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8. Koide, M., Miyara, T., Higa, F., Kusano, N., Tateyama, M., Kawakami, K. et al. 1997 ; . In vitro and in vivo evaluation of the antimicrobial activity of azithromycin against Legionella species. Journal of Infection and Chemotherapy 3, 906. 9. Tsuchiya, S., Yamabe, M., Yamaguchi, Y., Kobayashi, Y., Konno, T. & Tada, K. 1980 ; . Establishment and characterization of a human acute monocytic leukemia cell line THP-1 ; . International Journal of Cancer 26, 1716. 10. Prez-Prez, G. I., Shepherd, V. L., Morrow, J. D. & Blaser, M. J. 1995 ; . Activation of human THP-1 cells and rat bone marrowderived macrophages by Helicobacter pylori lipopolysaccharide. Infection and Immunity 63, 11837. 11. Fujii, T., Kadota, J., Morikawa, T., Matsubara, Y., Kawakami, K., Iida, K. et al. 1996 ; . Inhibitory effect of erythromycin on interleukin 8 production by 1-alpha, 25-dihydroxyvitamin D3-stimulated THP-1 cells. Antimicrobial Agents and Chemotherapy 40, 154851. 12. Cirillo, J. D., Falkow, S. & Tompkins, L. S. 1994 ; . Growth of Legionella pneumophila in Acanthamoeba castellanii enhances invasion. Infection and Immunity 62, 325461. 13. Ridgway, G. L., Salman, H., Robbins, M. J., Dencer, C. & Felmingham, D. 1997 ; . The in-vitro activity of grepafloxacin against Chlamydia spp., Mycoplasma spp., Ureaplasma urealyticum and Legionella spp. Journal of Antimicrobial Chemotherapy 40, Suppl. A, 314. 14. Liebers, D. M., Baltch, A. L., Smith, R. P., Hammer, M. C. & Conroy, J. V. 1989 ; . Susceptibility of Legionella pneumophila to eight antimicrobial agents including four macrolides under different assay conditions. Journal of Antimicrobial Chemotherapy 23, 3741. 15. Nakagawara, A. & Nathan, C. F. 1983 ; . A simple method for counting adherent cells: application to cultured human monocytes, macrophages and multinucleated giant cells. Journal of Immunological Methods 56, 2618. 16. Gimnez, D. F. 1964 ; . Staining Rickettsiae in yolk-sac cultures. Stain Technology 39, 13540. 17. Ramirez, J. A., Summersgill, J. T., Miller, R. D., Meyers, T. L. & Raff, M. J. 1993 ; . Comparative study of the bactericidal activity of ampicillin sulbactam and erythromycin against intracellular Legionella pneumophila. Journal of Antimicrobial Chemotherapy 32, 939. 18. Stout, J. E., Arnold, B. & Yu, V. L. 1998 ; . Activity of azithromycin, clarithromycin, roxithromycin, dirithromycin, quinupristin dalfopristin and erythromycin against Legionella species by intracellular susceptibility testing in HL-60 cells. Journal of Antimicrobial Chemotherapy 41, 28991. 19. Stokes, D. H., Wilkinson, M. J., Tyler, J., Slocombe, B. & Sutherland, R. 1989 ; . Bactericidal effects of amoxycillin clavulanic acid against intracellular Legionella pneumophila in tissue culture studies. Journal of Antimicrobial Chemotherapy 23, 54756. 20. Higa, F., Kusano, N., Tateyama, M., Shinzato, T., Arakaki, N., Kawakami, K. et al. 1998 ; . Simplified quantitative assay system for measuring activities of drugs against intracellular Legionella pneumophila. Journal of Clinical Microbiology 36, 13928. 21. Sato, K. & Tomioka, H. 1999 ; . Antimicrobial activities of benzoxazinorifamycin KRM-1648 ; and clarithromycin against Mycobacterium aviumintracellulare complex within murine peritoneal macrophages, human macrophage-like cells and human alveolar epithelial cells. Journal of Antimicrobial Chemotherapy 43, 3517. Received 31 January 2000; returned 4 May 2000; revised 25 May 2000; accepted 28 June 2000.

