Antibacterial Pharmacology: Tetracyclines and Sulfonamides Flashcards
What are tetracyclines mechanism of action?
- Similar mechanism of action as aminoglycosides
- Tetracyclines bind to the 16S rRNA of the 30S ribosomal subunit, inhibiting protein synthesis
- Unlike aminoglycosides, tetracyclines are bacteriostatic
What are tetracyclines spectrum of activity?
- Initially truly broad spectrum…
- When first discovered, tetracyclines were effective
against virtually all bacteria, but resistance is now very common among Gram+/- aerobes and anaerobic bacteria - Nowadays, only effective against infections caused by “atypical” bacteria (Rickettsia, Chlamydia, Mycoplasma, etc.)
- Often the drug of choice for these infections
What are the three atypical bacterial infections?
- Rickettsia infections
- Chlamydia infections
- Mycoplasma infections
Atypical bacterial infections - Rickettsia infections
- R. ricketsii is atypical because it is intracellular; it cannot live freely in the environment
- Transmitted via ticks, fleas, lice, mites, including dog and deer ticks
- Rickettsia multiply inside mammalian cells, especially capillary endothelial cells
- Disease: “Rocky Mountain Spotted Fever” in central & eastern Canada
- Deoxycycline is the tetracycline treatment
Atypical bacterial infections - Chlamydia infections
- Chlamydia trachomatis also lives intracellularly and an atypical cell wall (lacks a peptidoglycan layer)
- Causes the well-known sexually transmitted disease, but can also cause respiratory and ocular infections
- Was once the leading cause of blindness worldwide (“Trachoma”)
Atypical bacterial infections - Mycoplasma infections
- Mycoplasma exists intracellularly and lacks a
cell wall → difficult to develop vaccines and difficult to detect because no cell wall - What feature(s) would an antibiotic drug require to access intracellular pathogens? → be lipophilic
- E.g. M. pneumoniae is responsible for an atypical type of pneumonia (“walking pneumonia” - not as bad as normal pneumonia)
- FYI: M. bovis has become a major concern in dairy and beef cattle; can cause severe respiratory disease
Tetracyclines pharmacokinetics - distribution
- Tetracyclines come in two forms: Water-soluble and lipid-soluble
- Water-soluble tetracyclines (hydrophilic; i.e. chlortetracycline, tetracycline, oxytetracycline) distribute to extracellular fluid compartment, do not readily enter cells or CNS- Lipid-soluble tetracyclines (e.g., doxycycline) enter cells → important for certain intracellular pathogens
-Divalent cations in food (E.g., milk, cheese, antacids)
markedly inhibit oral absorption of tetracyclines
Tetracyclines pharmacokinetics - elimination
- Water-soluble tetracyclines: Excreted via urine and bile; tetracycline primarily gets excreted in urine → associated with renal toxicity in patients with pre-existing renal disease
- Lipid-soluble tetracyclines: Excreted mostly in the bile, making them safer for patients with renal disease
Tetracyclines resistance
- Unfortunately, resistance is widespread due to several acquired (i.e., plasmid-encoded) mechanisms
- Efflux pumps (main mechanism) remove drug from bacterial cell (see slide 20 in AG lecture)
- Efflux pump may be overwhelmed by high drug concentrations → explains improved efficacy with topical application in some situations
Tetracyclines adverse effects
Several, but we will focus on these:
- Tetracycline incorporation into growing teeth & bones (discoloration of teeth, impaired long bone growth)
- Renal tubular damage: administration of a tetracycline to dehydrated patients; use of expired (outdated) drug
- Photosensitization: Tetracyclines can cause a rash by damaging skin capillaries and surrounding cells
Attribute of sulfonamides
- Due to acquired resistance, sulfonamide (S) drugs are now largely ineffective when used alone
- Effectiveness is restored when combined with “diaminopyrimidine inhibitors” such as trimethoprim (TM) or ormetoprim
- TM + S = “potentiated sulfonamide” → increases activity
- Referred to as “TMS”, “trimethoprim-sulfamoxazole”
(Spectra), or “co-trimoxazole” (Bactrim) - While S drugs are bacteriostatic, trimethoprim- sulfamoxazole is often bactericidal
Sulfonamides mechanism of action - normal bacterial folic acid synthesis pathway
- Folic acid (Vitamin B9) is required for DNA, RNA, and protein synthesis
- Mammals acquire what they need from diet, bacteria must synthesize it from PABA (para-aminobenzoic acid
Sulfonamides mechanism of action
- Sulfonamides resemble PABA → take its place and inhibit its action
- Act as competitive inhibitors of dihydropteroate synthetase that catalyzes the condensation of PABA to pteridine
Trimethoprim resembles the pteridine portion of dihydrofolic acid - Inhibits dihydrofolate reductase that catalyzes the reduction of dihydrofolic acid to tetrahydrofolic acid
- Sulfonamides and trimethoprim inhibit different steps in the bacterial folic acid synthesis pathway:
Sulfonamides spectrum of activity
- Sulfonamides alone had truly broad spectrum when first marketed, but rapid selection for resistance occurred within the first decade of use
- Trimethoprim-Sulfamoxazole is more narrow spectrum; effective against some Gram positive (Staph aureus) and
some Gram negative bacteria (including E. Coli that is associated with traveller’s diarrhea but not Pseudomonas aeruginosa) - Frequently prescribed for lower urinary tract UTIs
- Drug of choice for a fungal infection (Pneumocystitis jirovecii) and community-acquired uncomplicated MRSA
- less effective against a broader range of bacteria
Sulfonamides pharmacokinetics - distribution and excretion
Distribution
- Trimethoprim and sulfonamides drugs distribute well to all tissues, can target intracellular pathogens
Excretion
- Partially excreted unchanged in the urine, some hepatic metabolism through CYP enzymes
- Toxic metabolites can accumulate in renal tissues → renal damage can be severe in dehydrated patients
Sulfonamides resistance
- The likelihood of a bacterium acquiring mutated versions of both enzymes is much lower, which is why potentiated sulfonamides are so much more effective than either a sulfa or TM alone
Increased PABA uptake in presence of pus & cellular debris renders drug ineffective
Sulfonamides main adverse effects
- Hypersensitivity reactions
Allergies somewhat common to oral preparations (~3% of the pop’n have a “sulfa allergy”; usually causes a rash or hives) - GI distress
- Precipitation of drug & metabolites in renal tubules
of dehydrated patients → renal damage - FYI: Contraindicated in pregnant patients! Sulfonamides can cross the placenta → lead to folate deficiency in the fetus (maybe)
- Sulfonamides are excreted in milk and may cause kernicterus in newborns (probably)
