Tetracycline, Vancomycin, Linezolid

Question 1

Vancomycin Chemistry

Answer 1

(Vancosin)

Complex tricyclic glycopeptide

Question 2

Vancomycin Spectrum of Action

Answer 2

Bacteriocidal VS Most Gram+ cocci and bacilli and blocks cell wall synthesis; IV Vancomycin used to treat sepsis or endocarditis caused by MRSA, Oral Vancomycin used to treat colitis caused by C. difficile - Poorly absorbed so remains GI tract; Oral Vancomycin used when Metronidazole (Flagyl) use is contraindicated in presence of liver disease or alcoholism or when 2 14-day courses of Metronidazole are ineffective; Oral Vancomycin is first drug choice for recurrent of severe C.difficile infection with AAC

Question 3

Vancomycin Mechanism of Action

Answer 3

Bacteriocidal, Inhibits cell wall synthesis by binding very tightly to acyl-D-alanyl-D-alanine terminus of cell wall precursor unit to inhibit peptidoglycan polymerization leading to cell lysis

Question 4

Vancomycin Pharmacokinetics

Answer 4

Administered IV for systemic action or oral for GI action, Well distributed including CSF inflammation, Excreted in urine as unchanged or does not concentrate in bile, 55% bound to proteins

Question 5

Vancomycin Resistance

Answer 5

Resistance to Vancomycin occurs when bacterium acquire DNA encoding enzymes that make D-Ala-D-Lactate that does not bind Vancomycin well - 2 enzymes are responsible - Van H is dehydrogenase that makes D-Lactate from pyruvate and Van A is ligase that links D-Ala to D-Lactate

Question 6

Vancomycin Adverse Effects

Answer 6

Rapid IV causes red-neck or red-man syndrome (flushing, tachycardia, hypotension and rash over neck, face, chest, wheezing, difficulty breathing), Due to Histamine release - Give IV slowly to avoid or pre injection antihistamines; Ototoxic - Permanent hearing loss possible, Nephrotoxic Less with current preparations

Question 7

Vancomycin Dosing

Answer 7

Vancomycin HCl pulses/Oral Vancomycin - First line therapy for initial or recurrent of severe CDI - Rx Vancomycin 125mg capsule, q6h 10-14days, Ineffective for systemic infections; Second recurrence treated with Oral Vancomycin tapered over 4wks - Pulse dosing prescription 1capsule q2-3days for 2-8wks; Systemic Infection - Rx Vancomycin 7.5mg/kg BW or 500mg-1g IV - 6-12hrs

Question 8

Teicoplanin

Answer 8

Similar to Vancomycin, IM or IV, Nephrotoxicity and Ototoxicity rare

Question 9

Linezolid

Answer 9

(Zyvox) Oxazolidinones; Active VS Gram+ organisms, Mycobacterium TB, Used for VRSA, Belong to oxazolidinones class of antibiotics, Inhibit protein synthesis by binding to 23S ribosomal RNA of 50S subunit and prevent formation of ribosome complex that initiates protein synthesis; Other agents- Prosizolid, Tedizolid

Question 10

Linezolid Pharmacokinetics

Answer 10

Taken oral with full bioavailability, T1/2 = 4-6hrs, No effect on P450 enzyme system, Dose is 600mg twice daily, Oral

Question 11

Linezolid Uses

Answer 11

Used to treat Vancomycin resistant E. faecium infections, pneumonia, and skin and soft tissue infection - Off-label use to treat multi-drug resistant TB and Nocardia infections

Question 12

Linezolid Adverse Effects

Answer 12

Short Term - Nausea, Vomiting, Diarrhea, Headache, Rash
Long Term - Bone marrow suppression, thrombocytopenia, constipation, dizziness, peripheral neuropathy, optic neuropathy, lactic acidosis are late onset side effects; Teeth and tongue discolor
Weak MAOI action - Cause Serotonin syndrome with SSRI, meperidine etc avoid tyramine rich foods

Question 13

Linezolid Drug Intercations

Answer 13

Monitor concurrent admin of sympathomimetic agents and Linezolid - Increase BP
Mechanism of synergistic sympathomimetic effect due to enhanced NE storage in adrenergic neurons (MAOI activity) and increased liberation of catecholamines (Indirect sympathomimetic activity)

Question 14

Quinupristin-Dalfopristin Mechanism of Action

Answer 14

Streptogramins; Combine Quinupristin (Strept-B) and Dalfopristin (Strept-A) in 30:70 ratio - Synergistic - A binds to 23S (of 50S) and changes conformation so B is 100X enhanced - A Inhibits peptidyl transferase - B binds 50S and prevents elongation of polypeptide (Clindamycin and Macrolides)
Bacteriocidal against many organism - Gram + cocci including MDR Strep, penicillin resistant S. pneumonia MRSA and Enterococcus faecium (not cidal) - Used to treat bone and joint infections = Bacteremias - E.faecalis is intrinsically resistant

