Antibiotics: (Mycin, Micin, Vanc, Zolid, Mulin, and other Miscellaneous agents) Flashcards
Macrolides I
History
Erythromycin derived from Streptomyces erythreus from soil in the Philippines => Azithromycin developed by modifying erythromycin => Clarithromycin developed by modifying azithromycin
Structure contain 14 member macrocyclic lactone ring => Class name of macrolide
MOA
Macrolides I
Inhibit protein synthesis by binding to 50S ribosomal subunit
- Bacteriostatic
Spectrum of Activity
Macrolides I
Gram-positives:
- Streptococci (including S.pneumoniae)
Gram-negatives:
- Haemophilus influenzae
- Moraxella catarrhalis
Atypicals:
- Legionella pneumophila
- Chlamydophila pneumoniae
- Mycoplasma pneumoniae
Clinical Uses
Macrolides I
- Community-acquired pneumonia
- Pertussis
- Pharyngitis (alternative therapy)
- Chlamydia
- Gonorrhea (alternative therapy)
- H.pylori infection
- Infectious diarrhea
- Skin and soft-tissue infections (alternative therapy)
- Gastroparesis (erythromycin only)
Adverse Effect
Macrolides I
- Nausea, vomiting, diarrhea
‒- Erythromycin»_space; clarithromycin, azithromycin - Dysgeusia (clarithromycin)
- QTc prolongation and cardiac events
- Hepatotoxicity (rare)
FDA Warning: Cardiac Events
Macrolides I
Azithromycin (2013): Risk of QTc prolongation and fatal torsades de pointes (based on retrospective study)
- Increased risk of all cause mortality and cardiovascular mortality compared to no antibiotics
- Increased risk of cardiovascular mortality compared with amoxicillin or ciprofloxacin
- Risk higher in patients with known cardiovascular disease
Clarithromycin (2017): Increased risk of death in patients with heart disease (based on 10 year follow up of a randomized controlled trial)
- Evaluated clarithromycin or placebo for atherosclerosis in patients with
coronary heart disease
- Clarithromycin arm had an increased all cause mortality and cardiovascular mortality
DDI
Macrolides I
Erthromycin and Clarithromycin more likely to have interactions than azithromycin
Inhibition of; CYP3A4:P- glycoprotein/ABCB1:OATP1/B3
- Erythromycin: Moderate : Yes : No
- Clarithromycin: Strong : Yes : Yes
- Azithromycin: Minor : Yes : No
Additive QTc prolongation with other QTc prolonging agents(e.g., amiodarone)
Formulation
Macrolides I
Erythromycin:
- Oral: Tablet delayed-release, as base (Ery-tab®)
- Intraveneous: Solution, aslactobionate (Erythrocin®)
- Topical: Gel (Erygel®)
- Topical: Pad (Ery®)
Clarithromycin
- Oral: Tablet (Biaxin®)
- Oral: Suspension: (Biaxin)
Azithromycin:
- Oral: Tablet (Zithromax®, Zithromax Tri-Pak® (500 mg
PO daily x 3 days), Zithromax Z-Pak® (500 mg PO on day 1, then 250 mg PO on days 2-5))
- Suspension (Zithromax®)
- Packet: (Zithromax®)
- Intravenous :Solution (Zithromax®)
- Ophthalmic: Solution (Azasite®)
Linocosamides
History
Lincomycin: Isolated from Streptomyces lincolnensis from soil near Lincoln, Nebraska in 1962 (rarely used today)
Clindamycin:
- Developed from lincomycin in 1966
- Routinely used
- One of the first antibiotics associated with Clostridioides difficile infection
Chemical Structure and Mechanism of Action
Lincosamides
Inhibit protein sysnthesis by binding to 50S ribosomal subunit
- Can inhibit toxin production in necrotizing infections
- Bacteriostatic
Spectrum of Activity
Lincosamides
Gram-positives
- Staphylococci (including MRSA)
- Streptococci (including S.pyogenes)
Anaerobes
- Bacteroidesspp.
- Clostridium perfringens
- Fusobacterium spp.
