Antimicrobial Part 2 Flashcards
What are protein synthesis inhibitors
▪ Many antibiotic families work by targeting bacterial ribosomes and inhibiting
bacterial protein synthesis—these drugs are bacteriostatic
▪ Bacterial ribosomes are composed of 30S and 50S subunits [mammals have
40S and 60S subunits]
▪ Being selective for bacterial ribosomes decreases potential AEs from disrupting
protein synthesis in the host
▪ However high doses of some of these agents can be toxic effects—as a result of an
interaction with the mitochondria ribosomes in the human—because the
mitochondrial ribosomes closely resemble those of the bacteria
Types of Protein Synthesis Inhibitors
- Tetracyclines-protype
- Glycylcyclines
- Aminoglycosides
- Macrolide/Ketolides
- Macrocyclics
- Lincosamides
- Oxazolidinones
MOA Tetracyclines
• Enter susceptible bugs via passive diffusion & energy-dependent transport protein mechanism unique to bacterial inner cytoplasmic membrane • Concentrate intracellularly in susceptible pathogens • Binds reversibly to 30S subunit—this prevents binding of tRNA to the mRNA-ribosome complex & inhibiting protein synthesis
Tetracyclines: Antibacterial Spectrum
Bacteriostatic • Cover: • Gram + • Gram – • Protozoa • Spirochetes • Mycobacteria • Atypical species • Commonly used to treat Chlamydia
Tetracyclines: Resistance
• Most common naturally occurring resistance is from an efflux pump that expels the drug out of the cell—preventing intracellular accumulation • Other mechanisms: • Enzyme inactivation of the drug • Production of bacterial proteins that prevent tetracyclines from binding to the ribosome • Resistance to one tetracycline does not mean resistance to all in the class
Tetracyclines: Absorption
• Adequately absorbed when taken orally • Giving with dairy, Magnesium, Calcium, aluminum antacids or iron decreases absorption—as a nonabsorbable chelate is formed [worse with tetracycline] • Doxycycline and Minocycline available in PO and IV forms
Tetracyclines: Distribution
• Concentrate well in bile, liver, kidney, gingival
fluid and skin
• Bind to tissues undergoing calcification
[teeth/bones] and tumors high in Ca++
content
• Penetration into most body fluids is
acceptable
• Only Minocycline and Doxycycline get to
therapeutic levels in the CSF
• Minocycline obtains high levels in saliva and
tears—can be used to treat meningococcal
carrier states
• ALL tetracyclines cross placental barrier and
concentrate in fetal bones and teeth
Tetracyclines: Elimination
• Tetracycline mainly in the urine • Minocycline is metabolized in the mainly in the liver, to a lesser degree in the kidney • Doxycycline is preferred in the patient with renal disease—as it is eliminated via the bile into the feces
Examples of tetracyclines
Doxycycline
Minocycline
Tetracyclines: ADE/GI Discomfort
• Epigastric distress from irritation of gastric mucosa • Esophagitis—can be decreased by giving with food [except dairy] or fluids and by prescribing tablets • Tetracycline should always be given on empty stomach
Tetracyclines: ADE/effects on calcified tissues
• In children, deposition in bones and teeth occurs during calcification process—leading to discoloration, hypoplasia of teeth and a temporary stunning of growth • Do not use tetracyclines in pediatric care
Tetracyclines: ADE/liver toxicity
• Rarely, liver toxicity can occur with high doses, especially in pregnant women, those with preexisting liver or kidney disease
Tetracyclines: ADE/sun sensitivity
• Severe sunburn can occur with all tetracyclines—most frequently seen with Tetracycline and Demeclocycline
Tetracyclines: ADE/vestibular dysfunction
• Dizziness, vertigo and tinnitus can be seen with Minocycline—which concentrates in endolymph of the ear and affects the function of the 8th CN
Tetracyclines: ADE/Pseudomotor cerebri
• Benign intracranial hypertension [HA, blurred vision] can occur rarely in adults • Stopping the drug reverses this condition, but permanent sequelae may occur— worse with Tetracycline
Tetracyclines: ADE/contraindications
• Should not be used in
pregnancy, breast
feeding or in children
younger than age 8
Sarecycline [Saysera]
▪ Approved for limited course [12 weeks] of therapy for acne vulgaris
▪ Weight based dosing
▪ Drug with very long ½ life—21 – 22 hours
▪ Bacteriostatic, exact MOA unknown
▪ Need baseline ophthalmologic exam—can cause blurred vision, and a change in green/blue color perception
▪ Main SE with this tetracycline is Pseudotumor Cerebri
Glycylcylines: Tigecycline [Tygacil]
-prototype
▪Derivative of Minocycline—1st member of this new antibiotic class
▪Indicated for treatment of complicated soft tissue infections, complicated intra-abdominal infections and CAP