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Brane and show a unidirectional transcellular transport of tetraethylammonium, a typical substrate for this system Inui et al., 1985; Saito et al., 1992 ; . Several of the quinolone antibacterial drugs developed to date have been used clinically. Levofloxacin, one such drug, is well absorbed from the intestine, distributed to tissues and mainly excreted into the urine in humans Nakashima et al., 1992 ; . Tubular secretion as well as glomerular filtration contribute to the renal excretion of levofloxacin Kamiya et al., 1992 ; . We have been interested in the mechanisms of tubular secretion of quinolones, because most of these drugs are zwitterions at physiological pH. We have previously shown that ofloxacin, a racemate of levofloxacin and its optical enantiomer, potently inhibits the H -dependent tetraethylammonium uptake by renal brush-border membrane vesicles Okano et al., 1990 ; . We have also demonstrated that levofloxacin potently inhibits the apical H organic cation antiport system in LLC-PK1 cells Ohtomo et al., 1996 ; . However, the transport mechanisms of quinolones themselves in the kidney have yet to be elucidated. In this study, the transport of levofloxacin and grepafloxacin by LLC-PK1 monolayers was evaluated. The findings indicate that quinolones are specifically transported from the basolateral to apical side by LLC-PK1 monolayers and have higher affinity for the transport system in the apical mem. Fluid disturbances eye infections convulsions rashes fractures subjects with fatal saes, n % ; part 2 subjects with non-fatal saes, n % ; biliary tract disorders lower respiratory infections convulsions allergic reaction to medicinal substances depressive disorders fractures subjects with fatal saes, n % ; lpv rtv rescue subjects with non-fatal saes, n % ; cardiomyopathies allergic reaction to medicinal substances subjects with fatal saes, n % ; conclusion: see publication below and guaifenesin.

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Figure 9. Bactericidal concentrations of grepafloxacin and ciprofloxacin. The number of two-fold dilutions below the MIC increasing concentration ; was tested for 30 strains including three strains each of the following: S. aureus methicillin-resistant ; , E. faecalis, E. faecium, S. agalactiae, E. coli, E. cloacae, K. pneumoniae, S. marcescens, P. aeruginosa and S. maltophilia.18. The 2002 team, young and full of new faces, will confront a challenging season, packed with tough competitors and an even tougher schedule as the Cougars look to improve upon its No. 17 NCAA finish at the end of 2001. "Although we are still a fairly young team, we gained some great experience last season with eight new starters in the lineup, " said head coach Jennifer Rockwood. "The opportunity to compete against so many ranked opponents during the 2001 season has helped us to prepare for this coming fall." Aleisha Cramer Rose, a two-time All-American, the 2001 MWC Player of the Year and last season's leading scorer, returns to the team for her third season as a key player in the midfield. Cramer Rose's accuracy in shooting as well as her exceptional ball handling skills will be an asset more than ever to the Cougars' young team. "Aleisha has had an outstanding first two years, " added Rockwood. "She has obviously made a tremendous impact on our program and is one of the best players in college at this time. As an upperclassman this year, we will look for her to take more of a leadership position, a role that she is very capable of fulfilling." Other top returning players who will play their final season for the Cougars include senior midfielders forwards Jeni Viernes and Kelly Hunsberger. Both are coming off their best season to date as each started every game for the Cougars in 2001. Also up front will be last year's MWC Tournament MVP: junior Lydia Ojuka, who had eight goals and seven assists on the season. With the return of seven starters, Cougar head coach Jennifer Rockwood feels confident in the team's ability to score. "Jeni, Kelly and Lydia will be key individuals in our offense this year, and we will look to each of them to put the ball in the back of the net. Jeni and Lydia will be running up top, which will be a tremendous amount of quickness and speed for any defense to handle." BYU's steady defense will be anchored by Annie Hoecherl, Farrah Hofheins Olmstead and Britney Holman. The crew may have to go through some adjustments to compensate for graduated players, but with the speed, strength and aggressiveness of these experienced defenders, the Cougar defense will remain solid. "We will look to Annie to hold down our defensive line this year. She had a solid sophomore year last fall and an even better spring season, " says Rockwood. "We have great confidence in her ability to bring the defense together. We also hope to have Farrah on the game field and healthy by the end of September. After having torn both ACL's this past year and missing all of last season, she is eager to find her way back and guanfacine.

