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.