4.AMINOGLYCOSIDES.docx

AMINOGLYCOSIDES 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...

AMINOGLYCOSIDES 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 Acronyms Tetracyclines MOA: Binds to 30s ribosomal subunit; thus, inhibiting protein synthesis Bacteriostatic Can be used for MSSA and MRSA (if susceptible), also covers atypicals Suppression therapy for MSSA and MRSA ADEs: N/V/D, staining and deformity of the teeth, esophagitis, photosensitivity, thrush, vertigo, liver toxicity, hyperpigmentation with long-term use (minocycline) Tigecycline (derivative of minocycline) SOA: Provides enhanced gram-negative coverage, VRE, MRSA, some Acinetobacter spp. Lacks Pseudomonas spp. Coverage FDA approved for cSSSI, cIAI, CABP NOT RECOMMENDED for bacteremia/sepsis Large Vd; thus, poor blood concentrations BBW = ↑ mortality; poor outcomes in patients receiving for non-FDA approved indications AMINOGLYCOSIDES GENTAMICIN Common TOBRAMYCIN Common AMIKACIN Common PLAZOMICIN Reserved for MDRO STREPTOMYCIN Gram positive synergy when gentamicin cannot be used, secondary IV agent for tuberculosis KANAMYCIN Secondary IV agent for tuberculosis NETILMICIN No longer available in the United States NEOMYCIN Used more as a topical agent; in triple antibiotic ointment AMINOGLYCOSIDES Structure of amikacin Aminoglycoside Spectrum Red: Anaerobes, Atypical Yellow: Gram – positive Green: Gram – negative Review of spectrum of activity Comparison of aminoglycosides Gentamicin DOC for gram positive synergy More nephrotoxic than tobramycin, less ototoxic than tobramycin No longer to be used for PsAr Tobramycin Better anti-pseudomonal activity than gentamicin and amikacin (more predictable) Less nephrotoxic than gentamicin, but more ototoxic Amikacin Reserved for organisms resistant to other aminoglycosides Only to be used for Pseudomonas aeruginosa in the urine Available as a liposomal inhalation suspension; can be used for Mycobacterium avium-intracellulare and cystic fibrosis (case-by-case basis) AMINOGLYCOSIDES Black box warnings Ototoxicity Nephrotoxicity Neuromuscular blockade Close monitoring for renal and eight-nerve function Concurrent therapy of other neurotoxic, nephrotoxic, and potent diuretics (ethacrynic acid, or furosemide) Teratogenicity (Embryo-fetal toxicity in Pregnancy) GENTAMICIN (GARAMYCIN) Aminoglycoside, IV/IM, ophthalmic 30s Ribosomal Subunit inhibitor Serious ADEs: Neuromuscular blockade finding, Ototoxicity, Nephrotoxicity, Respiratory tract paralysis (especially with concomitant anesthesia and muscle relaxants) Maintain adequate fluid intake and avoid dehydration during drug therapy, as this may increase risk of toxicity TOBRAMYCIN (NEBCIN, TOBI NEBS) Aminoglycoside, IV/IM, ophthalmic, inhalation 30s Ribosomal Subunit inhibitor Serious ADEs: Erythema multiforme, Erythroderma, SJS, TEN, Ototoxicity, Nephrotoxicity AMIKACIN (AMIKIN, ARIKAYCE NEBS) Aminoglycoside, IV/IM, inhalation 30s Ribosomal Subunit inhibitor Serious ADEs: Neuromuscular blockade finding, Ototoxicity, Nephrotoxicity, Respiratory tract paralysis Inhalation products Aminoglycoside dosing schemes Various Dosing Schemes Traditional Dosing Once Daily Dosing (a.k.a. Extended-interval aminoglycoside dosing - EIAD) Tobramycin Extended-interval dosing in Cystic Fibrosis patients AMINOGLYCOSIDES Plazomicin (Zemdri™) FDA approved June 25, 2018 Manufactured by Achogen Pharmaceuticals Approved for adult complicated UTI (cUTI) Dosing: Plazomicin 15 mg/kg IV q24h (over 30 minutes) CrCl weight: use TBW; patients weighing 25% ≥ IBW, use IBW Dosing weight: use TBW; patients weighing 25% ≥ IBW, use AdjBW Drug Monitoring: Monitoring only for CrCl ≥ 15 mL/minute to < 90 mL/minute! Trough only monitoring! Measure plasma trough concentration within 30 minutes prior to second dose Desired trough: < 3 mcg/mL If trough concentration is ≥ 3 mcg/mL, extend dosing interval by 1.5 fold (i.e., from every 24 hours to 36 hours or from every 48 hours to 72 hours) Plazomicin (Zemdri™) – AUC/MIC Aminoglycoside, IV 30s Ribosomal Subunit Inhibitor Common ADEs: Hypertension, Hypotension, Diarrhea, Nausea, Vomiting, Headache Serious ADEs: Hypersensitivity reaction, Neurological muscle weakness, ototoxicity, nephrotoxicity Advise patient to maintain adequate hydration to prevent nephrotoxicity 97.5% of plazomicin is excreted unchanged through the urine Half-life: 3.5 hours in patients with normal renal function; prolonged in patients with decreased renal clearance NEOMYCIN Aminoglycoside, PO (available as a tablet, powder, topical ointment, ophthalmic drops, otic drops/suspension) 30s Ribosomal Subunit Inhibitor Common ADEs: Diarrhea, Nausea, Vomiting Serious ADEs: Ototoxicity, Nephrotoxicity, Respiratory tract paralysis Maintain adequate hydration Poor oral hydration Adverse Effects/Toxicity Adverse Effects Nephrotoxicity Ototoxicity Neuromuscular blockade Neurotoxicity Respiratory paralysis Toxicity Risk – Limits use Narrow Therapeutic Index Worry about accumulation! Nephrotoxicity Ototoxicity Drug-Drug Interactions Increased nephrotoxicity E.g., vancomycin, amphotericin B, cyclosporin, IV contrast dye Increased ototoxicity E.g., loop diuretics, salicylates, NSAIDs, analgesics, anti-cancer medications, anti-malarials, iron-chelating agents Increased neuromuscular blockade E.g., succinylcholine, vecuronium, etc. Inactivation of aminoglycosides E.g., penicillin G, ampicillin, nafcillin, carbenicillin, ticarcillin PK-PD Principles SELECT ACTIVITY, PK/PD INFORMATION DRUG SPECIFICS Self-assessment questions The aminoglycosides have excellent activity against aerobic _________ bacteria. The aminoglycosides are used at synergistic doses along with cell wall active agents to treat some aerobic _______________ bacteria. The two major toxicities associated with the aminoglycosides are _______________ and _________________.