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1994. Emergence of drug-resistant pneumococcal infections in the United States. J. Am. Med. Assoc. 271: 18311835. Di Modugno, E., I. Erbetti, L. Ferrari, G. Galassi, S. M. Hammond, and L. Xerri. 1994. In vitro activity of the tribactam GV 104326 against grampositive, gram-negative, and anaerobic bacteria. Antimicrob. Agents Chemother. 38: 23622368. Efthymiopoulos, C., A. Capriati, P. Barrington, J. Patel, E. V. B. Shenoy, and A. Bye. 1994. Pharmacokinetics of GV 104326, a novel tribactam antibiotic, following single intravenous and oral as its prodrug GV 118819X ; administration in man, abstr. F82, p. 129. In Abstracts of the 34th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington, D.C. Friedland, I. R., and G. H. McCracken, Jr. 1994. Management of infections caused by antibiotic-resistant Streptococcus pneumoniae. N. Engl. J. Med. 331: 377382. Hecht, D. W., and L. Lederer. 1995. In vitro activity of GV 104326 compared with six other antibiotics against anaerobic bacteria, abstr. F137, p. 137. In Abstracts of the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington, D.C. Jacobs, M. R. 1992. Treatment and diagnosis of infections caused by drugresistant Streptococcus pneumoniae. Clin. Infect. Dis. 15: 119127. Linares, J., T. Alonso, J. L. Perez, J. Ayats, M. A. Domi ~ nguez, R. Pallares, and R. Marti 1992. Decreased susceptibility of penicillin-resistant pneun. mococci to twenty-four -lactam antibiotics. J. Antimicrob. Chemother. 30: 279288. Linares, J., R. Pallares, T. Alonso, J. L. Perez, J. Ayats, F. Gudiol, P. F. ~ Viladrich, and R. Martin. 1992. Trends in antimicrobial resistance of clinical isolates of Streptococcus pneumoniae in Bellvitge hospital, Barcelona, Spain 19791990 ; . Clin. Infect. Dis. 15: 99105. National Committee for Clinical Laboratory Standards. 1993. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. NCCLS publication no. M7-A3. National Committee for Clinical Laboratory Standards, Villanova, Pa. Nelson, C. T., E. O. Mason, Jr., and S. L. Kaplan. 1994. Activity of oral antibiotics in middle ear and sinus infections caused by penicillin-resistant Streptococcus pneumoniae: implications for treatment. Pediatr. Infect. Dis. J. 13: 585589. Pankuch, G. A., M. R. Jacobs, and P. C. Appelbaum. 1994. Study of comparative antipneumococcal activities of penicillin G, RP 59500, erythromycin, sparfloxacin, ciprofloxacin and vancomycin by using time-kill methodology. Antimicrob. Agents Chemother. 38: 20652072. Pankuch, G. A., M. R. Jacobs, and P. C. Appelbaum. 1995. Activity of CP 99, 219 compared to DU-6859a, ciprofloxacin, ofloxacin, levofloxacin, lomefloxacin, tosufloxacin, sparfloxacin and grepafloxacin against penicillin-susceptible and -resistant pneumococci. J. Antimicrob. Chemother. 35: 230232. Pankuch, G. A., M. R. Jacobs, and P. C. Appelbaum. 1995. Comparative activity of ampicillin, amoxycillin, amoxycillin clavulanate and cefotaxime against 189 penicillin-susceptible and -resistant pneumococci. J. Antimicrob. Chemother. 35: 883888. Singh, K. V., T. M. Coque, and B. E. Murray. 1995. In vitro activity of Glaxo's GV-104326 against gram-positive organisms, abstr. F136, p. 136. In Abstracts of the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington, D.C. Spangler, S. K., M. R. Jacobs, and P. C. Appelbaum. 1992. Susceptibilities of penicillin-susceptible and -resistant strains of Streptococcus pneumoniae to RP 59500, vancomycin, erythromycin, PD 131628, sparfloxacin, temafloxacin and guarana.

