Pharm Week 13 (Antibiotics Part 2)

What is the spectrum of activity of macrolides (general)?

- Gram positive cocci

- Atypical pathogens (respiratory pathogens like Moraxella, Chlamydia)

What are the primary indications for macrolides?

- Respiratory infections

- Skin and soft tissue infections

What are limitations of erythromycin (very first macrolide)?

- Insufficient activity against H. influenzae (not really used in respiratory inf. anymore because of this)

- Unstable in gastric acid

- Poor oral bioavailability, need for frequent dosing

What are some added properties of azithromycin due to the addition of methyl nitrogen at C9?

- Increased acid stability

- Longer T 1/2

- Sufficient activity against H. influenzae

What are some added properties of telithromycin (ketolides) due to the replacement of the l-cladinose moiety at C3 with a 3-ketone?

Increased bacterial potency against macrolide resistant bacteria

Why was telithromycin discontinued in the US?

Due to respiratory failure

What are the different macrolides?

- Erythromycin

- Clarithromycin

- Azithromycin

- Telithromycin

What is the mechanism of action of macrolides?

Inhibition of RNA dependent protein synthesis by binding to the 23S ribosomal RNA molecule of the 50S ribosomal subunit

This then:

- Blocks elongation of growing peptide chain

- Blocks translocation and tRNA production

- Stimulate the dissociation of t-RNA from ribosomes

What are some pharmacodynamic properties of macrolides?

- Bacteriostatic effect

- Exhibits both concentration dependent and independent killing effects (increasing the dose leads to good killing activity of the abx)

- Post-antibiotic effect

The post antibiotic effect of macrolides is longer in:

- Gram positives

- Streptococci (than in Staphylococci)

What gram-positive bacteria do macrolides have activity against?

- Streptococcus pneumoniae

- Streptococcus pyogenes

- Staphylococcus aureus (MSSA)

What atypical bacteria do macrolides have activity against?

- Mycoplasma pneumoniae

- Chlamydia pneumoniae

- Legionella pneumophila

Which gram-negative bacteria do macrolides have activity against?

- Haemophilus influenze

- Moraxella catarrhalis

- Neisseria gonorrhea

mostly associated w/respiratory infections

What other organisms do macrolides have activity against?

- Helicobacter pylori

- Pasteurella multocida

- Mycobacterium avium

Which bacteria are macrolides NOT active against?

- MRSA

- Enterococci

What bacteria have resistance to erythromycin?

- S. pneumoniae (>27% in 1997)

- H. influenzae and Staph aureus also on the rise

If a bacteria has resistance to erythromycin, would you prescribe azithromycin?

no! switch to another class

What are the indications for erythromycin?

- Upper and lower respiratory tract infections

- Skin and soft tissue infections

- Sexually transmitted diseases

- Pelvic inflammatory disease

- Gastroparesis (off-label use)

What are the indications for clarithromycin?

- Pharyngitis/tonsillitis

- Acute exacerbation of chronic bronchitis

- MAC prophylaxis

- Community acquired pneumonia

- Otitis media

- Skin and soft tissue infections

- H. pylori infection

What are the indications for azithromycin?

- Pharyngitis/tonsillitis

- Acute exacerbation of chronic bronchitis

- MAC prophylaxis

- Community acquired pneumonia

- Skin and soft tissue infections

- Sexually transmitted diseases

What is the absorption of macrolides?

Generally low to moderate oral bioavailability

Effect of food varies by formulation

What is the distribution of macrolides?

Large volume of distribution

What is the metabolism of macrolides?

Display affinity for CYP450 EXCEPT azithromycin

What is the elimination of macrolides?

Primarily biliary excretion, renal excretion limited to clarithromycin

Which macrolide has renal excretion?

Clarithromycin

Which macrolide does NOT display affinity for CYP450?

Azithromycin

A patient presents with an upper respiratory tract infection. They have a past medical history of kidney dysfunction and have multiple daily medications. You want to prescribe a macrolide to treat the URI. Which macrolide would be most appropriate?