- Peptostreptococcus spp.
Non-bacterial Organisms
- Toxoplasma gondii
- Pneumocystis jirovecii
- Babesia spp.
- Plasmodium spp.
Clinical Uses
Lincosamides
Skin and soft- tissue infections
Necrotizing fasciitis
Aspiration pneumonia
Bacterial vaginosis
Pneumocystis pneumonia (in combination with other agents)
Toxoplasmosis (in combination with other agents)
Malaria (in combination with other agents)
Acne vulgaris (topical)
Adverse Effects
Lincosamides
- GI: Diarrhea occurs in up to 20% of patients
- Clostridioides difficile infection (boxed warning)
– Clindamycin is considered a high risk antibiotic for causing C.difficile infections - Allergic reaction (cutaneous)
Formulation
Lincosamides
Clindamycin:
Oral:
- Capsule, hydrochloride Cleocin®
- Solution, palmitate
- hydrochloride Cleocin®
Intravenous Solution: (Cleocin Phosphate®)
Topical:
- Cream, vaginal (Cleocin®, Clindesse®)
- Foam, external (Evoclin®)
- Gel, external (Cleocin-T®, Clindagel®)
- Kit, external (Clindacin ETZ®, Clindacin Pac®)
- Lotion, external (Cleocin-T®)
- Solution, external (Cleocin-T®)
- Suppository, vaginal (Cleocin®)
- Swab, external (Cleocin-T®, Clindacin ETZ)
Clindamycin benzoyl peroxide
Topical:
Gel, external
- Acanya®
- BenzaClin®
- BenzaClin with Pump®
- Duac®
- Neuac®
- Onexton®
Kit, external
- Neuac®
Clindamycin and tretinoin
Topical Gel, external
- Veltin®
- Ziana®
Aminoglycosides
Mycin
Streptomycin: First aminoglycoside
- 1940s during screening of soil actinomycetes for antimicrobials
- Produced by Streptomyces griseus
Nomenclature varies
- Name ending in mycin: derived from streptomyces
- Name ending in micin: derived from micromonospora
Aminoglycoside Family
- Streptomycin: Streptomyces griseus:1944
- Neomycin: Streptomyces fradiae:1949
- Paramomycin: Streptomyces fradiae:1959: Part of neomycin family
- Gentamicin: Micromonospora spp. : 1963
- Tobramycin: Streptomyces tenebrarius: 1967: Natural derivative of kanamycin
- Amikacin: Streptomyces kanamyceticus: 1972: Semisynthetic derivative of kanamycin
- Plazomicin: Micromonospora spp.: 2018: Semisynthetic derivative of sisomycin
Chemical Structure
Aminoglycoside
Aminoglycosides contain amino sugars linked to an aminocyclitol ring by glycosidic bonds
MOA
Inhibit protein synthesis by binding to 30S ribosomal subunit
- Bactericidal activity
- Concentration: dependent killing
- Have post antiboitic effect
Spectrum of Activity
Aminoglycoside
Gram (+): limited activity
- May be used in combination with cell-wall active agent
Gram (-): Pesudomonas aeruginosa
- Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumanii,…
Other organisms:
- Mycobacterium tuberculosis, Non-tuberculous
mycobacteria, Some parasites
Clinical Use
aminoglycoside
- In combination for serious gram (-) infections
- In combination for multi-drug resistant gram (-) infections
- In combination for gram (+) endocarditis (gentamicin only)
- Urinary tract infections
- Mycobacterial infections
- Hepatic encephalopathy (neomycin, paramomycin)
Adverse Effects
Aminoglycoside
Nephrotoxicity
- Occur in 10-20% of patients
- Tend to be reversible
Ototoxicity:
- Manifest as vestibular toxicity or cochlear damage
- Can be irreversible
Neuromuscular blockade
Therapeutic Drug Monitoring
Serum Drug Concentration Monitoring
- Required for IV aminoglycosides
- Minimizes toxicity and resistance
- Maximize efficacy
Types of drug levels vary based on dosing strategy
Formulation
- Gentamicin:IV, Opththalmic (Ointment Gentak®) Topical
- Tobramycin:IV, Inhalation (Bethkis®, Kitabis Pak®, Tobi®) Ophthalmic (Tobrex®)
