2. DAPTOMYCIN.docx

DAPTOMYCIN & POLYMYXINS 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 differe...

DAPTOMYCIN & POLYMYXINS 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 (Cubicin) Mechanism of Action Daptomycin binds to components of the cell membrane of susceptible organisms and causes rapid depolarization, inhibiting intracellular synthesis of DNA, RNA, and protein. Daptomycin is bactericidal in a concentration-dependent manner. Clinical uses: Endocarditis, severe skin soft tissue infections, osteomyelitis Dosing 4 mg/kg for SSTI 6 mg/kg for MRSA bacteremia (up to 10 mg/kg) 8 mg/kg for Enterococcal infections (up to 10 mg/kg) Daptomycin spectrum Red: Gram-negative, Atypical Yellow: Anaerobes Green: Gram-positive Second-line agent for Intravenous Gram Positive Coverage in the Hospital unless there is a contraindication! Daptomycin (Cubicin) Cyclic lipopeptide, IV Cell membrane inhibitor Severe ADEs: Disorder of muscle, Increased creatine kinase level, Rhabdomyolysis, Renal failure, Pulmonary eosinophilia, Disease due to Gram-negative bacteria, Increased LFTs Avoid using HMG-CoA reductase inhibitors Minimal CNS penetration (animal meningitis mode: 2% with non-inflamed meninges and 6% with meningitis). High protein binding: 92% Primarily excreted as unchanged drug in the kidney (78%) with little metabolism to inactive metabolites Half-life: 8.2 hours Inactivated by lung surfactant; not to be used for PNA SELECT ACTIVITY, PK/PD INFORMATION Avoid in pneumonia because of lung surfactant inactivation Colistin (Polymyxin E, Colistimethate) Mechanism of Action Colistimethate (or the sodium salt [colistimethate sodium]) is the inactive prodrug that is hydrolyzed to colistin, which acts as a cationic detergent and damages the bacterial cytoplasmic membrane causing leaking of intracellular substances and cell death Uses Bronchiectasis Cystic fibrosis HAP/VAP due to MDR PsAr or Acinetobacter baumannii (nebulized) Treatment of acute or chronic infections due to sensitive strains of certain gram-negative bacilli (particularly Pseudomonas aeruginosa) which are resistant to other antibacterials or in patients allergic to other antibacterials Colistin spectrum Red: Gram – positive, Anaerobes, Atypical Green: Gram-negative Fallen out of favor because of adverse effects (nephrotoxicity/neurotoxicity); was commonly used in combination therapy regimens for MDR Gram negative (e.g. Pseudomonas aeruginosa, Acinetobacter spp.) prior to the introduction of the newer agents Colistin (Polymyxin E, Colistimethate) Polymyxin, IV/INH Cell membrane inhibitor; Cationic detergent Common ADEs: Phlebitis at infusion site Severe ADEs: Reversible dose dependent nephrotoxicity (up to 31%), C. difficile diarrhea, Neurological muscular paralysis, Neurotoxicity, Respiratory failure, Respiratory tract paralysis Advise patient against driving or performing hazardous tasks during therapy, as drug can cause tingling of extremities, vertigo, or dizziness Widely distributed into tissues, except synovial, pleural, and pericardial fluid Protein Binding: 50% Colistimethate and metabolites excreted unchanged in the urine Half-life: 1.5-8 hours ICU patients: 7.4-14 hours Colistin drug-drug interactions Aminoglycosides May increase risk of neuromuscular blockade Nephrotoxic drugs E.g., amphotericin B, aminoglycosides, vancomycin, cidofovir, foscarnet May increase risk of nephrotoxicity. Avoid co-administration. Non-depolarizing muscle relaxants E.g., rocuronium, cisatracurium, atracurium, vecuronium, pancuronium, tubacurarine Neuromuscular blockade may be enhanced with IM or IV use Polymyxin B Polymyxin, IV/Opthalmic/INH Cell membrane inhibitor Common ADEs: Diarrhea Serious ADEs: C. difficile diarrhea, Neurotoxicity, Acute kidney injury (34.5-46.1%), Renal failure (Up to 14.6%), Circumoral and peripheral paresthesia, Respiratory tract paralysis, Bronchospasm (21% with nebulized solution) Undetectable in BAL fluid and poor CNS penetration Protein Binding: 55% <1% of dose excreted unchanged by the kidney 4.3-6.0 hours; may be prolonged in renal insufficiency MOA: Binds to phospholipids, alters permeability, and damages the bacterial cytoplasmic membrane permitting leakage of intracellular constituents Treatment of Pseudomonal infections, treatment of serious infections caused by susceptible strains, when less potentially toxic drugs are ineffective or contraindicated (H. influenzae, E. coli, Aerobacter aerogenes, Klebsiella pneumoniae) SELECT ACTIVITY, PK/PD INFORMATION DRUG SPECIFICS SELF-ASSESSMENT QUESTIONS The structure of Daptomycin is a _________________. Daptomycin has excellent activity against aerobic ______________ bacteria. Colistin binds to and disrupts ______________ in the bacterial outer membrane. Colistin has activity against aerobic _____________ bacteria. T/F: Colistin is more nephrotoxic and neurotoxic than Polymyxin B. DAPTOMYCIN MOA Daptomycin binds to components of the cell membrane of susceptible organisms and causes rapid depolarization, inhibiting intracellular synthesis of DNA, RNA, and protein. Daptomycin is bactericidal in a concentration-dependent manner. POLYMYXINs MOA: Act like a cationic detergent by binding to the phospholipids of the bacterial cytoplasmic membranes and causing damage, which results in alteration of the osmotic barrier/permeability and leakage of essential intracellular substances, leading to cell death. AGENTS IN CLASS: COLISTIN (POLYMYXIN E), POLYMYXIN B