Azithromycin

It has biliary excretion (will bypass the kidneys) and has little affinity to CYP450 (will not interfere with the other meds the patient is taking)

Which macrolides have interactions with the CYP450 system?

Erythromycin and clarithromycin are CYP3A inhibitors

What are examples of CYP3A4 substrates that can potentially interact with macrolides?

- Statins

- R-warfarin

- Digoxin

- Carbamazepine

- Triazolam

- Midazolam

- Cyclosporin

- Disopyramide

- Ergot alkaloids

- Felodipine

- Valproic acid

- Alfentanil

- Sulfentanil

- Clozapin

What are the adverse effects of macrolides?

Generally well tolerated

- GI intolerance

- Dysgeusia with clarithromycin (altered tase)

- Hepatitis/cholestatic jaundice (erythromycin estolate)

- Infusion site reactions (erythromycin lactobionate)

- QTc prolongation (erythromycin lactobionate)

- Adverse effects in pregnancy

Which macrolide has ADR of dysgeusia (distorted sense of taste)?

Clarithromycin

Which macrolide has ADR of hepatitis/cholestatic jaundice?

Erythromycin estolate

Which macrolide has ADR of infusion site reactions and QTc prolongtion?

Erythromycin lactobionate

Which macrolides are contraindicated in pregnancy?

Category B:

- Erythromycin

- Azithromycin

Category C:

- Clarithromycin (more teratogenic)

Why is erythromycin used off label to treat gastroparesis?

It will trigger gastric inflammation to help treat the immobility in gastroparesis

What is fidaxomicin?

Dificid, therapeutic category macrolide but has different clinical use

What is the mechanism of action of fidaxomicin (Dificid)?

Inhibits RNA polymerase

What is fidaxomicin (Dificid) indicated for?

Treatment of C. difficle infection (CDI)

How does fidaxomicin work for CDI?

Fidaxomicin is not absorbed well systemically, will sit in the GI tract

When given orally for C. diff infection, it will concentrate in the cellular tissues of the gut in order to eradicate the bacteria

What are some adverse effects of fidaxomicin (Dificid)?

- GI-related nausea and vomiting

- Abdominal distension

- Bloating

Which is superior for C. diff infection: fidaxomicin or oral vancomycin?

Fidaxomicin non-inferior to oral vancomycin (aka neither is superior)

Controversy on whether or not it prevents future recurrence of infection

How is oral vancomycin used to treat C. diff infection?

Vancomycin will be given as IV first to treat the inflammation in the gut associated with C. diff

After this has been treated, oral vancomycin is started to sit in the gut and get rid of the infection itself

What is clindamycin?

Lincosamide, acts at the same site in the 50 S ribosomal subunit as macrolides

What is the spectrum of activity of clindamycin?

Gram positives:

- Streptococcus spp.

- MSSA

- Community acquired-MRSA

Anaerobes:

- B. fragilis

- Clostridium perfringens (cause of gas gangrene)

Other pathogens:

- Pneumocystis jiroveci

- Toxoplasmosis gondii

What are some adverse effects of clindamycin?

Generally well tolerated and absorbed

Main ADR: GI effects

If diarrhea occurs, monitor for pseudomembranous colitis (C. difficile)

What are the indications of clindamycin?

Very popular for skin infections (cellulitis, gangrenous cellulitis) since it covers Clostridium perfringens

What are the streptogramins?

Quinupristin/Dalfopristin

Combination drug that acts synergistically to inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit

What is the spectrum of activity of quinipristin/dalfopristin (streptogramins)?

- Bactericidal against Staphylococci and Streptococci

- Bacteriostatic against Enterococcus faecium and Vancomycin-resistant strains

- Gram positive bacteria including MRSA

NO activity against E. faecalis (intrinsically resistant)

Which enterococcal species do streptogramins have activity against?

E. faecium and Vancomycin-resistant strains

NOT E. faecalis

What are the indications for streptogramins?

- Bacteremia

- Pneumonia

- SSSIs

What are some adverse effects of streptogramins?

- Phlebitis (is IV central line only, can cause local pain and irritation at infusion site)

- Myalgias

- Arthralgias

- Hyperbilirubinemia

What are the first generation tetracyclines?