Glycylcylines: MOA
• Bacteriostatic by reversibly
binding to the 30S ribosome
subunit and inhibiting
bacterial protein synthesis
Glycylcylines: Antibacterial spectrum
• Broad Spectrum 💠 Covers: • MRSA • Multi-drug resistant streptococci • VRE • Extended spectrum ß-lactamase-producing Gram – pathogens • Acinetobacter baumanni • Many anaerobes 💠Does NOT cover: • Morganella • Proteus • Providencia • Pseudomonas species
Glycylcylines: Resistance
• Drug developed to overcome emergence of tetracycline-resistant bugs that utilize efflux pumps and ribosomal protection to cause resistance • Resistance has been seen to this agent—mainly due to overexpression of efflux pumps
Glycylcylines: Pharmacokinetics
• Given IV, large volume of distribution • Penetrates tissues well but gets low plasma levels • Poor option for bloodstream infections • Eliminated via bile and feces • No dose reduction for renal disease, but dose reduction is needed in those with liver disease
Glycylcylines: ADEs
• Nausea and vomiting
• Acute pancreatitis [including death]
• Increased LFTs and creatinine can occur
• All cause mortality in those getting this agent is higher than with
other agents
• BB warning—this agent should be used for situations where other
treatments are not an option
• Other ADEs—similar to tetracyclines—photosensitivity,
pseudotumor cerebri, discolored teeth [if used during tooth
development], fetal harm if given during pregnancy
• Tigecycline decreases the clearance of Warfarin
Aminoglycosides are use for?
▪Used for the treatment of serious infections from aerobic Gram – bacilli, but utility is limited by serious toxicities
Examples of Aminoglycosides
▪Amikacin ▪Gentamicin—prototype drug ▪Neomycin ▪Streptomycin ▪Tobramycin
Aminoglycosides: MOA
• Diffuse through porin channels in outer membrane of susceptible pathogens
• Also have an O2-dependent system that transports the drug across the cytoplasmic
membrane
• In the cell, they bind the 30S ribosomal subunit where they interfere with assembly
of the functioning ribosome and/or cause the 30S subunit of the complete ribosome
to misread genetic code
• They are concentration-dependent bactericidal agents—their efficacy is dependent on
the Maximum Concentration [Cmax] of the drug above the MIC of the pathogen
• For this family, the target Cmax is 8 to 10 times the MIC
• They have a postantibiotic effect [PAE]—continued bacterial suppression after the
drug concentrations fall below the MIC [the larger the dose, the longer the PAE]
• Because of this PAE, high-dose extended interval dosing is often used—and this
prescribing strategy reduces renal damage
Aminoglycosides: Antibacterial spectrum
▪Majority of aerobic gram negative bugs, including [many
drug-resistance species]:
- Pseudomonas aeruginosa
-Klebsiella pneumonia
▪-Enterobacter species
▪Often given with a ß-lactam antibiotic to get a synergistic
effect, when treating:
- Enterococcus faecalis
- Enterococcus faecium infective endocarditis
Aminoglycosides: Resistance
▪Occurs from:
- Efflux pumps
- Decreased uptake
- Modification and inactivation by plasmid-associated synthesis of enzymes [each of these enzymes is specific to one aminoglycoside]—so cross-resistance is NOT the rule
Aminoglycosides: Absorption
• Polar, polycation structure prevents adequate oral absorption • All [except Neomycin] must be given IM or IV [neomycin causes renal damage if given parenterally—it is given topically for skin infections** or orally as a prep to decontaminate the bowel before GI surgery]
Aminoglycosides: Distribution
• Tissue concentration may be subtherapeutic and penetration is variable due to hydrophilicity • Levels in CSF no adequate, even when meninges are inflamed • To treat CNS infections, intrathecal or intraventricular routes needed • All of these agents cross the placental barrier and can accumulate in fetal plasma and in amniotic fluid
Aminoglycosides: Elimination
• Neomycin excreted unchanged in feces • Other drugs in the family— 90% of the agent is excreted unchanged in the urine after parenteral dosing—accumulation occurs in those with kidney disease—so these drugs must be renal dosed
Aminoglycosides: ADEs
*** Drug monitoring of Gentamicin, Tobramycin and Amikacin is a MUST to get
appropriate dose and to avoid toxicity
- Older adults most susceptible to nephrotoxicity and ototoxicity
▪ Ototoxicity—vestibular and auditory—related to high peak levels and duration
of therapy
- The drugs accumulate in the endolymph and perilymph of inner ear
- Deafness is usually irreversible and can affect a fetus