Question 15

Quinupristin-Dalfopristin

Answer 15

Streptogramins; Administer IV, Eliminate fecal, Both inhibit CYP3A4 which metabolizes warfarin, cyclosporin, NNRTI, resistance due to ribosomal modification, enzyme inactivation of Dalfopristin or efflux, Arthralgias and myalgias were most common adverse events related to treatment

Question 16

Tetracycline

Answer 16

Weak bases supplied as HCl salts, Broad spectrum of action, Factors influence healing, Positive effect on bone mineralization and repair (Impair osteoclast production and reduce bone resorption in osteoporosis by inhibiting MMPs), Inhibitory effects seen on osteoclast function and development could be detrimental to fracture repair (Fracture callous resorption and bone remodeling in later stages of fracture healing rely on intact osteoclast populations; therefore, inhibition of osteoclast function or decrease in osteoclast number could prolong bone healing); Treats periodontitis - GCF, strips to deliver, Doxycycline by reducing inflammation

Question 17

Tetracycline Mechanism of Action

Answer 17

Inhibits protein synthesis by binding to 30S subunit of ribosomes to prevent binding of aminoacyl-tRNA to acceptor (A) site on mRNA-ribosome complex, Primary bacteriostatic but may be bactericidal at high concentrations, Sub-antimicrobial doses 20mg inhibit metalloproteinases that degrade tissue so can be used to treat periodontitis

Question 18

Doxycycline Mechanism

Answer 18

Decreases MMP activity in by decreasing liberation of osteoclast stimulating cytokines TNFalpha-IL6 and IL1beta, Binds Zn making it unavailable for MMP transcription and binds direct to MMP

Question 19

Tetracycline Resistance

Answer 19

Increase efflux, Decrease influx, Decrease access of drugs to ribosomes due ribosome protection proteins

Question 20

Tetracycline Pharmacokinetics

Answer 20

Oral but parenteral preparations available, Doxycycline rapidly and almost completely absorbed from GI tract after oral - Absorption best under acidic conditions, Partially inactivated in GI tract by chelation (Tetracycline HCl - empty stomach, Doxycycline & Minocycline - Nondairy 2hr before bed - Reduce esophageal irritation/ulcer), Cleared unchanged by renal and bile secretion, Liver is not involved in metabolism of Doxycycline,

Question 21

Tetracycline Interactions

Answer 21

Metal ions in antacids; Absorption impaired by di and trivalent cations - Milk products, Ca and Mg salts, Al(OH)3 gets, Fe preparations, Mechanism include chelation to form non absorbable products, Quinapril (Accupril) - MgCO3 and Mg-stearate - Tablets USP w/Quinapril HCl - Each tablet with lactose monohydrate, magnesium carbonate, magnesium stearate, iron oxide - take incompatible preparations 2-3hr apart - Take tetracycline on empty stomach or 60min before/after meal; Enhance warfarin, sulfonylureas, digoxin, lithium, theophylline, furosemide, methotrexate, reduce effectiveness of OC, barbiturates and phenytoin reduce action of Doxycycline

Question 22

Tetracycline Adverse Effects

Answer 22

Bind to tissue undergoing calcification - during formation of bone, dentine and enamel of unerupted teeth, Deposition in bone and teeth leading to fluorescent, discolored bands, enamel hypoplasia, deformity and growth inhibition - Avoid during last half of pregnancy and in children > 9yrs, Liver toxicity particularly during pregnancy in patients with preexisting hepatic or kidney problems, Contraindicated in pregnancy, Photosensitization - particularly with demeclocycline; Vestibular reactions - Dizziness, nausea and vomiting with minocycline, GI effects, Superinfections - Intestinal, Vaginal or Oral candidiasis, Out of date tetracycline HCl can cause renal Fanconi syndrome (Aminoaciduria, Phosphaturia, Acidosis and Glycosuria); Contraindications - Pregnant, Children <9, Kidney disease &/Liver disease

Question 23

Tigecycline

Answer 23

Tygacil
Broad spectrum, Like Azithromycin - Accumulates in leukocytes, Parenterally, Reduces oral contraceptive and warfarin, Third choice drug, BBB possible increased mortality, Avoid in young and old, Not for ACC

Question 24

Tetracycline Dosing

Answer 24

Periodontal disease - Doxycycline (Periostat 20mg)
Acne - Doxycycline - 20mg 2X daily;
Doxycycline - 100/50mg - 11 capsules - 2 capsules PO 2hr prior to bed on Day 1 and 1 capsule 2hr prior to bed Day 2-10