Antibiotics Pharmacology PDF

Pharmacology of Antibiotics MIC Pharmacology kinetics and dynamics Drug concentration vs time Antibiotics My thoughts Bug? Drug? Host? Case Question? ½ time importance ? Research? Bac...

Pharmacology of Antibiotics MIC Pharmacology kinetics and dynamics Drug concentration vs time Antibiotics My thoughts Bug? Drug? Host? Case Question? ½ time importance ? Research? Bacteria population to the body microbiota?  The study of pharmacodynamics relates: Drug exposure to antibacterial activity 1- Antibiotics can be categorized as time-dependent killers or 2-Concentration-dependent killers. Dosing time-dependent antibiotics (e.g., β-lactams), it is important to: maximize time>MIC, Dosing concentration-dependent antibiotics (e.g., aminoglycosides), the peak:MIC ratio is the most important pharmacodynamic parameter to optimize. How will that work for the kidney? when making dose adjustments for kidney disease, knowing the pharmacodynamic properties of antibiotics can help guide the clinician when deciding whether to decrease the dose and keep the dosing frequency constant (often preferred with time-dependent antibiotics) or keep the dose the same and prolong the dosing interval (often preferred with concentration-dependent antibiotics).  Antibiotic Class Pharmacodynamic Profile Pharmacodynamic Parameter to Optimize Aminoglycosides Concentration-dependent Peak:MIC Penicillins Time-dependent Time>MIC Cephalosporins Time-dependent Time>MIC Carbapenems Time-dependent Time>MIC Vancomycin Time-dependent AUC:MIC Lipopeptides Concentration-dependent AUC:MIC; peak:MIC Oxazolidinones Time-dependent AUC:MIC Lipoglycopeptides Concentration-dependent AUC:MIC Fluoroquinolones Concentration dependent AUC:MIC Macrolides Time-dependent AUC:MIC Sulfamethoxazole-trimethoprim Limited data (65) Limited data (65)  β-Lactam Antibiotics The penicillin, cephalosporin, and carbapenem antibiotics all contain a β- lactam ring and work by inhibiting the last step in bacterial cell-wall peptidoglycan synthesis. β-lactams exhibit time-dependent pharmacodynamics , and so when adjusting these medications for kidney disease, it is often preferable to decrease the dose while maintaining the dosing interval. In recent years, a loading dose followed by extended or continuous infusions of β-lactams (e.g., piperacillin-tazobactam , ceftazidime, cefepime, meropenem, and doripenem ) have been proposed to maximize the time that concentrations stay above MIC. 1-What is Beta-lactamase give function? 5 points  When doses of β-lactams have not been adjusted appropriately, central nervous system (CNS) disturbances such as confusion, and seizures can occur This is primarily presumed to be because of decreased kidney clearance leading to higher than normal concentrations of β-lactams in the CNS. 2-What is uremic patients ? (2 points) Beta-Lactam antibiotics kill bacteria by inhibiting cell wall synthesis. The beta-lactam ring within the chemical structure of the antibiotic binds with the penicillin binding proteins (PBP's) within the bacteria cell wall, blocking their function.  Penicillins Despite increasing antimicrobial resistance. penicillins continue to play a valuable role in modern antibiotic therapy. Many penicillins have a short t1/2 (usually about 0.5–1.5 hours in patients with normal kidney function).  Penicillins are generally well tolerated in patients with kidney disease. Hypersensitivity reactions are commonly reported, and an association between penicillins and interstitial nephritis exists, but patients with kidney disease are not considered to be at higher risk. 3-Question: Some penicillins don't have direct antibacterial activity , give an example and explain why. (5points)  Cephalosporins One niche of the first generation cephalosporins is in treating catheter- related bacteremias due to methicillin-susceptible Staphylococcus aureus (MSSA). Once it becomes clear that the organism is MSSA, β-lactam agents are associated with better outcomes than vancomycin therapy  Carbapenems Further structural modifications to the β-lactam backbone gave rise to the carbapenem class of antibiotics and conferred a broader spectrum of activity, including activity against β-lactamase producing Gram-negative organisms. Imipenem, the first drug in the class, is associated with seizures in high doses and so should be used cautiously in those with CNS lesions, neurologic disorders, or kidney disease.  They penetrate bacterial cell wall and bind to enzymes known as penicillin binding proteins (PBPs) which are located on cell membrane. Transpeptidase is one of the PBP involved in synthesis of peptidoglycans. Binding of carbapenem to transpeptidase inhibits synthesis of peptidoglycans which leads to weakening of bacterial cell wall. The bacteria become vulnerable to rupture by solutes in surrounding medium. Carbapenems are resistant to hydrolysis by most of the beta- lactamases.  Vancomycin Vancomycin is a glycopeptide antibiotic with activity against the majority of Gram-positive bacteria. It inhibits bacterial cell-wall synthesis through high-affinity binding to D- alanyl-D-alanine cell-wall precursor units. Because of its primarily bacteriostatic profile, vancomycin should be used as a second-line drug to bactericidal β-lactam antibiotics, like cefazolin and oxacillin, in serious Gram-positive infections such as MSSA bacteremias. Vancomycin is eliminated by the kidneys with 90% excreted as unchanged drug.  