Vancomycin & Daptomycin PDF

VANCOMYCIN Relevant Pharmacology Elimination- primarily renal (90%) ○ Glomerular filtration ○ Unchanged drug ○ T1/2 = 4-6 hours ○ Dose adjustments in renal insufficiency Constantly rechecking dose Administered IV for s...

VANCOMYCIN Relevant Pharmacology Elimination- primarily renal (90%) ○ Glomerular filtration ○ Unchanged drug ○ T1/2 = 4-6 hours ○ Dose adjustments in renal insufficiency Constantly rechecking dose Administered IV for systemic infections PO administered stays in the gut- C. diff Nephrotoxicity ○ Historically thought to be related to historical impure products ○ Now known to be potentially nephrotoxic Mitigated by exposure AUC:MIC ratio of 400-600 Serum trough concentrations 15-20 mcg/ml for serious infections (10-20 for others) Relevant Microbiology Spectrum of activity (MRSA) ○ Active Gram-positive cocci Gram-positive bacilli Think STAPHYLOCOCCI (does cover strep) ○ Inactive Gram-negative cocci Gram-negative bacilli Most other organisms Summary cheap/effective Staphylococcal resistance to vanco is extremely rare Enterococcal resistance much more common Additive risk of nephrotoxicity when used concomitantly with piperacillin/tazobactam (broad-spectrum beta-lactam/beta-lactamase inhibitor) Vancomycin non-susceptible Staphylococcus- very rare clinically Susceptible: less than or equal to 2 Intermediate: 4-8 Resistant: greater than or equal to 4 VISA (vancomycin-intermediate Staph aureus)  ○ Vanco doesn’t allow cross-linking through transpeptidase ○ MOA for VISA= thickened cell wall (harder for vanco to), false binding sites created by bacteria, target beta-lactamase inhibitor instead of active drug “decoy” Switch therapy ○ Patient case: Classic VISA = vanco susceptible at day 1, repeat blood culture shows VISA VRSA (vancomycin-resistant Staph aureus) ○ MOA= VanA gene from vancomycin-resistant enterococcus via a Transposon Tn1546 ○ Very rare, described 52 times clinically ○ Common characteristics: NOT predictive, ONLY description Co-infection and co-colonization of VRE and MRSA common Prior use of vanco (last 3 months) Diabetes, ESRD (on hemodialysis), gangrenous wound, surgical wound DAPTOMYCIN =semisynthetic, cyclic lipopolypeptide derived from fermentation product of Streptomyces roseosporus MOA Through physiologic amounts of calcium, insert itself into phospholipid bilayer of the cell Come together to form a porin Destabilization of osmotic gradient for cell and it dies Relevant Pharmacology Not absorbed orally (only IV) Administered IV T1/2=8-9 hours 90% bound to serum proteins Site of metabolism not identified ○ Inactive metabolites found in urine Excretion primarily renal ○ Dose adjustment required in those with renal insufficiency Not likely to induce or inhibit P450 isoforms Microbiology Active: susceptible strains or aerobic gram-positive organisms ○ Staph aureus (including mrsa)  ○ Strep pyogenes ○ Enterococcus faecalis Both vanco-sensitive and resistant strains ○ Enterococcus faecium Both vanco-sensitive and resistant strains Inactive: gram-negative Indications Therapy of complicated skin/skin structure infections produced by susceptible strains of gram-positive aerobes ○ Staph aureus (MSSA and MRSA) ○ Strept pyogenes ○ Enterococcus faecalis (vanco-susceptible strains) Therapy of Staph aureus bacteremia (MSSA and MRSA) ○ Including right-sided (tricuspid or pulmonic) native valve endocarditis Caveat Dapto found to be inferior to ceftriaxone ○ Inactivated by lung surfactant Provided mechanical stability Prevents alveolar atelectasis (collapsed lung) Should not be used in treatment of pneumonia (MRSA pneumonia) ADEs Injection site reaction GI- nausea, constipation, diarrhea CNS- fever, headache, insomnia, dizziness Neuromuscular and skeletal ○ Rhabdomyolysis- caused by rapid dissolution of damaged or injured skeletal muscle Risks are higher dosage and higher serum levels, but also increased frequency of dosage Mitigated by once daily dosing Monitor by obtaining baseline then weekly CPK’s (creatinine phosphokinase) and