- Those getting other ototoxic drugs, such as Cisplatin or loop diuretics are especially
at risk
Aminoglycosides: ADE nephrotoxicity
Neuromuscular Paralysis Allergic Reactions • Retention of the agent by the proximal renal tubular cells disrupts Ca++ mediated transport processes • This retention causes kidney damage ranging from mild, reversible renal impairment to severe, potentially irreversible ATN
Aminoglycosides: Neuromuscular Paralysis
• Associated with a rapid increase in concentration OR concurrent administration with neuromuscular blockers • Those with MG are especially at risk • Prompt administration of Ca++ gluconate or Neostigmine can reverse the block that causes neuromuscular paralysis
Aminoglycosides: Allergic Reactions
• Contact dermatitis is a common reaction to topically applied Neomycin—so avoid triple antibiotic ointments [TAO]
True or False: at least 1/3 of people are sensitive to the neomycin topically and will develop dermatitis, that take the appearance of cellulitis, so not suggested 1st line as topical therapy
TRUE
Macrolides and Ketolides
▪Antimicrobials with a macrocyclic lactone structure to which one
or more deoxy sugars are attached
Examples of Macrolides and Ketolides
Erythromycin—prototype drug
Clarithromycin
Azithromycin
Telithromycin
Macrolides and Ketolides: MOA
▪Bind irreversibly to a site on the 50S ribosome subunit
of the bacterial ribosome and inhibiting translocation steps of protein synthesis
▪These agents are bacteriostatic, and may be bacteriocidal at higher doses
▪Their binding site is either identical to or near to that
for Clindamycin and Chloramphenicol
Macrolides and Ketolides: Antibacterial spectrum-ERYTHROMYCIN
• Same coverage as PCN G • Considered alternative for those with PCN allergy
Macrolides and Ketolides: Antibacterial spectrum-CLARITHROMYCIN
• Coverage is similar to Erythromycin, and also covers: • H. influenzae • Has greater activity against intracellular pathogens, such as: • Chlamydia • Legionella • Moraxella • Ureaplasma species • H. pylori
Macrolides and Ketolides: Antibacterial spectrum-AZITHROMYCIN
• Less active than Erythromycin against Streptococci and Staphylococci, YET • Much more active against respiratory bugs: - H. influenzae - Moraxella catarrhalis • Excess use of this agent has caused growing Streptococcus pneumoniae resistance
Macrolides and Ketolides: Antibacterial spectrum-TELITHROMYCIN
• Spectrum is much like
that of Azithromycin
• Structural change with ketolides neutralizes the most common resistance mechanisms that cause macrolide
resistance
• Ketolides are suspected to become important antimicrobials in the
future, as new drugs are in development
Macrolides and Ketolides: Resistance
▪ Inability of the organism to take up the antibiotic
▪ Presence of efflux pumps
▪ Decreased affinity of the 50S ribosomal subunit for the due to methylation
of an adenine in the 23S bacterial ribosomal RNA in Gram + pathogens
▪ Presence of plasmid-associated Erythromycin esterases in Gram –
pathogens
▪ Ketolides thought to be effective against macrolide-resistant organisms
Macrolides and Ketolides: Absorption
• Erythromycin base is destroyed by HCl- acid, so EC or esterified pills are given
• All forms are stable in stomach acid and are
easily absorbed PO
• Food interferes with absorption of Erythromycin and Azithromycin, but increases absorption of Clarithromycin
• Erythromycin/Azithromycin
are available IV
Macrolides and Ketolides: Distribution
• Erythromycin well distributed in all tissues except CSF—one of few antimicrobials that gets into prostate and it accumulates in
macrophages
• All drugs concentrate in the liver
• Clarithromycin, Azithromycin and Telithromycin widely distributed in tissues
• Azithromycin concentrates in neutrophils, macrophages and fibroblasts, but serum levels are LOW—it has the highest volume
of distribution of all macrolides
Macrolides and Ketolides: Elimination
• Erythromycin and Telithromycin are
metabolized in liver—they inhibit oxidation of many drugs through their interaction with CYP 450
• Clarithromycin interferes with metabolism of theophylline, statins and many AEDs
Macrolides and Ketolides: Excretion
• Azithromycin concentrated and
excreted in bile as active drug
• Erythromycin and metabolites are excreted in bile
• Clarithromycin metabolized in liver as an active drug and metabolites excreted in urine—dose adjust this drug in renal disease
Macrolides and Ketolides—ADEs GI
• GI upset is most common SE [especially Erythromycin] • High doses of Erythromycin can cause smooth muscle contractions that cause gastric contents to move into the duodenum—and the ADE used to treat gastroparesis and post- operative ileus
