注射用氨苄西林钠/丙磺舒钠体内药效学研究
摘要
建立绿脓杆菌(Pseudomonas aeruginosa)ATCC27853、金黄色葡萄球菌(Staphylococcus aureus)ATCC25925、大肠杆菌(Escherichia coli)ACTT25922致小鼠腹腔感染模型,通过药物治疗试验和腹腔液细菌学检查,在药效学方面比较氨苄西林钠/丙磺舒钠复方注射液(质量比3:1)和氨苄西林钠单方注射液抗感染方面的治疗效果,结果表明:(1)受试药物氨苄西林钠/丙磺舒钠复方注射液治疗组比对照药物氨苄西林钠单方注射液治疗组小鼠总保护率分别高出7.50%、8.34%和8.33%,平均生存日分别延长0.525d、0.634d和0.583d,ED50值分别高出14.41mg/kg、9.64mg/kg和6.23mg/kg,去除丙磺舒钠在复方制剂比重中占25%的影响,氨苄西林钠在复方制剂中的ED50值比在单方制剂中分别减少18.57%、20.48%和21.57%;(2)在ICR小鼠体内,受试药物氨苄西林钠/丙磺舒钠复方注射液针对绿脓杆菌、金黄色葡萄球菌、大肠杆菌腹腔感染的治疗指数TI分别为9.51、10.23、12.20;(3)腹腔液细菌学检查方面,除绿脓杆菌AMP/PRO266.67mg/kg组与AMP450mg/kg组腹腔液细菌计数在统计学上无差别外,其余受试药物所选三个剂量组的腹腔液细菌计数结果在统计学上显著低于对照药物450mg/kg剂量组。分析上述试验结果可知:(1)受试药物氨苄西林钠/丙磺舒钠复方注射液在小鼠体内抗绿脓杆菌、金黄色葡萄球菌和大肠杆菌感染的治疗效果优于对照药物氨苄西林钠单方注射液;(2)丙磺舒钠能够增强氨苄西林钠在小鼠体内的抗菌疗效;(3)氨苄西林钠/丙磺舒钠复方注射液在抗感染治疗中具有较高的安全性;(4)丙磺舒钠可以作为一种注射型抗菌增效剂与抗生素联合应用于抗感染治疗。
Initially antibiotics are product of metabolism of microorganisms which are able to inhibit or kill other microorganisms. Since 1940 penicillin was applied to clinic, many important antibiotics, such as streptomycin, chloromycetin, tetracycline and so on, emergence one after the other. In 1960’s antibiotics walked into an age of semisynthesis after artificial semisynthetic penicillin was successfully synthetized. Ampicillin is a kind of semisynthetic penicillin, hydrogen of benzyl group in side chain R1 of penicillin replaced by amino group, which made it easy for ampicillin to permeate the coat of lipopolysaccharide and phospholipid of bacterial cell wall and destroy the synthesis of peptidoglycan. Therefore, ampicillin is a broad-spectrum antibiotic which has a strong antibacterial action against Gram-negative bacteria. When the carboxyl group of ampicillin was combined with sodium, ampicillin became ampicillin sodium, a dissolvable substance proper for intramuscular or intravenous injection. The antibacterial activity of ampicillin is similar to that of Penicillin G against Gram-positive bacteria, superior to it against Streptococcus riridans and enterococci, but inferior to it against other bacteria, and ineffective against penicillin G-resistant Staphylococcus aureus. Some Gram-negative bacteria, such as gonococci, meningococcus, Hemophilus influenzae, Bacillus pertussis, Escherichia coli, Bacillus paratyphosus, Bacillus typhi, Bacillus dysenteriae, Proteus mirabilis, Bacterium burgeri and so on, are sensitive to ampicillin but easily develop drug resistance. Ampicillin mainly cures various organ infections caused by sensitive bacteria, including urinary system, respiratory apparatus, biliary tract, intestinal tract, meningitis, encarditis and et al. Animal experiments and human body researches have established that the most important parameter determining in vivo antibacterial activity of beta-lactams is duration of serum free drug concentration above MIC of the specific pathogen. We called this phenomenon time-dependence killing mechanism. A T>MIC of 40-50% of the