In clinical practice, vancomycin is the first-line agent for the treatment of serious methicillin-resistant S. aureus infections. Increased vancomycin use has resulted in the emergence of S. aureus isolates with reduced vancomycin susceptibility. 4-What will you do here (Hint MIC) (2 points) Nephrotoxicity is a common concern with vancomycin therapy, and is associated with concurrent nephrotoxin administration,  Lipopeptides Daptomycin is the only member of the lipopeptide class of antibiotics. It exhibits concentration-dependent bactericidal activity against a variety of Gram-positive bacteria through depolarization of bacterial cell membranes, causing loss of membrane potential and subsequent cell death. Daptomycin is highly protein bound with a low volume of distribution, thus making it an ideal agent in the treatment of bloodstream infections. Daptomycin should be avoided in pulmonary infections as it is inactivated by pulmonary surfactant.  Daptomycin is primarily (78%) excreted in the urine as unchanged drug. The t1/2 of daptomycin is prolonged to 30 hours in patients receiving hemodialysis compared with 8 hours in patients with normal kidney function. A serious side effect of daptomycin therapy is myopathy. 5-What is meant by broad spectrum antibiotics and are they used.  Oxazolidinones Until the release of tedizolid in 2014, linezolid was the sole agent in the oxazolidinone class. Targeting the P-site on the 50S ribosomal subunit, these bacteriostatic agents block bacterial protein synthesis Linezolid is metabolized via oxidation to two inactive metabolites, aminoethoxyacetic acid and hydroxyethyl glycine. Prolonged courses of linezolid have been associated with optic and peripheral neuropathies and myelosuppression.  Lipoglycopeptides First released in 2009, telavancin was the original member of the lipoglycopeptide class with dalbavancin and oritavancin receiving US Food and Drug Administration approval in 2014. These agents are structurally related to vancomycin and share a similar mechanism of action; however, they display increased potency because of their ability to dimerize and anchor themselves to bacterial cell walls via lipophilic side chains. Telavancin and oritavancin disrupt membrane potential and permeability, resulting in cell lysis. Lipoglycopeptides are concentration-dependent bactericidal antibiotics  Telavancin primarily undergoes elimination via the kidneys with 76% found in the urine as unchanged drug, thus dose adjustments are necessary when 6- Why check creatinine clearance falls below 50 ml/min 5 points Aminoglycoside Antibiotics Aminoglycosides are a bactericidal class of antibiotics that exert their effects through inhibition of bacterial protein synthesis. Risks of nephrotoxicity has led clinicians to limit their use. Aminoglycosides have retained activity against many multidrug resistant organisms, and so still play an important role in antibiotic therapy today. They exhibit concentration-dependent pharmacodynamics Are most associated with antibacterial efficacy in Gram-negative infections. Traditionally the aminoglycosides are dosed by giving lower doses (e.g., gentamicin doses of 3–6 mg/kg per day) Divided into two or three doses per day, with serum concentration monitoring to guide dose adjustments. Aminoglycosides are highly polar cations and are very poorly absorbed from the intestinal tract. IM: peak concentrations ~ 30 – 60 minutes post-dose - IV (given over 30-60 minutes): peak concentrations ~ 30 – 60 minutes post-infusion. Aminoglycosides are indicated in the treatment of urinary tract infections, bacteremia, respiratory tract infections, gastrointestinal tract infections, skin and soft tissue infections, endocarditis, osteomyelitis, and meningitis. In general, aminoglycosides are used in combination with a β-lactam antibiotic and are not used as monotherapy in the treatment of these infections.  Aminoglycosides Gentamicin (generic version is IV only) Amikacin (IV only) Tobramycin. Gentak and Genoptic (eye drops) Kanamycin. Streptomycin. Neo-Fradin (oral) Neomycin (generic version is IV only) The higher the aminoglycoside dosage, the greater the post-antibiotic effect, up to a certain maximal response. In vivo, the post-antibiotic effect for aminoglycosides is prolonged by the synergistic effect of host leukocyte activity. It is believed that leukocytes have enhanced phagocytosis and killing activity after exposure to aminoglycosides  Tetracyclines: Tetracycline antibiotics are another class of antibiotics categorised by their chemical structure. A tetracycline has four hydrocarbon rings within their chemical formula Tetracycline is a broad spectrum antibiotic. Its chemical formula is C22H24N2O8 and molecular weight is 444.44.The structure is: Tetracycline is a bacteriostatic drug acts by binding reversibly to the 30S subunit of the bacterial ribosome. This inhibits addition of amino acids to the growing peptide resulting in Extended dosing or concentrated dosing? Clinicians must be cautious when using this high dose, extended interval dosing in patients with creatinine clearance