requiring dose adjustments in renal dysfunction.
  • Neomycin is excreted unchanged in feces.
• Adverse effects:
  • Ototoxicity (vestibular and auditory) is related to high peak plasma concentrations and treatment duration; may be irreversible.
  • Nephrotoxicity results from retention in proximal tubular cells, disrupting calcium-mediated transport.
  • Neuromuscular paralysis can occur with high doses or concurrent neuromuscular blockers; treat with calcium gluconate or neostigmine.
  • Allergic reactions (contact dermatitis) are common with topical neomycin.

Macrolides and Ketolides

• Macrolides have a macrocyclic lactone structure with attached deoxy sugars.
• Erythromycin was the first, used as a first-line drug or alternative to penicillin.
• Clarithromycin and azithromycin have some improvements over erythromycin.
• Telithromycin is a semisynthetic ketolide derivative.
• Mechanism: Bind irreversibly to the 50S subunit of the bacterial ribosome, inhibiting translocation steps of protein synthesis.
  • Generally bacteriostatic but can be bactericidal at higher doses.
  • Binding site is near clindamycin and chloramphenicol binding sites.
• Spectrum:
  • Erythromycin: Similar to penicillin G.
  • Clarithromycin: Similar to erythromycin, but also effective against Haemophilus influenzae and intracellular pathogens.
  • Azithromycin: Less active against streptococci and staphylococci but more active against respiratory pathogens like H. influenzae and Moraxella catarrhalis.
  • Telithromycin: Similar to azithromycin; structural modification neutralizes common macrolide resistance mechanisms.
• Resistance:
  • Inability of the organism to take up the antibiotic.
  • Efflux pumps.
  • Decreased affinity due to methylation of adenine in 23S rRNA.
  • Plasmid-associated erythromycin esterases in gram-negative organisms.
  • Erythromycin use is limited due to increasing resistance.
  • Telithromycin may be effective against macrolide-resistant organisms.
• Pharmacokinetics:
  • Erythromycin base is destroyed by gastric acid, so enteric-coated tablets or esterified forms are used.
  • Clarithromycin, azithromycin, and telithromycin are stable in stomach acid and readily absorbed; food interferes with erythromycin and azithromycin absorption but increases clarithromycin absorption.
  • Erythromycin and azithromycin are available in IV formulations.
  • Erythromycin distributes well to all body fluids except CSF and accumulates in macrophages.
  • Clarithromycin, azithromycin, and telithromycin are widely distributed in tissues.
  • Erythromycin and telithromycin undergo hepatic metabolism, inhibiting the cytochrome P450 system.
• Excretion:
  • Azithromycin is concentrated and excreted in bile as active drug.
  • Erythromycin and its metabolites are excreted in bile.
  • Clarithromycin is hepatically metabolized, and the active drug and metabolites are excreted in urine; dosage should be adjusted in renal impairment.
• Adverse effects:
  • Gastric distress is the most common side effect.
  • Cholestatic jaundice occurs with the estolate form of erythromycin.
  • Transient deafness is associated with erythromycin, especially at high dosages; azithromycin is associated with irreversible sensorineural hearing loss.
  • Macrolides and ketolides may prolong the QTc interval.
• Contraindications:
  • Use cautiously in patients with hepatic dysfunction.
  • Severe hepatotoxicity with telithromycin has limited its use.
• Drug Interactions:
  • Erythromycin, telithromycin, and clarithromycin inhibit the hepatic metabolism of other drugs.
  • Interaction with digoxin may occur.

Fidaxomicin

• Macrocyclic antibiotic similar to macrolides with a unique mechanism of action.
• Mechanism: Acts on the sigma subunit of RNA polymerase, disrupting bacterial transcription, terminating protein synthesis, and causing cell death.
• Spectrum: Narrow spectrum limited to gram-positive aerobes and anaerobes.
  • Primarily used for bactericidal activity against Clostridium difficile.
• No documented cross-resistance with other antibiotic classes.
• Pharmacokinetics:
  • Minimal systemic absorption after oral administration, remaining primarily in the gastrointestinal tract.
• Adverse effects:
  • Nausea, vomiting, and abdominal pain.
  • Anemia and neutropenia observed infrequently.
  • Hypersensitivity reactions (angioedema, dyspnea, and pruritus) have occurred.
  • Use with caution in patients with a macrolide allergy due to increased risk of hypersensitivity.