Initially antibiotics are product of metabolism of microorganisms which are able to inhibit or kill other microorganisms. Since 1940 penicillin was applied to clinic, many important antibiotics, such as streptomycin, chloromycetin, tetracycline and so on, emergence one after the other. In 1960’s antibiotics walked into an age of semisynthesis after artificial semisynthetic penicillin was successfully synthetized. Ampicillin is a kind of semisynthetic penicillin, hydrogen of benzyl group in side chain R1 of penicillin replaced by amino group, which made it easy for ampicillin to permeate the coat of lipopolysaccharide and phospholipid of bacterial cell wall and destroy the synthesis of peptidoglycan. Therefore, ampicillin is a broad-spectrum antibiotic which has a strong antibacterial action against Gram-negative bacteria. When the carboxyl group of ampicillin was combined with sodium, ampicillin became ampicillin sodium, a dissolvable substance proper for intramuscular or intravenous injection. The antibacterial activity of ampicillin is similar to that of Penicillin G against Gram-positive bacteria, superior to it against Streptococcus riridans and enterococci, but inferior to it against other bacteria, and ineffective against penicillin G-resistant Staphylococcus aureus. Some Gram-negative bacteria, such as gonococci, meningococcus, Hemophilus influenzae, Bacillus pertussis, Escherichia coli, Bacillus paratyphosus, Bacillus typhi, Bacillus dysenteriae, Proteus mirabilis, Bacterium burgeri and so on, are sensitive to ampicillin but easily develop drug resistance. Ampicillin mainly cures various organ infections caused by sensitive bacteria, including urinary system, respiratory apparatus, biliary tract, intestinal tract, meningitis, encarditis and et al. Animal experiments and human body researches have established that the most important parameter determining in vivo antibacterial activity of beta-lactams is duration of serum free drug concentration above MIC of the specific pathogen. We called this phenomenon time-dependence killing mechanism. A T>MIC of 40-50% of the
引文
[1] 张建民,冯玲玲,李勇,谢军平.抗菌药物增效剂[J].中国药师, 2003(03): 172-173.
[2] Kanra G. Experience with ampicillin/sulbactam in severe infections. J Int Med Res. 2002;30 Suppl 1:20A-30A.
[3] Dajani A. Use of ampicillin/sulbactam and sultamicillin in pediatric infections: a re-evaluation. J Int Med Res. 2001 Jul-Aug;29(4):257-69.
[4] Lode H. Role of sultamicillin and ampicillin/sulbactam in the treatment of upper and lower bacterial respiratory tract infections. Int J Antimicrob Agents. 2001 Sep;18(3):199-209.
[5] Cunha BA. Ampicillin/sulbactam in lower respiratory tract infections: a review. Clin Ther. 1991 Nov-Dec;13(6):714-26.
[6] Zenon GJ 3rd, Cadle RM, Hamill RJ. Ampicillin-sulbactam therapy for multiple pyogenic hepatic abscesses. Clin Pharm. 1990 Dec;9(12):939-47.
[7] Bluestone CD. Role of sulbactam/ampicillin and sultamicillin in the treatment of bacterial infections of the upper respiratory tract of children. APMIS Suppl. 1989;5:35-40.
[8] Benson JM, Nahata MC. Sulbactam/ampicillin, a new beta-lactamase inhibitor/beta-lactam antibiotic combination. Drug Intell Clin Pharm. 1988 Jul-Aug;22(7-8):534-41.
[9] Levin AS, Levy CE, Manrique AE, Medeiros EA, Costa SF. Severe nosocomial infections with imipenem-resistant Acinetobacter baumannii treated with ampicillin/sulbactam. Int J Antimicrob Agents. 2003 Jan;21(1):58-62.
