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1. The antibiotic doripenem (Doribax®) is recommended for use in patients with complicated urinary tract infections, including pyelonephritis. Describe in detail what pyelonephritis is and the likely causative micro-organism(s)? (7 marks) Do not exceed this page – PTO 2. Describe the antimicrobial action of doripenem. Include in your answer details ofbacterial resistance mechanisms towards this class of antimicrobials. (12 marks) Do not exceed this page – PTO 3. Describe the chemistry of doripenem (Doribax®) and explain how its structure confers antimicrobial activity. In comparison to amoxicillin, outline the unique chemical features of doripenem. The New Delhi metallo--lactamase (NDM-1) from K. pneumoniae is highly efficient in the inactivation of doripenem. Briefly discuss the properties of NDM-1 and the mechanism of doripenem inactivation. (10 marks) Doripenem (C15H24N4O6S2) is a member of carbapenem beta lactam antibiotic. Doripenem display antibacterial activity mostly against Gram-negative bacteria. The IUPAC name of Doripenem is (+)-(4R,5S,6S)-6-(1-hydroxyethyl)-4-methyl-7-oxo-3-[(3S,5S)-5-(sulfamoylamino)methyl]pyrrolidin-3-yl]thio-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid and molecular weight of 420.50. The chemical structure of doripenem is similar to other carbapenem antibiotic. It compromised a beta lactam ring fused with 5-membered ring. Differ with penicillin, at carbon 1, doripenem has a beta methyl group which prevent hydrolysis of DHP-1. Among carbapenem members, only imipenem does not exert this physical feature. Therefore, imipenem need an additional of dehydropeptidase-1 inhibitor to sustain the microbial activity. Oth... ... middle of paper ... ...a concentration builds up. When the amount of drug has built up to effective therapeutic regimen and there are balance between administered and clearance of drug, it is known as a steady state which usually takes four half-life of a drug to be stable. Since doripenem has short half-life (1 hour), it will take short time to reach the steady state. The renal clearance is 10.8L/h. Renal clearance demonstrates the excretion of drug into the urine by the kidneys. The value of renal clearance suggests that doripenem is prominent to go through glomerular filtration and active tubular secretion as the renal clearance value is more than the product of glomerular filtration rate by the unbound fraction. However, all mechanism of excretion are operating at the same time including tubular reabsorption, but in doripenem case, only filtration and secretion dominate over the other.

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