- Tobramycin and dexamethasone: TobraDex®, TobraDex ST® (Ophthalmic)
- Amikcin: IV and inhalation (Suspension:Arikayce®)
- Plazomicin: IV (solution: Zemdri)
- Streptomycin: Intramuscular/intravenous
- Paromomycin: Oral
- Neomycin: Oral
Glycopeptides
Vancomycin
First glycopeptide antibiotic
- Introduced into clinical practice for S.aureus infection
- Rarely used adter penicillinase-resistant beta-lactams
Gram Positive only:
- Staphylococci (including MRSA), Streptococci, Enterococci, Clostridioides difficile,…
Chemical Structure
Vancomycin
Tricyclic glycopeptide that contains a 7-membered peptide chain and an attached disaccharide composed of vancosamine and glucose
MOA
Inhibit cell wall synthesis
- Bind to D-alanyl-D-alanine terminus of cell wall precursors
Bactericidal
Features of time dependent and concentration dependent activity
Clincal Uses
Vancomycin
- Serious gram (+) infection: IV vancomycin ONLY
- Clostridiodies difficile infection: PO vancomycin ONLY
Adverse Effect
IV Vancomycin
Infusion reaction
- Histamine mediated infusion reaction
- Not an allergic reaction
- Avoided by limiting infusion rate (1000mg/60min)
Nephrotoxicity
- Incidence is variable
- Correlated with high through and high AUC
Ototoxicity
Therapeutic Drug Monitoring
Serum drug concentration monitoring
- Usually required for IV vancomycin
‒ Minimize toxicity, resistance
‒ Maximize efficacy
Monitoring strategy is changing
- Trough-based -> AUC/MIC-based
Formulations
Vanomycine:
- IV: Solution
- Oral (Capsules: Vancocin®, Solution: Firvanq®)
Macrolides III
Fidaxomicin
Macrolide-Like antibiotic
- Developed from Dactylsporangium auranticum
- Approved in 2011
- Inhibit Bacterial RNA Polymerase
- Bactericidal
Clinical Uses, Adverse Effects
Fidaxomicin
Narrow Spectrum of Activity
- Clostridioides difficile
Only used to treat C.difficile infections
- Reduced rate of infection recurrence compared with PO vancomycin
- Minimal systemic absorption = Minimal adverse effect
-
Formulation
Fidaxomicin
Fidaxomicin: Oral (Tablet and suspension: Dificid®)
Lipopeptide
Daptomycin
Early 1980: produced by streptomyces roseosporus
- Clinical trials in 1990s halted to skeletal muscle toxicity but reinteroduced in 2003 with one daily dosing
Spectrum of Activity
Gram (+) only:
- Staphylococci (including MRSA), Streptococci, Enterococci (including VRE), …
Some strains of enterococci have become daptomycin non- susceptible
Clinical Uses
Daptomycin
- Skin and soft-tissue infections
- Bacteremia
- Endocarditis
- Osteomyelitis
- Other serious gram-positive infections (cannot be used for pneumonia as it is inactivated by pulmonary surfactant)
Adverse Effects
Daptomycin
Generally well tolerated
Myopathy and/or rhabdomyolysis
- Uncommon
- Monitor creatinine phosphokinase (CPK) during treatment
Formulation
Daptomycin
Daptomycin: IV (Solution: Cubicin®, Cubicin RF®)
Lipoglycopeptides
Telavancin, Dalbavancin, Oritavancin
Semisynthetic derivative of glycopeptides
- Longer half-life
- Increased Potency
FDA Approval
- Telavacin (derivative of vancomycin) => Dalbavancin (derivative of teicoplanin) => Oritavancin (derivative of chloroeremomycin)
Chemical Structures
Lipoglycopeptides
Contain lipophilic side chains which serve to increase potency and half-life.
MOA
Lipoglycopeptides
Same as vancomycin
- Telavancin and oritavancin have an additional mechanism: Disrupting cell membrane integrity
- Bactericidal
Gram-positives only
- Streptococci, Enterococci (some strains of VRE),….