[10] Okimoto N, Kurihara T, Honda N, Asaoka N, Fujita K, Ohba H, Nakamura J. Clinical effect of ampicillin with beta-lactamase inhibitor (sulbactam/ampicillin) on community-acquired pneumonia in the elderly. J Infect Chemother. 2003 Jun;9(2):183-6.
[11] Seven H, Sayin I, Turgut S. Antibiotic prophylaxis in clean neck dissections. J Laryngol Otol. 2004 Mar;118(3):213-6.
[12] Acquarolo A, Urli T, Perone G, Giannotti C, Candiani A, Latronico N. Antibiotic prophylaxis of early onset pneumonia in critically ill comatose patients. A randomized study. Intensive Care Med. 2005 Apr;31(4):510-6. Epub 2005 Mar 8.
[13] Jaureguy F, Carton M, Panel P, Foucaud P, Butel MJ, Doucet-Populaire F. Effects of intrapartum penicillin prophylaxis on intestinal bacterial colonization in infants. J Clin Microbiol. 2004 Nov;42(11):5184-8.
[14] Yerdel MA, Akin EB, Dolalan S, Turkcapar AG, Pehlivan M, Gecim IE, Kuterdem E. Effect of single-dose prophylactic ampicillin and sulbactam on wound infection after tension-free inguinal hernia repair with polypropylene mesh: the randomized, double-blind, prospective trial. Ann Surg. 2001 Jan;233(1):26-33.
[15] Maezawa Y, Hirasawa A, Abe T, Kawamura H, Sekiguchi K, Kunimoto M, Sato T, Wakabayashi Y, Nishikawa T. Successful treatment of listerial brain abscess: a case report and literature review. Intern Med. 2002 Nov;41(11):1073-8.
[16] Brown JC, Burns JL, Cummings P. Ampicillin use in infant fever: a systematic review. Arch Pediatr Adolesc Med. 2002 Jan;156(1):27-32.
[17] Marget W, Seeliger HP. Listeria monocytogenes infections--therapeutic possibilities and problems. Infection. 1988;16 Suppl 2:S175-7.
[18] Drusano GL, Craig WA. Relevance of pharmacokinetics and pharmacodynamics in the selection of antibiotics for respiratory tract infections. J Chemother. 1997 May;9 Suppl 3:38-44.
[19] Redington J, Ebert SC, Craig WA. Role of antimicrobial pharmacokinetics and pharmacodynamics in surgical prophylaxis. Rev Infect Dis. 1991 Sep-Oct;13 Suppl 10:S790-9.
[20] Jacobs MR. How can we predict bacterial eradication? Int J Infect Dis. 2003 Mar;7 Suppl 1:S13-20.
[21] Craig WA. Choosing an antibiotic on the basis of pharmacodynamics. Ear Nose Throat J. 1998 Jun;77(6 Suppl):7-11; discussion 11-2.
[22] Garton AM, Rennie RP, Gilpin J, Marrelli M, Shafran SD. Comparison of dose doubling with probenecid for sustaining serum cefuroxime levels. J Antimicrob Chemother. 1997 Dec;40(6):903-6.
[23] Sarasola P, McKellar QA. Effect of probenecid on disposition kinetics of ampicillin in horses. Vet Rec. 1992 Aug 22;131(8):173-5.
[24] Schentag JJ. Antimicrobial action and pharmacokinetics/pharmacodynami- cs: the use of AUIC to improve efficacy and avoid resistance. J Chemother. 1999 Dec;11(6):426-39.
[25] Schentag JJ, Birmingham MC, Paladino JA, Carr JR, Hyatt JM, Forrest A, Zimmer GS, Adelman MH, Cumbo TJ. In nosocomial pneumonia, optimizing antibiotics other than aminoglycosides is a more important determinant of successful clinical outcome, and a better means of avoiding resistance. Semin Respir Infect. 1997 Dec;12(4):278-93.