- Chlortetracycline

- Oxytetracycline

- Tetracycline

- Demeclocycline

What are the second generation tetracyclines?

- Methacycline

- Doxycycline

- Minocycline

What are the third generation tetracyclines?

Tigecycline

What is the mechanism of action of tetracyclines?

Inhibit bacterial protein synthesis by:

- Binding to 30S ribosomal subunit

- Preventing access of tRNA on the mRNA ribosome complex

- Preventing addition of a new amino acid in a growing peptide chain

How do tetracyclines enter bacteria to exhibit their activity?

By passive diffusion through porins by an energy dependent process

What is the spectrum of activity of tetracyclines?

BROAD!!

- Gram positive

- Gram negative

- Chlamydia sp.

- Mycoplasma sp.

- Spirochetes

- Rickettsia sp.

What are the indications for tetracyclines?

Respiratory infections:

- Atypical pneumonia

Genital infections:

- Chlamydia trachomatis (non-gonococcal urethritis, PID, lymphogranuloma venereum)

- Granuloma inguinale

Systemic infections:

- H. pylori infection

- Rickettsia (Rocky Mountain spotted fever, endemic and epidemic typhus, Q fever)

- Brucellosis

- Lyme borreliosis

- Ehrlichiosis

- Vibrio cholera

Other:

- Acne vulgaris

- Mefloquine resistant Plasmodium falciparum malaria

What is the absorption of tetracyclines?

- Incompletely absorbed from the GI tract

- Greater in fasting state

- Impaired with polyvalent ions due to chelation (Ca, Al, Mg< Fe, Zn, Cr)

What is the distribution of tetracyclines?

- Widely distributed in body tissues and fluids

- Poor in CSF

What is the metabolism of tetracyclines?

Enterohepatic circulation

What is the elimination of tetracyclines?

- Renal

- Hepatobiliary tract

What are the drug interactions associated with tetracyclines?

- Chelation with multivalent cations (Mg, Al, Fe, Ca, Zn, Cr)

- Reduces effectiveness of oral contraceptives

- Potentiate effects of oral anticoagulants

- Increased hepatic metabolism and clearance of carbamazepine, barbiturates, chronic ethanol ingestion

**Less propensity of interactions with doxycycline

There is less propensity of drug interactions with which tetracycline?

Doxycycline

What are some adverse effects associated with tetracyclines?

- Deposition in the bones (inhibits bone growth, tooth discoloration --> CI in pregnancy, breastfeeding, children <8)

- Hepatotoxicity (acute fatty necrosis with high dose therapy, caution in pregnant women, pts with renal failure)

- Photosensitivity

- Hypersensitivity reactions (including anaphylaxis, urticaria, rash)

What are the specific adverse effects of minocycline?

- Skin and mucous membrane pigmentation (to blue or blue-black appearance)

- Vestibular side effects (dizziness, ataxia, vertigo)

What are the specific adverse effects of doxycycline?

- Esophageal ulceration (caps > tablet)

Minimized with adequate fluid intake

What are the specific adverse effects of tetracycline?

- Gastrointestinal intolerance

- Diarrhea

- Fungal superinfection (caution in critical care patients)

What is tigecycline?

Similar structure to minocycline, but with added side chain (to improve coverage and decrease ADRs)

What is the spectrum of activity of tigecycline?

Broad coverage of gram-positives, gram-negatives, anaerobes, atypicals

Includes activity vs. MRSA, VRE but NO pseudomonas activity

Can develop resistance to Proteus, Providencia, and Morganella spp.

What are some adverse effects of tigecycline?

- Nausea and vomiting (20-30%)

- Pancreatitis (rare)

- Tetracycline class AEs

- BBW: increased mortality

What is the black box warning associated with tigecycline?

Increased mortality (should be reserved for use in situations when alternative treatments are not suitable)

What is the mechanism of action of aminoglycosides?

Bind to 30S ribosomal subunit to exhibit bactericidal effect

How are aminoglycosides administered?

Poorly absorbed from the gut --> usually given parenterally for systemic infections

Occasionally given orally for GI infections

Topically for skin infections, mucous membranes, ocular tissue

What are the different aminoglycosides available?