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19. Wise, R., Andrews, J. M. & Brenwald, N. 1993 ; . The in-vitro activity of OPC-17116, a new 5-methyl substituted quinolone. Journal of Antimicrobial Chemotherapy 31, 497504. 20. Bauernfeind, A. 1993 ; . Comparative in-vitro activities of the new quinolone, Bay y 3118, and ciprofloxacin, sparfloxacin, tosufloxacin, CI-960 and CI-990. Journal of Antimicrobial Chemotherapy 31, 50522. 21. Wise, R., Andrews, J. M. & Brenwald, N. 1993 ; . The in-vitro activity of Bay y 3118, a new chlorofluoroquinolone. Journal of Antimicrobial Chemotherapy 31, 7380. 22. Cohen, M. A., Huband, M. D., Mailloux, G. B., Yoder, S. L., Roland, G. E. & Heifetz, C. L. 1991 ; . In vitro antibacterial activities of the fluoroquinolones PD 117596, PD 124816, and PD 127391. Diagnostic Microbiology and Infectious Disease 14, 24558. 23. Barrett, M. S., Jones, R. N., Erwin, M. E., Johnson, D. M. & Briggs, B. M. 1991 ; . Antimicrobial activity evaluations of two new quinolones, PD127391 CI-960 and AM-1091 ; and PD131628. Diagnostic Microbiology and Infectious Disease 14, 389401. 24. Nakane, T., Iyobe, S., Sato, K. & Mitsuhashi, S. 1995 ; . In vitro antibacterial activity of DU-6859a, a new fluoroquinolone. Antimicrobial Agents and Chemotherapy 39, 28226 25. Dalhoff, A., Petersen, U. & Endermann, R. 1996 ; . In vitro activity of BAY 12-8039, a new 8-methoxyquinolone. Chemotherapy 42, 41025. 26. Woodcock, J. M., Andrews, J. M., Boswell, F. J., Brenwald, N. P. & Wise, R. 1997 ; . In vitro activity of BAY 12-8039, a new fluoroquinolone. Antimicrobial Agents and Chemotherapy 41, 1016. 27. Balfour, J. A. & Wiseman, L. R. 1999 ; . Moxifloxacin. Drugs 57, 36373. 28. Perry, C. P., Barman Balfour, J. A. & Lamb, H. M. 1999 ; . Gatifloxacin. Drugs 58, 68396. 29. Ramirez, J. A. 1999 ; . Introduction. Journal of Respiratory Diseases 20, Suppl. 11, S610. 30. Neu, H. C. & Chin, N.-X. 1994 ; . In vitro activity of the new fluoroquinolone CP-99, 219. Antimicrobial Agents and Chemotherapy 38, 261522. 31. Cormican, M. G. & Jones, R. N. 1997 ; . Antimicrobial activity and spectrum of LB20304, a novel fluoronaphthyridone. Antimicrobial Agents and Chemotherapy 41, 20411. 32. Oh, J.-I., Paek, K.-S., Ahn, M.-J., Kim, M.-Y., Hong, C. Y., Kim, I.-C. et al. 1996 ; . In vitro and in vivo evaluations of LB20304, a new fluoronaphthyridone. Antimicrobial Agents and Chemotherapy 40, 15648. 33. Eliopoulos, G. M., Gardella, A. & Moellering, R. C. 1984 ; . In vitro activity of ciprofloxacin, a new carboxyquinoline antimicrobial agent. Antimicrobial Agents and Chemotherapy 25, 3315. 34. Ball, P. 1994 ; . Bacterial resistance to fluoroquinolones: lessons to be learned. Infection 22, Suppl. 2, S1407 35. Fuhr, U., Anders, E. M., Mahr, G., Sorgel, F. & Staib, A. H. 1992 ; . Inhibitory potency of quinolone antibacterial agents against cytochrome P450IA2 activity in vivo and in vitro. Antimicrobial Agents and Chemotherapy 36, 9428. 36. Jaillon, P., Morganroth, J., Brumpt, I. & Talbot, G. 1996 ; . Overview of electrocardiographic and cardiovascular safety data for sparfloxacin. Journal of Antimicrobial Chemotherapy 37, Suppl. A, 1617. 