[26] Cazzola M, Matera MG, Noschese P. Parenteral antibiotic therapy in the treatment of lower respiratory tract infections. Strategies to minimize thedevelopment of antibiotic resistance. Pulm Pharmacol Ther. 2000;13(6):249-56.
[27] Nawaz M, Hafeez M, Khan FH, Nawaz R, Iqbal T. Bioavailability, disposition kinetics and renal clearance of ampicillin following three routes of administration in sheep. Zentralbl Veterinarmed A. 1989 Feb;36(2):84-9.
[28] Frimodt-Moller N. How predictive is PK/PD for antibacterial agents? Int J Antimicrob Agents. 2002 Apr;19(4):333-9.
[29] Nicolau DP, Quintiliani R. Choosing between the new cephalosporin antibiotics: a pharmacodynamic approach. Pharmacoeconomics. 1994;5(Suppl 2):34-9.
[30] Song JH. Introduction: the goals of antimicrobial therapy. Int J Infect Dis. 2003 Mar;7 Suppl 1:S1-4.
[31] Turnidge JD. The pharmacodynamics of beta-lactams. Clin Infect Dis 1998; 27(1): 10-22.
[32] Levison ME. Pharmacodynamics of antibacterial drugs. Infect Dis Clin North Am 2000; 14(2): 281-91, vii.
[33] Vogelman B, Gudmundsson S, Leggett J, Turnidge J, Ebert S, Craig WA. Correlation of antimicrobial pharmacokinetic parameters with therapeutic efficacy in an animal model. J Infect Dis 1988; 158(4): 831-47.
[34] de Hoog M, Mouton JW, van den Anker JN. New dosing strategies for antibacterial agents in the neonate. Semin Fetal Neonatal Med 2005 Apr; 10(2): 185-94.
[35] Drusano GL. Role of pharmacokinetics in the outcome of infections. Antimicrob Agents Chemother 1988; 32: 289-97.
[36] Jacobs MR. How can we predict bacterial eradication?. Int J Infect Dis 2003 Mar;7 Suppl 1:S13-20.
[37]Auckenthaler R. Pharmacokinetics and pharmacodynamics of oral beta-lactam antibiotics as a two-dimensional approach to their efficacy. J Antimicrob Chemother 2002; 50 Suppl: 13-7.
[38] Frimodt-Moller N. How predictive is PK/PD for antibacterial agents?. Int J Antimicrob Agents 2002; 19(4): 333-9.
[39] Jacobs MR. Building in efficacy: developing solutions to combat drug-resistant S. pneumoniae. Clin Microbio Infect 2004; 10 Suppl 2:18-27.
[40] MacGowan AP. Pharmacokinetic and pharmacodynamic profile of linezolid in healthy volunteers and patients with Gram-positive infections. J Antimicrob Chemother 2003; 51 Suppl 2:ii17-25.
[41] Burnell JM, Kirby WM. Effectiveness of a new compound, benemid, inelevating serum penicillin concentrations. J Clin Invest 1951 Jul; 30(7): 697-700.
[42] Lepsy CS, Guttendorf RJ, Kugler AR, Smith DE. Effects of organic anion, organic cation, and dipeptide transport inhibitors on cefdinir in the isolated perfused rat kidney. Antimicrob Agents Chemother. 2003 Feb; 47(2): 689-96.
[43] Overbosch D, Van Gulpen C, Hermans J, Mattie H. The effect of probenecid on the renal tubular excretion of benzylpenicillin. Br J Clin Pharmacol. 1988 Jan;25(1):51-8.
[44] Mattie H. Clinical pharmacokinetics of aztreonam. Clin Pharmacokinet. 1988 Mar;14(3):148-55.
[45] Itoh T, Ishida M, Onuki Y, Tsuda Y, Shimada H, Yamada H. Stereoselective renal tubular secretion of carbenicillin. Antimicrob Agents Chemother. 1993 Nov;37(11):2327-32.