IV/IM:

- Gentamicin

- Tobramycin

- Amikacin

IM:

- Streptomycin

PO:

- Neomycin

- Paromomycin

Which aminoglycoside is part of triple antibiotic with polymixin B and bacitracin?

Neomycin

What is the spectrum of activity of aminoglycosides?

Gram negatives ONLY:

- Pseudomonas: Tobra > Amk > Gent

- Resistant organism: Amk is better option

Gram positives only works for synergy with cell wall active agent --> gentamicin >> others

Mycobacteria:

- Streptomycin best for TB

- Amikacin best for non-TB

What are some adverse effects of aminoglycosides?

- Nephrotoxicity (nonoliguric azotemia, increased BUN and SCr)

- Ototoxicity

How do aminoglycosides cause nephrotoxicity?

Accumulation of aminoglycosides in the renal tubule, a saturable process, is an initiating factor

Elevated troughs have been linked to increased toxicity (monitor the trough and make sure the abx is not lingering too long in the body)

Nonoliguric azotemia is seen due to proximal tubule damage, can see increase in BUN and serum Cr

What are risk factors for development of nephrotoxicity or ototoxicity with aminoglycosides?

- Prolonged high troughs

- Long duration of therapy (>2 weeks)

- Underlying renal dysfunction

- Elderly

- Other nephrotoxins (ex. vancomycin)

How do aminoglycosides cause ototoxicty?

Accumulation of drug in the labyrinth and hair cells of the cochlea

Can cause 8th cranial nerve damage (which sometimes can be irreversible)

What are signs and symptoms of ototoxicity in response to aminoglycosides?

- Vestibular: dizziness, vertigo, ataxia

- Auditory: tinnitus, decreased hearing, deafness

What kind of dosing do we use with aminoglycosides?

Extended-interval dosing

What are the advantages of extended-interval dosing with aminoglycosides?

- Convenience

- Increased bactericidal activity

- Provides drug-free interval

- Requires normal renal function

What are the oxazolidinones?

Linezolid and tedizolid

What is the mechanism of action of oxazolidinones?

Inhibits bacterial protein synthesis by binding to bacterial 23S ribosomal RNA of the 50S subunit

What is the spectrum of activity of oxazolidinones?

Active against gram-positives (including MRSA and VRE!)

These are broad spectrum for gram positive infections

What are the indications for oxazolidinones?

- Skin and soft tissue infections

- Pneumonia (MRSA, very good lung penetration)

- VRE infections

Oxazolidinones have excellent:

Oral bioavailability

IV = PO

What are some adverse effects associated with linezolid?

- Thrombocytopenia (2-4%, usually with tx > 2 weeks, reversible)

- Serotonin syndrome (weak MAOI, avoid with sympathomimetic and dopaminergic agents)

- Peripheral and optic neuropathy (with tx >28 days)

- Lactic acidosis (rare)

What are some features of tedizolid?

- IV and oral formulations (80% bioavailability)

- Once daily dosing (half-life 12 hours)

- Infused over 60 minutes (IV)

- No dose adjustment for renal/hepatic impairment

What are the indications for tedizolid?

Acute bacterial skin and skin structure infections

What are some adverse effects of tedizolid?

Designed to have less of the traditional oxazolidinone adverse effects

Main one is neutropenia (monitor CBC with diff)

What is the mechanism of action of mupirocin (Bactroban)?

Prevents bacterial synthesis by binding to tRNA synthetase

What is the spectrum of activity of mupirocin?

Active against most staphylococci (including some MRSA strains)

What are the indications for mupirocin?

Effective topical therapy (creams and ointments) for impetigo

Also used to eradicate nasal colonization of MRSA, but this was discontinued

Why were several fluoroquinolones withdrawn from the market?

Due to toxicity from QTc prolongation

What are the second generation fluoroquinolones?

- Ciprofloxacin

- Ofloxacin

What are the third generation fluoroquinolones?

- Levofloxacin

- Moxifloxacin

Which fluoroquinolones are for ophthalmic use only?

Besifloxacin and gatifloxacin