Ceutics - Glycopeptides (AA) PDF

ANTIMICROBIALS a Glycopeptides and other cell wall inhibitors Dr Abdulaziz Alobaid [email protected] Glycopeptides and other cell wall inhibitors if A class of antibiotics ori...

ANTIMICROBIALS a Glycopeptides and other cell wall inhibitors Dr Abdulaziz Alobaid [email protected] Glycopeptides and other cell wall inhibitors if A class of antibiotics originally isolated from plant and soil bacteria and is bactericidal against Gram-positive bacteria. Due to their large molecular weight and hydrophilicity, glycopeptides do not permeate the cell membrane of Gram-negative bacteria. 1st generation glycopeptide antibiotics: 2nd generation glycopeptide antibiotics aka “lipoglycopeptides”: – Vancomycin – Telavancin – Teicoplanin – Oritavancin – Dalbavancin Other cell wall inhibitors: – Fosfomycin Time vs concentration dependent activity To help define the response to antibiotic treatment a combination of PK parameters and bacterial sensitivity (MIC) were recognized such as: – Cmax/MIC: the drug’s Cmax divided by the MIC. it I for concentration-dependent antibiotics where Cmax is I IIitiiiii the maximum antibiotic concentration. – t > MIC: the duration of time in which the drug concentration remains above the MIC during a dose t.ir5 interval. n coTnc.us for time-dependent antibiotics effectivness – AUC/MIC: AUC measured in a 24 h period divided by the MIC. where AUC is the area under the concentration time curve that could be used as exposure to the antibiotic. Vancomycin orally not absorbed Vancomycin is not usually absorbed into the blood after oral administration. poorabsorption areaT However, absorption may occur after oral administration in patients with (pseudomembranous) colitis. – This may lead to vancomycin accumulation in patients with co-existing renal impairment. absorber Therapeutic guidelines recommend an initial oral vancomycin dose of 125 mg every 6 h for C. difficile associated diarrhea. At this ‘low dose’, oral vancomycin can reach concentrations > 1000-timenaner the MIC for the organism at the site of action without significant systemic absorption. Vancomycin Administered by intravenous (IV) infusion over 60 minutes (at rate of 10 mg/min) or greater to reduce the risk of infusion reactions: Long rash – Including and not limited to red-man or red-neck syndrome, shock, cardiac arrest, wheezing, muscular and chest pain. Not given as intramuscular (IM) intramuscular pain, vancomycin is very irritating to tissue and should not be given intramuscularly as this causes injection site necrosis. Of manT Vancomycin IV vancomycin poorly penetrates the lung tissue. – Nebulized vancomycin (under research). w Vancomycin does not enter the central nervous system in appreciable amounts when given intravenously, thus, higher steady-state peak and trough concentrations are needed. css fluid may be necessary. – Alternatively, direct administration into the cerebral spinal The elimination half-life of vancomycin is 4 to 6 hours in patients with normal renal function. Primarily excreted by the kidney: 80% urine in the first 24 h. The drug accumulates if renal function is impaired, and dosage adjustments must be made. Vancomycin-induced renal damage was reported. c effect Vancomycin: trough concentration 20 10 Steady-state vancomycin trough levels 15-20 µg/mL toxicconcentration minimum increased incidence of nephrotoxicity. __ window Vancomycin displays concentration-independent activity with the AUC divided by the MIC of the target organism as the primary predictive parameter for efficacy. On basis of in vitro, animal and limited human data, an OEEE AUC/MIC ratio of 400 has been established as a PK/PD target to achieve clinical effectiveness with vancomycin. To achieve this target when MICs are 1.0 µg/mL, dosing in the upper range and high trough serum concentrations (10-20 µg/mL ) are required. Teicoplanin (TARGOCID®) GHighly bound to plasma proteins, primarily to serum albumin (90- 95%). Poor oral absorption, however, can be administered orally as a solution to treat C. difficile bacterial infection locally in the gut. IV and IM administration are well tolerated, bioavailability of >90%. Long terminal elimination half-life (100 h), allowing for once daily dosing. Primarily excreted unchanged by the kidney (80%) within 16 days. Hence, dosage adjustments of teicoplanin are required for patients with mild to severe renal impairment. Telavancin (VIBATIV®) Highly bound to plasma proteins, primarily to serum albumin (90-95%). Poor oral absorption. IV administration over 60 minutes. Elimination half-life (8 h) daily dosing. Primarily excreted by the kidney: 70-80% urine;