[46] Schrogie JJ, Rogers JD, Yeh KC, Davies RO, Holmes GI, Skeggs H, Martin CM. Pharmacokinetics and comparative pharmacology of cefoxitin and cephalosporins. Rev Infect Dis. 1979 Jan-Feb;1(1):90-8.
[47] Bergan T. Pharmacokinetic properties of the cephalosporins. Drugs. 1987;34 Suppl 2:89-104.
[48] Shiba K, Yoshida M, Shimada J, Saito A, Matsubayashi K, Hashimoto S, Yoshida K, Osada Y, Sakai O. Effect of probenecid on the pharmacokinetics of DQ-2556, a new 3-quaternary ammonium cephalosporin antibiotic, in humans. Chemotherapy. 1992;38(6):369-75.
[49]Tjandramaga TB, Mullie A, Verbesselt R, De Schepper PJ, Verbist L. Piperacillin: human pharmacokinetics after intravenous and intramuscular administration. Antimicrob Agents Chemother. 1978;14(6):829-37.
[50] Goodwin CS, Raftery EB, Goldberg AD, Skeggs H, Till AE, Martin CM. Effects of rate of infusion and probenecid on serum levels, renal excretion, and tolerance of intravenous doses of cefoxitin in humans: comparison with cephalothin. Antimicrob Agents Chemother. 1974; 6(3): 338-46.
[51] Liu C, Hinthorn DR, Hodges GR, Harms JL, Couchonnal G, Dworzack DL. Penetration of cefoxitin into cerebrospinal fluid:comparison with cefamandole, ampicillin and penicillin. Rev Infect Dis 1979 ;1(1):127-31.
[52] Garton AM, Rennie RP, Gilpin J, Marrelli M, Shafran SD. Comparison of dose doubling with probenecid for sustaining serum cefuroxime levels. J Antimicrob Chemother 1997; 40(6): 903-6.
[53] Paulsen O, Hoglund P, Schalen C. Pharmacokinetic comparison of two models of endocarditis prophylaxis with amoxycillin. Scand J Infect Dis1989; 21(6): 669-73.
[54] Allen MB, Fitzpatrick RW, Barratt A, Cole RB. The use of probenecid to increase the serum amoxycillin levels in patients with bronchiectasis. Respir Med 1990; 84(2): 143-6.
[55] Ko H, Cathcart KS, Griffith DL, Peters GR, Adams WJ. Pharmacokinetics of intravenously administered cefmetazole and cefoxitin and effects of probenecid on cefmetazole elimination. Antimicrob Agents Chemother. 1989 Mar;33(3):356-61.
[56] Baddour LM, Busby L, Shapiro E, Cox KB, Glassco S, Johnson JK. Evaluation of treatment with single-dose ampicillin/sulbactam with probenecid or ceftriaxone in patients with uncomplicated gonorrhea. Sex Transm Dis. 1992 Nov-Dec;19(6):341-5.
[57] Massarotti EM, Luger SW, Rahn DW, Messner RP, Wong JB, Johnson RC, Steere AC. Treatment of early Lyme disease. Am J Med. 1992 Apr;92(4):396-403.
[58] Dattwyler RJ, Volkman DJ, Conaty SM, Platkin SP, Luft BJ. Amoxycillin plus probenecid versus doxycycline for treatment of erythema migrans borreliosis. Lancet. 1990 Dec 8;336(8728):1404-6.
[60] 林志彬,金有豫 主编.医用药理学(第四版).世界图书公司北京公司,1998: 324-348.
[61] 王镜岩,朱圣庚,徐长法 主编.生物化学(第三版)(上册).高等教育出版社, 2002: 523-549.
[62] 刘定远 主编. 医药数理统计方法(第三版). 北京:人民卫生出版社,1999: 205-208.
[2] Kanra G. Experience with ampicillin/sulbactam in severe infections. J Int Med Res. 2002;30 Suppl 1:20A-30A.
[3] Dajani A. Use of ampicillin/sulbactam and sultamicillin in pediatric infections: a re-evaluation. J Int Med Res. 2001 Jul-Aug;29(4):257-69.