Chloramphenicol

• Broad-spectrum antibiotic restricted to life-threatening infections with no alternatives.
• Mechanism: Binds reversibly to the bacterial 50S ribosomal subunit, inhibiting protein synthesis at the peptidyl transferase reaction.
  • May inhibit protein and ATP synthesis in mammalian mitochondrial ribosomes at high concentrations, causing bone marrow toxicity.
• Spectrum: Active against many microorganisms, including chlamydiae, rickettsiae, spirochetes, and anaerobes.
  • Primarily bacteriostatic, but can be bactericidal depending on dose and organism.
• Resistance: Via enzymes that inactivate chloramphenicol, decreased penetration, or altered ribosomal binding site.
• Pharmacokinetics:
  • Administered intravenously and widely distributed throughout the body, reaching therapeutic concentrations in CSF.
  • Primarily undergoes hepatic metabolism to an inactive glucuronide, which is secreted by the renal tubule and eliminated in the urine.
• Adverse effects:
  • Anemias: Dose-related anemia, hemolytic anemia (in patients with glucose-6-phosphate dehydrogenase deficiency), and aplastic anemia.
  • Gray baby syndrome: Due to low glucuronidation capacity and underdeveloped renal function in neonates, leading to drug accumulation and mitochondrial ribosome interference.
• Drug Interactions:
  • Chloramphenicol inhibits hepatic mixed-function oxidases, preventing the metabolism of drugs like warfarin and phenytoin.

Clindamycin

• Mechanism: Similar to macrolides.
• Used primarily for infections caused by gram-positive organisms (including MRSA and streptococcus) and anaerobic bacteria.
• Resistance mechanisms are the same as for erythromycin.
  • C. difficile is resistant to clindamycin.
• Available in IV and oral formulations.
  • Oral use is limited by gastrointestinal intolerance.
• Distributes well into all body fluids but has poor entry into the CSF.
• Undergoes extensive oxidative metabolism and is excreted into bile and urine.
  • Low urinary excretion limits its utility for urinary tract infections.
• Accumulation reported in patients with severe renal impairment or hepatic failure.
• Adverse effects:
  • Skin rash and diarrhea, which may represent pseudomembranous colitis caused by C. difficile overgrowth.

Quinupristin/Dalfopristin

• Mixture of two streptogramins (30:70 ratio).
• Reserved for severe infections caused by vancomycin-resistant Enterococcus faecium (VRE) when other options are unavailable.
• Mechanism: Each component binds to a separate site on the 50S bacterial ribosome, synergistically interrupting protein synthesis.
  • Dalfopristin disrupts elongation.
  • Quinupristin prevents elongation and causes release of incomplete peptide chains.
  • Bactericidal against most susceptible organisms and has a long PAE.
• Spectrum: Active primarily against gram-positive cocci, including those resistant to other antibiotics.
  • Primary use is for E. faecium infections (including VRE strains), against which it is bacteriostatic.
  • Not effective against E. faecalis.
• Resistance: Enzymatic processes, such as ribosomal enzyme methylation or acetyltransferase inactivation of dalfopristin, or active efflux pumps.
• Pharmacokinetics:
  • Available intravenously; does not achieve therapeutic concentrations in CSF.
  • Undergoes hepatic metabolism, with excretion mainly in the feces.
• Adverse effects:
  • Venous irritation is common.
  • Hyperbilirubinemia occurs in about 25% of patients.
  • Arthralgia and myalgia reported at higher doses.
  • Quinupristin/dalfopristin inhibits the cytochrome P450 CYP3A4 isoenzyme.

Oxazolidinones

• Linezolid and tedizolid are synthetic oxazolidinones developed to combat gram-positive organisms, including resistant isolates like MRSA, VRE, and penicillin-resistant streptococci.
• Mechanism: Bind to the bacterial 23S ribosomal RNA of the 50S subunit, inhibiting the formation of the 70S initiation complex and translation of bacterial proteins.
• Spectrum: Primarily against gram-positive organisms such as staphylococci, streptococci, and enterococci, Corynebacterium species and Listeria monocytogenes.
  • Moderately active against Mycobacterium tuberculosis.
  • Linezolid is an alternative to daptomycin for VRE infections.
• Resistance: Primarily occurs via reduced binding at the target site.
  • Cross-resistance with other protein synthesis inhibitors does not occur.
• Pharmacokinetics:
  • Well absorbed after oral administration; IV formulations are also available.
  • Distribute widely throughout the body.
  • Linezolid is metabolized via oxidation to two inactive metabolites.
  • Tedizolid is metabolized by sulfation, and the majority of elimination occurs via the liver.
• Adverse effects:
  • Gastrointestinal upset, nausea, diarrhea, headache, and rash.
  • Thrombocytopenia reported, usually in patients taking the drug for longer than 10 days.
  • May lead to serotonin syndrome if given with large quantities of tyramine-containing foods, selective serotonin reuptake inhibitors, or monoamine oxidase inhibitors.
  • Irreversible peripheral neuropathies and optic neuritis have been associated with greater than 28 days of use.