37. Lipsky, B. A., Dorr, M. B., Magner, D. J. & Talbot, G. H. 1999 ; . Safety profile of sparfloxacin, a new fluoroquinolone antibiotic. Clinical Therapeutics 21, 14859. 38. Stahlmann, R. & Schwabe, R. 1997 ; . Safety profile of grepafloxacin compared with other fluoroquinolones. Journal of Antimicrobial Chemotherapy 40, Suppl. A, 8392. 39. Weiss, K., Laverdiere, M. & Restieri, C. 1998 ; . Comparative activity of trovafloxacin and Bay 12-8039 against 452 clinical isolates of Streptococcus pneumoniae. Journal of Antimicrobial Chemotherapy 42, 5235. 40. Breen, J., Skuba, K. & Grasela, D. 1999 ; . Safety and tolerability of gatifloxacin, an advanced third-generation 8-methoxy fluoroquinolone. Journal of Respiratory Diseases 20, Suppl. 11, S706. 41. Johnson, D. M., Jones, R. N. & Erwin, M. E. 1999 ; . Anti-streptococcal activity of SB-265805 LB20304 ; , a novel fluoronaphthyridone, compared with five other compounds, including quality control guidelines. Diagnostic Microbiology and Infectious Disease 33, 8791. 42. Kelly, L. M., Jacobs, M. R. & Appelbaum, P. C. 1998 ; . Antipneumococcal activity of SB-265805 LB20304a ; , a new broadspectrum quinolone, compared with nine compounds by MIC. In Program and Abstracts of the Thirty-Eighth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 1998. Abstract F-087, p. 254. American Society for Microbiology, Washington, DC. 43. Brenwald, N., Gill, M. J., Boswell, F. & Wise, R. 1999 ; . Activity of gemifloxacin against S. pneumoniae in strains resistant to fluoroquinolones by an efflux mechanism. Abstract P477. Journal of Antimicrobial Chemotherapy 44, Suppl. A, 145. 44. Felmingham, D. & Washington, J. 1999 ; . Trends in the antimicrobial susceptibility of bacterial respiratory tract pathogens--findings of the Alexander Project 19921996. Journal of Chemotherapy 11, Suppl. 1, 521. 45. Chen, D. K., McGeer, A., de Azavedo, J. C. & Low, D. E. 1999 ; . Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada. New England Journal of Medicine 341, 2339. 46. Schito, G.-C., Debbia, E. A. & Marchese, A. 2000 ; . The evolving threat of antibiotic resistance in Europe: new data from the Alexander Project. Journal of Antimicrobial Chemotherapy, 46, Topic 1, 39. 47. Felmingham, D., Robbins, M. J., Dencer, C., Salman, H., Mathias, I. & Ridgway, G. L. 1999 ; . In vitro activity of gemifloxacin against S. pneumoniae, H. influenzae, M. catarrhalis, L. pneumophila and Chlamydia spp. Abstract P408. Journal of Antimicrobial Chemotherapy 44, Suppl A, 131. 48. Hannon, P. & Woodnutt, G. 1998 ; . SB-265805 LB20304a ; : susceptibility of human mycoplasmas in vitro. In Program and Abstracts of the Thirty-Eighth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 1998. Abstract F-101, p. 257. American Society for Microbiology, Washington, DC. 49. Allen, A., Bygate, E., Teillol-Foo, M., Oliver, S. D., Johnson, M. R. & Ward, C. 1999 ; . Pharmacokinetics and tolerability of gemifloxacin after administration of single oral doses to healthy volunteers. Abstract P440. Journal of Antimicrobial Chemotherapy 44, Suppl. A, 137. 50. Allen, A., Bygate, E., Teillol-Foo, M., Oliver, S. D., Johnson, M. R. & Ward, C. 1999 ; . Multiple-dose pharmacokinetics and tolera and grepafloxacin.