[4] Lode H. Role of sultamicillin and ampicillin/sulbactam in the treatment of upper and lower bacterial respiratory tract infections. Int J Antimicrob Agents. 2001 Sep;18(3):199-209.
[5] Cunha BA. Ampicillin/sulbactam in lower respiratory tract infections: a review. Clin Ther. 1991 Nov-Dec;13(6):714-26.
[6] Zenon GJ 3rd, Cadle RM, Hamill RJ. Ampicillin-sulbactam therapy for multiple pyogenic hepatic abscesses. Clin Pharm. 1990 Dec;9(12):939-47.
[7] Bluestone CD. Role of sulbactam/ampicillin and sultamicillin in the treatment of bacterial infections of the upper respiratory tract of children. APMIS Suppl. 1989;5:35-40.
[8] Benson JM, Nahata MC. Sulbactam/ampicillin, a new beta-lactamase inhibitor/beta-lactam antibiotic combination. Drug Intell Clin Pharm. 1988 Jul-Aug;22(7-8):534-41.
[9] Levin AS, Levy CE, Manrique AE, Medeiros EA, Costa SF. Severe nosocomial infections with imipenem-resistant Acinetobacter baumannii treated with ampicillin/sulbactam. Int J Antimicrob Agents. 2003 Jan;21(1):58-62.
[10] Okimoto N, Kurihara T, Honda N, Asaoka N, Fujita K, Ohba H, Nakamura J. Clinical effect of ampicillin with beta-lactamase inhibitor (sulbactam/ampicillin) on community-acquired pneumonia in the elderly. J Infect Chemother. 2003 Jun;9(2):183-6.
[11] Seven H, Sayin I, Turgut S. Antibiotic prophylaxis in clean neck dissections. J Laryngol Otol. 2004 Mar;118(3):213-6.
[12] Acquarolo A, Urli T, Perone G, Giannotti C, Candiani A, Latronico N. Antibiotic prophylaxis of early onset pneumonia in critically ill comatose patients. A randomized study. Intensive Care Med. 2005 Apr;31(4):510-6. Epub 2005 Mar 8.
[13] Jaureguy F, Carton M, Panel P, Foucaud P, Butel MJ, Doucet-Populaire F. Effects of intrapartum penicillin prophylaxis on intestinal bacterial colonization in infants. J Clin Microbiol. 2004 Nov;42(11):5184-8.
[14] Yerdel MA, Akin EB, Dolalan S, Turkcapar AG, Pehlivan M, Gecim IE, Kuterdem E. Effect of single-dose prophylactic ampicillin and sulbactam on wound infection after tension-free inguinal hernia repair with polypropylene mesh: the randomized, double-blind, prospective trial. Ann Surg. 2001 Jan;233(1):26-33.
[15] Maezawa Y, Hirasawa A, Abe T, Kawamura H, Sekiguchi K, Kunimoto M, Sato T, Wakabayashi Y, Nishikawa T. Successful treatment of listerial brain abscess: a case report and literature review. Intern Med. 2002 Nov;41(11):1073-8.
[16] Brown JC, Burns JL, Cummings P. Ampicillin use in infant fever: a systematic review. Arch Pediatr Adolesc Med. 2002 Jan;156(1):27-32.
[17] Marget W, Seeliger HP. Listeria monocytogenes infections--therapeutic possibilities and problems. Infection. 1988;16 Suppl 2:S175-7.
[18] Drusano GL, Craig WA. Relevance of pharmacokinetics and pharmacodynamics in the selection of antibiotics for respiratory tract infections. J Chemother. 1997 May;9 Suppl 3:38-44.
[19] Redington J, Ebert SC, Craig WA. Role of antimicrobial pharmacokinetics and pharmacodynamics in surgical prophylaxis. Rev Infect Dis. 1991 Sep-Oct;13 Suppl 10:S790-9.
[20] