pharm lecture 22 & 23
Azithromycin MOA & adverse effects
Bind to a small region of 23S rRNA of the 50S ribosomal subunit near the peptidyl transferase active center. Increase in gastrointestinal motility. Arrythmia caused by prolonged QT interval Acute cholestatic hepatitis; rash and eosinophilia. Exacerbation of myasthenia gravis (contraindication)
macrolides MOA
Bind to the 23S rRNA of the 50S ribosomal subunit Blockage of translocation Inhibition of bacterial protein synthesis Bacteriostatic effect
doxycycline therapeutic uses
Acne Cholera (Vibrio cholerae) Chlamydial infections (MRSA) Lyme Disease Atypical pneumonia Rocky mountain spotted fever Malaria prophylaxis Primary and secondary syphilis Anthrax, including treatment for bioterrorism exposures. Dental
tetracycline absorption impaired by
Antacids (containing magnesium, aluminum, calcium). Medications that contain divalent cations (such as iron-containing preparations, sucralfate, bismuth subsalicylate).
Tetracyclines Broad-spectrum -
Effective against a wide variety of organisms, including grampositive and gram-negative bacteria, protozoa, spirochetes, mycobacteria, and atypical species.
Clarithromycin MOA & therapeutic euses
Bind to a small region of 23S rRNA of the 50S ribosomal subunit near the peptidyl transferase active center. Respiratory tract infections (including atypical pneumonias and soft-tissue infections) for non-tuberculous mycobacterial infections such as Mycobacterium aviumcomplex (treatment).
Erythromycin MOA & adverse effects
Bind to a small region of 23S rRNA of the 50S ribosomal subunit near the peptidyl transferase active center. Increase in gastrointestinal motility Arrythmia caused by prolonged QT interval Acute cholestatic hepatitis. Clostridium difficile diarrhea Rash and eosinophilia.
Eravacycline has resistance among
Enterobacteriaceae (Escherichia coli and Klebsiella pneumoniae) and gram-negative anaerobes limits the utility of the tetracyclines for intra-abdominal infections. Active against Staphylococcus aureus and Enterococcus spp.(Enterococcus faecalis, Enterococcus faecium). Active against B fragilis.
Other mechanisms of bacterial resistance to tetracyclines
Enzymatic inactivation of the drug Production of bacterial proteins that prevent tetracyclines from binding to the ribosome.
Gastric discomfort (tetracyclines)
Epigastric distress commonly results from irritation of the gastric mucosa (results in noncompliance). Esophagitis may be minimized through coadministration with food (other than dairy products) or fluids and the use of capsules rather than tablets
Macrolides
Erythromycin Azithromycin Clarithromycin Telithromycin
Eravacycline therapeutic uses:
Exhibits potent activity against a broad spectrum of clinically relevant Grampositive and -negative aerobic and anaerobic bacteria. Complicated intra-abdominal infections (cIAI).
tetracyclines adverse effects
Gastric discomfort Effects on calcified tissues Hepatotoxicity Phototoxicity Pseudotumor cerebri Pregnancy
Aminoglycosides
Gentamicin Tobramycin Neomycin Amikacin Streptomycin "Mean" (aminoglycoside) GTNAS cannot kill anaerobes
Helicobacter pylori is a common cause of.. (& what is the treatment)
Peptic ulcer disease combo of: bismuth, metronidazole, tetracycline, and protein pump inhibitor
Hepatotoxicity (tetracyclines)
Rarely hepatotoxicity may occur with high doses, particularly in pregnant women and those with preexisting hepatic dysfunction or renal impairment.
Aminoglycosides elimination
Renal route
Azithromycin Therapeutic uses:
Respiratory tract infections Sexually transmitted diseases Travelers' diarrhea Atypical pneumonias In cystic fibrosis For non-tuberculous mycobacterial infections
Tetracyclines antagonize the
bactericidal effects of penicillins, and this antagonism likely occurs with any combination of a bacteriostatic inhibitor of protein synthesis and a β-lactam drug or an aminoglycoside
A boxed warning states that tigecycline should
be reserved for use in situations when alternative treatments are not suitable.
why use Demeclocycline for SIADH
because of its inhibition of antidiuretic hormone in the renal tubule. Effective and convenient to use in SIADH because this action is both dose-dependent and reversible.