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12. Preston, S. L., Drusano, G. L., Berman, A. L., Fowler, C. L., Chow, A. T., Dornseif, B. et al. 1998 ; . Pharmacodynamics of levofloxacin: a new paradigm for early clinical trials. Journal of the American Medical Association 279, 1259. 13. Hyatt, J. M., McKinnon, P. S., Zimmer, G. S. & Schentag, J. J. 1995 ; . The importance of pharmacokinetic pharmacodynamic surrogate markers to outcome. Focus on antibacterial agents. Clinical Pharmacokinetics 28, 14360. 14. Vogelman, B. & Craig, W. A. 1986 ; . Kinetics of antimicrobial activity. Journal of Pediatrics 108, 83540. 15. Thomas, J. K., Forrest, A., Bhavnani, S. M., Hyatt, J. M., Cheng, A., Ballow, C. H. et al. 1998 ; . Pharmacodynamic evaluation of factors associated with the development of bacterial resistance in acutely ill patients during therapy. Antimicrobial Agents and Chemotherapy 42, 5217. 16. Burgess, D. S. 1999 ; . Pharmacodynamic principles of antimicrobial therapy in the prevention of resistance. Chest 115, Suppl. 3, 19S23. 17. Forrest, A., Chodosh, S., Amantea, M. A., Collins, D. A. & Schentag, J. J. 1997 ; . Pharmacokinetics and pharmacodynamics of oral grepafloxacin in patients with acute bacterial exacerbations of chronic bronchitis. Journal of Antimicrobial Chemotherapy 40, Suppl. A, 4557. 18. Paladino, J. A. & Fell, R. E. 1994 ; . Pharmacoeconomic analysis of cefmenoxime dual individualization in the treatment of nosocomial pneumonia. Annals of Pharmacotherapy 28, 3849. 19. Paladino, J. A., Zimmer, G. S. & Schentag, J. J. 1996 ; . The economic potential of dual individualization methodologies. Pharmacoeconomics 10, 53945. 20. Paladino, J. A., Sperry, H. E., Backes, J. M., Gelber, J. A., Serrianne, D. J., Cumbo T. J. et al. 1991 ; . Clinical and economic evaluation of oral ciprofloxacin after an abbreviated course of intravenous antibiotics. American Journal of Medicine 91, 46270. 21. Jensen, K. M. & Paladino, J. A. 1997 ; . Cost-effectiveness of abbreviating the duration of intravenous antibacterial therapy with oral fluoroquinolones. Pharmacoeconomics 11, 6474. 22. Partsch, D. J. & Paladino, J. A. 1997 ; . Cost-effectiveness comparison of sequential ofloxacin versus standard switch therapy. Annals of Pharmacotherapy 31, 113745. 23. Walters, D. J., Solomkin, J. S. & Paladino, J. A. 1999 ; . Cost effectiveness of ciprofloxacin plus metronidazole versus imipenemcilastatin in the treatment of intra-abdominal infections. Pharmacoeconomics 16, 55161. 24. Dresser, L. D., Niederman, M. S. & Paladino, J. A. 2001 ; . Costeffectiveness of gatifloxacin vs ceftriaxone with a macrolide for the treatment of community-acquired pneumonia. Chest 119, 143948. 25. Rifenburg, R. P., Paladino, J. A., Bhavnani, S. M., Haese, D. D. & Schentag, J. J. 1999 ; . Influence of fluoroquinolone purchasing patterns on antimicrobial expenditures and Pseudomonas aeruginosa susceptibility. American Journal of Health-System Pharmacy 56, 221723. 26. Patrick, M. S. 1992 ; . Benchmarkingtargeting `best practices'. Healthcare Forum Journal 35, 712. 27. Bergman, R. 1994 ; . Hitting the mark. Benchmarking: management tool in the quest for improved clinical quality. Hospital and Health Networks 68, 48, 501. Witt, M. J. 2001 ; . Improving group practice performance with benchmarking. Healthcare and Financial Management 55, 6770. 29. Murphy, J. E. 2000 ; . Using benchmarking data to evaluate and support pharmacy programs in health systems. American Journal of Health-System Pharmacy 57, Suppl. 2, S2831. 30. Schentag, J. J., Paladino, J. A., Birmingham, M. C., Zimmer, G., Carr, J. R. & Hanson, S. C. 1995 ; . Use of benchmarking techniques to justify the evolution of antibiotic management programs in healthcare systems. Journal of Pharmacy Technology 11, 20310. 31. Rifenburg, R. P., Paladino, J. A., Hanson, S. C., Tuttle, J. A. & Schentag, J. J. 1996 ; . 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