About_editors 1..1 - Free

-Lactam Pharmacodynamics 143Ethnic differences of valid biomarkers such as CYP2C9, 2C19 and 2D6 affectplasma concentration of drugs (71) and their metabolites that are related withFDA Guidance 2005 “Safety testing of metabolites” (72). SNIP of CYP andtransporter genes need genotype diagnosis for tailor-made chemotherapy. Genomics,proteomics and metabolomics of bacterium are important to develop newantibiotics to be studied by microdose clinical studies (73) or exploratory INDstudies (74).b-Lactamases inactivate beta-lactam antibiotics and are a major cause ofantibiotic resistance. The recent outbreaks of Klebsiella pneumoniae carbapenemresistant(KPC) infections mediated by KPC type b-lactamases are creating aserious threat to our “last resort” antibiotics, the carbapenems. KPC b-lactamasesare serum carbapenemases and are a subclass of class A b-lactamases that haveevolved to efficiently hydrolyze carbapenems and cephamycins which containsubstitutions at the alpha-position proximal to the carbonyl group that normallyrender these b-lactams resistant to hydrolysis. To investigate the molecular basisof this carbapenemase activity, we have determined the structure of KPC-2 at1.85 Å resolution (75).REFERENCES1. Fleming A. On the antibacterial action of cultures of a penicillium, with special reference totheir use in the isolation of B influenzae. Br J Exp Pathol 1929; 10:226.2. Abraham EP, Loder PB. Isolation of the cephalosporium sp. in Sardinia. In: Flynn EH, ed.Cephalosporins and Penicillins. Chemistry and Biology. New York & London: AcademicPress, 1972:3–5.3. Bodey GP, Ketchel SJ, Rodrigues N. A randomized study of carbenicillin plus cefamandoleor tobramycin in the treatment of febrile episodes in cancer patients. Am J Med 1979; 67:608–616.4. Craig WA, Interrelationship between pharmacokinetics and pharmacodynamics in determiningdosage regimens for broad spectrum cephalosporins. Diagn Microbiol Infect Dis 1995; 21:1–8.5. Leggett JE, Fantin B, Ebert S, et al. Comparative antibiotics dose-effect relations at severaldosing intervals in murine pneumonitis and thigh-infection models. J Infect Dis 1989;159:281–292.6. Craig WA, Ebert SC. Continuous infusion of b-lactam antibiotics. Antimicrob AgentsChemother 1992; 36:2577–2583.7. Dagan R, Abramason O, Leibovitz E, et al. Bacteriologic response to oral cephalosporins.J Infect Dis 1997; 176:1253–1259.8. Dagan R, Leibovitz E, Fliss DM, et al. Bacteriologic efficacies of oral cefaclor in treatmentof acute otitis media in infant and young children. Antimicrob Agents Chemother 2000;44:43–50.9. Dangan R et al. Evidence to support the rationale that bacterial eradication in respiratorytract infection is an important aim of antimicrobial therapy. J Antimicrob Chemother 2001;47:129–140.10. Craig WA, Andes D. Pharmacokinetics and pharmacodynamics of antibiotics in otitis media.Pediatr Infect Dis J 1996; 15:255–259.11. Georgopapadakou NH. Penicillin-binding proteins and bacterial resistance to b-lactams.Antimicrob Agents Chemother 1993; 37:2045–2053.12. Danziger LH, Pendland SL. Bacterial resistance to b-lactam antibiotics. Am J Health-SystPharm 1995; 52(suppl 2):S3–S8.13. Pitout JD, Sanders CC, Sanders WE Jr. Antimicrobial resistance with focus on b-lactamresistance in gram-negative bacilli. Am J Med 1997; 103:51–59.14. Neuwirth C, Siebor E, Duez JM. Imipenem resistance in clinical isolates of Proteus mirabiliswith alteration in penicillin-binding proteins. J Antimicrob Chemother 1995; 36:335–342.15. Nikaido H. Prevention of drug access to bacterial targes: permeability barieres and activesefflux. Science 1994; 264:382–388.