Clinical Uses
Lipoglycopeptides
Telavancin:
- Skin and soft-tissue infections, Hospital-pneumonia, Ventilator-associated pneumonia, Bacteremia
Dalbavancin and Oritavancin: Skin and soft-tissue infections only (single dose)
Adverse Effect
lipoglycopeptides
Telavancin:
- Infusion reaction (similar to vancomycin)
- Nephrotoxicity (boxed warning)
- QTc prolongation
Dalbavancin and oritavancin
- Infusion reaction (similar to vancomycin)
Formulation
Lipoglycopeptides
Telavancin: IV (Solution Vibativ®)
Dalbavancin: IV (Solution Dalvance®)
Oritavancin IV (Solution Orbactiv®, Kimyrsa®)
Oxazolidinones
Linezolid, Tedizolid
Prepared by organic synthesis
- Inhibit protein synthesis by binding to 50s ribosomal subunit
- Bacteriostatic
Gram-positives only;
- Streptococci, Enterococci (some strains of VRE)
Clinical Use
Oxazolidnones
Linezolid:
- Nosocomial pneumonia (S.aureus or S.pneumoniae), Community-pneumonia (S.aureus or S.pneumoniae), Skin and soft-tissue infections, VRE infections
Tedizolid: Skin and soft tissue infection
Adverse Effect
Oxazolidinones
Myelosuppression:
- Thrombocytopenia is most common blood dyscrasia
- Occurs at > 2 week of treatment
Mitochondial toxicity
- Peripheral neuropathy, optic neuritis, lactic acidosis
- Occur at > 4 weeks of treatment
Serotonin Syndrome (rare
AE is less common with tedizolid
DDI
Oxazolidinones
Risk of serotonin syndrome when used with proserotonergic drugs
- Linezolid is a reversible, nonselective MAOI
- Tedizolid is a weak MAOI (appears to have ↓ risk for this interaction)
Signs/symptoms
- Agitation, confusion, hallucinations, hyperreflexia, myoclonus, shivering, tachycardia
Formulation
Oxazolidinones
Linezolid: IV (Solution: Zyvox®) and Oral (Tablet, Suspension: Zyvox®)
Tedizolid: IV (Solution: Sivextro®) And Oral (Tablet: Sivextro®)
Pleuromutilins
Lefamulin (approved 2019)
Used in veterinary medicine and topical use in humans (retapamulin)
- Due to toxcicity concerns with older products
Inhibit protein synthesis by binding to 50S ribosomal subunit
- Bactericidal/Bacteriostatic
Spectrum of Activity
Lefamulin
Gram- positives
- Staphylococci (including MRSA), Streptococci (including S.pneumoniae)
Gram-negatives
- Haemophilus influenzae, Moraxella catarrhalis
Atypicals
- Legionella pneumophila, Chlamydophila pneumoniae, Mycoplasma pneumoniae
Clinical Uses and Adverse Effect
Lefamulin
Clinical Use:
- Community-pneumonia
Adverse Effect:
- Nausea, Diarrhea, QTc prolongation
DDI:
- Moderate CYP3A4 inhibitor,
- Additive QTc prolongation with other QTc prolonging drugs
Contraindication:
- Concommitant use with CYP3A3 substrates that prolong QTc
Formulation
Lefamulin
Lefamulin: IV (Solution: Xenleta®) and Oral (Tablet: Xenleta®)
IMPORTANT MESSAGE
- Many antibioties are derived from natural sources
- Macrolides are mainly used for respiratory infections
- Clindamycin was one of the first antibiotics to be associated with C. difficile infection
- PO Vancomycin and fidaxomicin can be used to treat C. difficile infection
IMPORTANT MESSAGE II
- Aminoglycosides have poten Gram-negative activity but limited by toxicities
- Vancomycin is GREAT for serious Gram-positive infection in hospital seting
- Vancomycin and aminoglycosides require therapeutic drug monitoring
- Liinezolid and daptommycin can be used to treat VRE infections