Minocycline absorption is not impaired
by food (may be taken with food).
legionnaires disease
fluroquinolones or azithromycin are preferred therapeutic options
Azithromycin has a high
hepatic excretion - use in patients with liver disease should be avoided.
Aminoglycosides diffuse through porin channels
in the outer membrane of susceptible organisms. These organisms also have an oxygen-dependent system that transports the drug across the cytoplasmic membrane.
chlamydia trachomatis is a major cause of (&what is the treatment)
sexually transmitted diseases, nongonococcal urethritis, pelvic inflammatory disease & lymphogranuloma venereum doxyxyxline or azithromycin
Carbamazepine, phenytoin, barbiturates and chronic alcohol ingestion may
shorten the halflife of tetracycline, doxycycline, and eravacycline by 50% (due to induction of hepatic enzymes)
Tetracyclines concentrate intracellularly in
susceptible organisms and bind reversibly to the 30S subunit of the bacterial ribosome. Preventing binding of aminoacyl-tRNA to the mRNA-ribosome complex, thereby inhibiting bacterial protein synthesis.
Tetracyclines consist of four fused rings with a
system of conjugated double bonds. Substitutions on these rings alter the individual pharmacokinetics and spectrum of antimicrobial activity.
Tigecycline Broader spectrum of activity than
tetracyclines; infections requiring deep tissue penetration.
Eravacycline Broader spectrum of activity
than tetracyclines; infections requiring deep tissue penetration. Poorly absorbed orally and must be administered intravenously
Tetracycline eliminated by
the kidney and in the bile and are also distributed widely to tissues and body fluids except for cerebrospinal fluid.
Erythromycin effective against Gram-positive organism (staphylococci and streptococci; because
these accumulate the drug more efficiently). Some activity against Gram-negative bacteria (such as Legionella spp., Campylobacter spp., and Bordetella pertussis). Haemophilus influenzae is somewhat less susceptible.
Efflux and methylase production are the most important
resistance mechanisms in gram-positive organisms.
rickettsia rickettsii causes & treatment
ricky mountain spotted fever tetracyclines early in the disease process
chlamydia psittaci causes & treatment
psittacosis ~pneumonia doxyxyxline or azithromycin
Tetracycline Therapeutic uses
Acne Cholera Chlamydial infections (MRSA) Lyme Disease Atypical pneumonia Rocky mountain spotted fever Gastric and duodenal ulcer
As compared to tigecycline and eravacycline
Omadacycline has lower protein-binding and available as oral formulation.
Minocycline Undergoes hepatic metabolism and
eliminated lesser extent via the kidney.
Tetracycline should be taken on
empty stomach (absorption is impaired by food, calcium interference) Incomplete GI absorption (60-70%).
Minocycline Concentrates in the
endolymph of the ear and affects functions (dizziness, vertigo, and tinnitus-high doses or prolonged administration).
corynebacterium diptheriae
erythromycin or penicillin is used to eliminate the carrier state
Demeclocycline should be taken on empty stomach
(absorption is impaired by food, calcium interference). Incomplete GI absorption (60-70%). Eliminated mainly in bile and urine.
Intermediate-acting:
Demeclocycline
Minocycline therapeutic uses
Acne Cholera Chlamydial infections Community-acquired MRSA Lyme Disease Atypical pneumonia Dental use [to treat periodontitis].
Tetracyclines
Bacteriostatic agents Inhibits protein synthesis
Pseudotumor cerebri (tetracyclines)
Benign, intracranial hypertension characterized by headache and blurred vision may occur rarely in adults.
post antibiotic effect aminoglycosides
(persistent suppression of bacterial growth after removal of antibiotic) Clinical utility is limited due to serious toxicities. Patients on aminoglycosides should have their serum creatinine monitored to detect nephrotoxicity.
Eravacycline
A novel fully synthetic fluorocycline, consists of the tetracyclic core scaffold with unique modifications in the tetracyclic D ring.
Omadacycline Therapeutic uses:
Acute Bacterial Skin and Skin Structure Infections (ABSSSI) Community-Acquired Bacterial Pneumonia (CABP)
Azithromycin (semisynthetic derivative of erythromycin)
Additional activity against gram-negative organism - Haemophilus influenzae, Neisseria gonorrhoeae, and Chlamydia spp Less effective than erythromycin against gram-positive organisms (staphylococci and streptococci).
Pregnancy (tetracyclines)
All tetracyclines cross the placental barrier and concentrate in fetal bones and dentition. Bind to tissues undergoing calcification (for example, teeth and bones) or to tumors that have high calcium content.
Macrolide resistance can be conferred by chromosomal mutations leading to
Alteration of the 50S ribosomal binding site Production of methylases that alter the 50S binding site. - Production of esterases that degrade macrolides Reduced permeability of the cell membrane or active efflux.
mycoplasma pneumonia
Azithromycin or doxyxyxline
Aminoglycosides inhibits protein synthesis and are
Bactericidal agents Concentration-dependent bactericidal activity against gram-negative aerobes. Require O2 for uptake; therefore, ineffective against anaerobes.
at higher concentration macrolides can be
Bactericidal and activity in enhanced at alkaline pH
Demeclocycline therapeutic uses:
Chronic hyponatremia off-label in the treatment of syndrome of inappropriate secretion of antidiuretic hormone (SIADH)
Tigecycline therapeutic uses
Complicated skin and subcutaneous infections. Complicated intra-abdominal infection. Community-Acquired Bacterial Pneumonia (CABP).
Effects on calcified tissues (tetracyclines)
Deposition in the bone and primary dentition occurs during the calcification process in growing children. This may cause discoloration and hypoplasia of teeth and a temporary stunting of growth (limited in pediatrics).
Only tetracycline not contraindicated in renal failure
Doxycycline Primarily eliminated via the bile into the feces No dose adjustment
Long-acting:
Doxycycline, Minocycline
Tetracyclines selective action -
Higher uptake by bacterial than by human cells. Bacteriostatic effect. Limited CNS penetration.
Telithromycin adverse effects
Increase in gastrointestinal motility. Arrythmia caused by prolonged QT interval (due to an effect on potassium channels). Acute cholestatic hepatitis; rash and eosinophilia. Exacerbation of myasthenia gravis (contraindication). Respiratory failure.
Clarithromycin adverse effects
Increase in gastrointestinal motility. Arrythmia caused by prolonged QT interval Acute cholestatic hepatitis. Rash and eosinophilia. Clostridium difficile diarrhea.
Clarithromycin (semisynthetic derivative of erythromycin)
Increased activity against Haemophilus influenzae.
Telithromycin (third semisynthetic derivative of erythromycin; ketolide)
Its higher affinity for the 50S subunit and its lack of induction of expression of some genes mediating resistance allows telithromycin to be used in treating infections by macrolide-resistant gram-positive strains. Bactericidal against gram-positive bacteria.
Demeclocycline MOA
Protein synthesis inhibitor (30S ribosomal unit)
Doxycycline MOA
Protein synthesis inhibitor (30S ribosomal unit)
Minocycline MOA
Protein synthesis inhibitor (30S ribosomal unit)
Eravacycline MOA and adverse effects
Protein synthesis inhibitor (30S ribosomal unit) Nausea and vomiting
Tigecycline MOA & adverse effects
Protein synthesis inhibitor (30S ribosomal unit) Nausea, vomiting, acute pancreatitis (including fatality), elevation of liver enzymes and serum creatinine.
Omadacycline Mechanism of action and adverse effects
Protein synthesis inhibitor (30S ribosomal unit) Nausea, vomiting, headache, diarrhea, insomnia, constipation, elevation of liver enzyme.
Telithromycin MOA & therpeutic use
Protein synthesis inhibitor (50S ribosomal unit). Higher affinity for the 50S ribosomal submit due to ability to bind an additional site on 23S rRNA. Respiratory tract infections (including atypical pneumonias and soft-tissue infections).
Phototoxicity (tetracyclines)
Severe sunburn may occur in patients receiving a tetracycline who are exposed to sun or ultraviolet rays. Patients should be advised to wear adequate sun protection.
Omadacycline
Synthetic aminomethylcycline derivative of minocycline Broader spectrum of activity than tetracyclines; infections requiring deep tissue penetration.
Short-acting:
Tetracycline
Tetracycline Resistance
The most commonly encountered naturally occurring resistance to tetracyclines is an efflux pump ↑ efflux out of bacterial cells by plasmid-encoded transport pumps.
Long-acting (new class):
Tigecycline, Eravacycline, Omadacycline
Tigecycline is poorly
absorbed orally and must be administered intravenously
Aminoglycosides used for treatments of serious infections due to
aerobic gram-negative bacterial infections (Pseudomonas aeruginosa, Klebsiella pneumoniae, and Enterobacter spp.).
tetracycline can enhance the
anticoagulant effects in patients taking warfarin. and the effects of neuromuscular blocking drugs.
chlamydial infections
azithromycin or doxycycline are perferred therpeutic options
Doxycycline achieve therapeutic levels in the
cerebrospinal fluid (CSF) Tetracycline-resistant strains may be susceptible to doxycycline.
Minocycline achieves therapeutic levels in the
cerebrospinal fluid (CSF) and achieves high-concentrations in saliva and tears
Tetracyclines Not given to
children less than 8 years of age due to its deposition in bone or teeth (Warning/contraindication).
vibrio cholerae is the common cause of... (&what is the treatment)
cholera doxyxyxline (reduces intestinal vibrios and fluid replacement)
mycobacterium avium complex
clarithromycin with rifampin and enthambutol once weekly azithromycin used with MAC prophylaxis in patients with AIDS
Mycoplasma pneumoniae is a common cause of... (& what is the treatment)
community acquired pneumonia in young adults living close to confines such as military camps doxycycline
when taking tetracyclines avoid
concomitant use with retinoic acid derivatives, such as acitretin (risk of intracranial hypertension).
Inside the cell, aminoglycosides causes
irreversible inhibition of initiation complex through binding to 16S rRNA of the 30S ribosomal subunit → mRNA misreading.
Doxycycline absorption GI 90-100% and
is not impaired by food (may be taken with food). Preferred in patients with renal failure.
Borrelia burgdorferi is a common cause of... (& what is the treatment)
lyme disease (via tick) doxycycline
Macrolides compounds characterized by a
macrocyclic lactone ring (usually containing 14 or 16 atoms) to which deoxy sugars are attached. Inhibits protein synthesis - Bacteriostatic agents.
Resistance to one tetracycline does
not confer universal resistance to all tetracyclines The development of cross-resistance may be dependent on the mechanism of resistance.
Tigecycline semisynthetic derivative
of minocycline; first member of the glycylcycline antimicrobial class.
Tetracyclines enter susceptible organisms via
passive diffusion and by an energy-dependent transport protein mechanism unique to the bacterial inner cytoplasmic membrane.
Tetracyclines absorption occurs mainly in the
upper small intestine and is impaired by multivalent cations (Ca2+, Mg2+, Fe2+, Al3+); by dairy products and antacids, which contain multivalent cations; and by alkaline pH.
Glycylcycline antimicrobial agents spectra of activity are
very broad, and many tetracycline-resistant strains are susceptible because they are not affected by the common resistance determinants.
Glycylcycline antimicrobial agents (derivative of tetracyclines)
were developed to overcome the emergence of tetracycline class-resistant organisms that utilize efflux pumps and ribosomal protection to confer resistance.
Aminoglycosides may be added to
ß-lactams for synergy for select serious gram-positive infections (Enterococcus spp.) β-lactams inhibit cell wall synthesis → facilitated entry of aminoglycoside drugs into the cytoplasm.