discontinue if: Symptomatic: increase in CPK > 5 times ULN or 1000 units/L Asymptomatic: CPK > or = 10 times ULN Known other drugs/agents that may cause: Statins- should be held (HMG-CoA reductase inhibitors) Antilipid agents (ex. Gemfibrozil, ezetimibe)  Psychiatric agents Abused substances Antihistamines Eosinophilic pneumonia ○ Stop drug and give steroids Resistance, Drug Interactions Resistance very rare Low-level non-susceptible isolates are slightly more common ○ Thickened cell wall- dapto can’t get through No clinically-significant interactions Less virulent strains of Staph that are more likely to produce tolerant mechanisms to vanco and dapto Significant Points Bactericidal cell-wall active agent with unique MOA ○ PD: concentration-dependent “killer” (higher dosing=more rapid cell death) ○ S. aureus based on ABW or AdjBW in obese dosing q24h in normal renal ○ Enterococcus ABW or AdjBW in obese dosing q24h in normal renal ○ Serum CPK monitored weekly on therapy Renally eliminated Cannot be used to treat pneumonias because of binding to human pulmonary surfactant Alone and in combination with other antibiotics represent greatest utility for refractory disease OXAZOLIDINONES (linezolid, tedizolid) Spectrum Active: ○ Aerobic gram-positive Enterococcus faecium Enterococcus faecalis Streptococcus pneumoniae (penicillin resistant) Viridans group streptococci Staphylococci (both MSSA and MRSA) ○ Some anaerobic bacteria ○ Mycobacteria MOA Affects translation at ribosome (slower cell death than those that work at cell wall ex. dapto) ○ Binds to 23S portion of 50S ribosomal subunit Distorts binding site Prevents association with 30S subunit Prevents formation at 70S ribosome Precludes ribosome assembly and protein synthesis Indications Skin and skin structure infections ○ Uncomplicated Strept pyogenes MSSA ○ Complicated strept pyogenes, other strept species MSSA and MRSA ○ Vancomycin-resistant entercococcus faecium ○ Nosocomial pneumonia (MRSA pneumonia- vanco and linezolid as equals) ○ CAP PK IV and oral Oral BA = 100% Peak concentrations 1-2 hrs T1/2: 4.5 hours Protein binding: 30% Penetrates CNS Non-renal elimination ○ Hepatic- none ○ serum/other site esterases/reagents Renal elimination ○ Renal clearance- 40ml/min ○ Renal excretion- 35% ADEs Hematologic ○ Thrombocytopenia ○ Anemia ○ Leukopenia, neutropenia Serotonin syndrome (linezolid= weak monoamine oxidase inhibitor) ○ Higher risk in advanced gen. (ex. citalopram) OR concurrent use of several drugs including selective and non-selective agents- excess serotonergic activity in the CNS  ○ Symptoms: Neuromuscular excitability Autonomic instability Cognitive symptoms ○ Linezolid’s ability of monoamine oxidase inhibition (buildup of neurotransmitters in brain) Summary 600 mg IV or PO Q12H for 10-14 days (not weight based) Excellent BA Excellent MRSA pneumonia Potential for use in bacteremia TELAVANCIN Semisynthetic cyclic lipoglycopeptide Goal of creating modified vanco ○ Improve activity through structural modifications/additions ○ Lipophilic side-chain ○ Phosphonic acid MOA ○ Same as vanco ○ Hydrophobic tail may serve as anchor and additional enhancement of cell wall disruptive activity ○ From MIC, more potent Relevant Pharmacology ○ Only IV ○ T1/2: 8 hrs, 90% protein bound ○ Renal excretion ○ Monitor creatinine clearance Adjust in renal impairment ○ No serum therapeutic monitoring (unlike vanco) Microbiology ○ MSSA and MRSA staph aureus ○ Vanco-susceptible enterococcus faecalis ○ Strep pyogenes ○ Complicated skin and skin structure infection ○ hospital-acquired/ventilator-associated bacterial pneumonia where 1st line not available Signal of increased mortality ○ Black box warning  CEFTAROLINE Advanced generation cephalosporin ○ Sometimes referred to as 5th gen / advanced gen ○ Very expensive Activity ○ Against MRSA Binds to PBP 2a of MRSA that has low affinity for other B-lactams ○ Gram-negative like ceftriaxone; poor against pseudomonas, enterococci, anaerobes Indications ○ IV only ○ T1/2: 2.6 hrs ○ Renal elimination