3.TETRACYCLINES.docx

TETRACYCLINES Objective Understand the basic principles of antibiotics, with a focus on: Mechanism of action (MOA) Adverse effects Counseling points (including Administration details) Know brand and generic names for antimicrobial agents  Identify structural similarities and differences between a...

TETRACYCLINES Objective Understand the basic principles of antibiotics, with a focus on: Mechanism of action (MOA) Adverse effects Counseling points (including Administration details) Know brand and generic names for antimicrobial agents  Identify structural similarities and differences between antibiotics, in terms of spectrum of activity Review the spectrum of activity of each agent Daptomycin MOA: Binds to the cell membrane components of gram-positive organisms, causing rapid depolarization and cell death Bactericidal SOA: Covers only gram-positive bacteria, including MRSA Used in infective endocarditis, severe SSTI, osteomyelitis NOT for PNA, because it is inactivated by lung surfactant Dosing: 4 mg/kg for SSTI 6 mg/kg for MRSA bacteremia 8 mg/kg for Enterococcus ADEs: myopathy, elevated LFTs, and eosinophilic PNA Check CPK and LFTs at baseline and weekly Recommend to hold statins Polymyxins Colistin (Polymyxin E) and Polymyxin B SOA: Only gram-negative bacteria Reserved for MDR gram-negative infections ADEs: Nephrotoxicity, neurotoxicity 30S PROTEIN SYNTHESIS INHIBITORS TETRACYCLINES, AMINOGLYCOSIDES First-generation Tetracyclines: Doxycycline, Minocycline, Tetracycline Second-generation Tetracyclines: Tigecycline, Eravacycline, Omadacycline MECHANISM OF ACTION Tetracycline class spectrum Red: Gram – positive Yellow: Gram – negative, Anaerobes Green: Atypical Review of spectrum of activity These bugs are intrinsically resistant to the tetracyclines Tetracyclines Doxycycline, Minocycline, Tetracycline Mechanism of Action: Inhibit protein synthesis- binds to 30S ribosomal subunits Bacteriostatic MSSA and MRSA (susceptible isolates) Suppressive therapy Adverse effects: N/V/diarrhea, staining and deformity of teeth, esophagitis, photosensitivity, thrush, vertigo, liver toxicity, hyperpigmentation with long term use (minocycline) Doxycycline (Vibramycin) Tetracycline, IV/PO (First generation) Common ADEs: Photosensitivity, Diarrhea, Nasopharyngitis, Esophagitis Serious ADES: DRESS, Erythema multiforme, SJS, TEN, Hepatotoxicity, Hypersensitivity reaction, Pseudotumor cerebri Advise patient to use sunscreen and avoid tanning beds, as drug causes photosensitivity Take drug with adequate fluids to prevent esophageal irritation or ulceration, and with food to prevent gastric irritation Instruct patient to avoid concomitant oral use with iron, bismuth subsalicylate, or antacids containing aluminum, calcium, or magnesium Absorption: 90% Excreted mainly by nonrenal routes Long-half life: 18 hours Doxycycline doc for: Chlamydia trachomatis (has overtaken Azithromycin) Borrelia burgdorferi (Lyme Disease) Rickettsia rickettsii (Rocky Mountain Spotted Fever) Alternate agent to Azithromycin for Community-acquired pneumonia (CAP) for Streptococcus pneumoniae coverage Minocycyline (Minocin) Tetracycline, IV/PO (First-generation) 30s Ribosomal subunit inhibitor Common ADEs: Dizziness, Headache, Fatigue Severe ADEs: Long laundry list; Enamel hypoplasia, Tooth discoloration, Arrestment of bone development and/or growth; Pseudotumor cerebri Administer with or without food. Absorption: 90% Administer with adequate fluid to decrease the risk of esophageal irritation and ulceration. Widely distributed Liver metabolism Long half-life: 18-23 hours MINOCYCLINE doc for: Community-acquired-Methicillin-resistant Staphylococcus aureus (CA-MRSA) Add-on therapy for severe Stenotrophomonas maltophilia infections Add-on therapy for carbapenem-resistant Acinetobacter baumannii (CRAB) infections High-dose minocycline Standard Dose: Minocycline 100 mg IV/PO BID High-Dose: Minocycline 200 mg IV/PO BID Approved for use in severe Stenotrophomonas maltophilia infections Approved for use in CRAB The AMR 3.0 Guidelines even mention PD data stating a loading dose of 700 mg IV/PO x 1, followed by 350 mg IV/PO BID, when given in combination with medications like high-dose ampicillin/sulbactam. TETRACYCLINE Used in H. pylori infections; alternate agent for certain types of Syphilis in penicillin-allergic. Tetracycline, PO (First-generation) 30s Ribosomal subunit inhibitor Common ADEs: Tooth Discoloration Severe ADEs: Phototoxicity, Acidosis, Azotemia, Serum BUN elevated, Bulging fontanelle, Pseudotumor cerebri, Raised intracranial pressure Drug causes sun-sensitivity. Advise patient to use sunscreen and avoid tanning beds May Decrease effectiveness of OC Administer on an empty stomach (i.e., 1 hour prior to, or 2 hours after meals) to increase total absorption and with adequate amount of fluid to reduce risk of esophageal irritation and ulceration. Administer at least 1 to 2 hours prior to, or 4 hours after antacids and supplements because aluminum, magnesium, calcium cations may chelate with tetracycline and reduce its total absorption. Widely Distributed, but poor CSF penetration TIGECYCLINE (TYGACIL) TIGECYCLINE SPECTRUM Green: Gram-positive, Gram-negative, Anaerobes, Atypical Broad Spectrum Agent, but does not cover Pseudomonas aeruginosa, Providencia spp., and Proteus spp.; Black Box Warning!!! DO NOT USE unless you absolutely have to! TIGECYCLINE (TYGACIL) Glycylcycline, or 2nd Generation Tetracycline Common ADEs: GI: nausea (24-35%), vomiting (16-30%), diarrhea, abdominal pain; Headache Severe ADEs: Many!, Mortality (BBW), Acute pancreatitis, Elevated LFTs, Pseudotumor cerebri May reduce efficacy of OC Widely distributed. Vd = 500 to 700 L Long half-life: 42 hours at steady state ERAVACYCLINE (XERAVA) Fluorocycline, Tetracycline, IV (Second generation) 30s Ribosomal Subunit inhibitor Common ADEs: Infusion reaction, Nausea, Vomiting Serious ADEs: Many! Photosensitivity, Acute pancreatitis, Staining of teeth, Abnormal liver function, Arrest of bone development and/or growth, Pseudotumor cerebri, Azotemia, Serum BUN elevation High Protein Binding: 90% Long Half-life: 20 hours ERAVACYCLINE CLAIM TO FAME: Eravacycline is 2- to 4-fold more active against Gram-positive cocci, and 2- to 8- fold more active against Gram-negative bacilli compared to tigecycline Overcomes the “tet resistance genes” that confer resistance against the 1st Generation Tetracyclines OMADACYCLINE (NUZYRA) Tetracycline, IV/PO (Second generation; aminomethylcycline, a minocycline derivative) 30s Ribosomal Subunit inhibitor Common ADEs: Tooth discoloration, Enamel hypoplasia, Arrest of bone development and/or growth; Teratogenic; Nausea, Vomiting, Infusion reaction, Constipation, Diarrhea, ALT/SGPT elevation, GGT elevation, AST elevation, Headache, Insomnia Severe ADEs: Mortality imbalance was observed in the CAP trial*, Photosensitivity, Acidosis, Hyperphosphatemia, Clostridioides difficile diarrhea, Acute pancreatitis, Abnormal Liver function, Anaphylaxis, Hypersensitivity reaction, Azotemia, Serum BUN elevation Reduced efficacy of OC Bioavailability: 35% Instruct patient to fast for 4 hours before and 2 hours after taking tablets; take with plenty of water. No food or drink, except water Avoid consuming dairy products, antacids, or multivitamins with multivalent cations for 4 hours after taking tablets Large Volume of Distribution, Long Half-life: 16 hours OMADACYCLINE CLAIM TO FAME: Omadacycline is active in vitro against Gram-positive organisms that express efflux pumps (tet K and tet L) and ribosomal protection proteins (tet M), which confer resistance to tetracycline. Used for Non-tuberculous mycobacteria (NTM) Normal renal physiology Fanconi syndrome SELECT ACTIVITY, PK/PD INFORMATION Vd extremely high with tigecycline, leaving low serum concentrations (avoid in patients with sepsis because of increased mortality) PK-PD Principles Standard Counseling Point for Antibiotics Complete full course of antibiotics, even if you are feeling better! Take until all gone! Any antibiotic can cause antibiotic-associated diarrhea (and C. difficile colitis) DRUG SPECIFICS Self-assessment questions Tetracyclines inhibit bacterial growth by binding to bacterial _______________. Tetracyclines have excellent activity against ___________________. Because of problems with discoloration of teeth and deposition in bones, tetracyclines should not be used in ________________ and should be used with caution in ________________. Tigecycline is a member of the class of antibiotics called _________________. Tigecycline has activity against many highly resistant aerobic ______________ and _________________ bacteria. TETRACYCLINES TETRACYCLINES COUNSELING POINTS Report severe diarrhea; onset may occur up to 2 months after drug administration Use sunscreen and avoid tanning beds, as drug causes photosensitivity Report symptoms of pseudotumor cerebri or severe skin reactions Hyperpigmentation may be seen with minocycline Warn male and female patients to avoid pregnancy. Additional form of birth control recommended due to potential for decreased effectiveness of oral contraceptives ADMINISTRATION DETAILS Take drug with adequate fluids to prevent esophageal irritation or ulceration Instruct patient to avoid concomitant oral use with iron, bismuth subsalicylate, or antacids containing aluminum, calcium, or magnesium Take doxycycline with food to prevent gastric irritation Minocycline can be taken with or without food Tetracycline should be administered on an empty stomach (i.e., 1 hour prior to, or 2 hours after meals) to increase total absorption and with adequate amount of fluid to reduce risk of esophageal irritation and ulceration. Administer at least 1 to 2 hours prior to, or 4 hours after antacid because aluminum and magnesium cations may chelate with tetracycline and reduce its total absorption. Omadacycline should be taken on an empty stomach (after fasting ≥ 4 hours); no food or drink (except water) for 2 hours after administration. Avoid dairy and other products with multivalent cations (e.g., antacids, multivitamins) for 4 hours after administration. TIGECYCLINE (TYGACIL) TETRACYCLINES Binds to 30S ribosomal subunit → inhibit protein synthesis Bacteriostatic Can be used for MSSA and MRSA (if susceptible) Suppressive therapy AE – N/V/D, staining and deformity of teeth, esophagitis, photosensitivity, thrush, vertigo, liver toxicity, hyperpigmentation with long-term use (minocycline) TIGECYCLINE Derivative of minocycline Provides enhanced gram negative coverage, VRE, MRSA, some Acinetobacter spp. Lacks Pseudomonas spp., Providencia spp., and Proteus spp. coverage Used in severe SSTIs, intra-abdominal infections, CAP Not recommended for bacteremia Large Vd, thus poor blood concentrations Poor outcomes in pts receiving for non-FDA approved indications like HAP/VAP and sepsis (BBW ↑mortality)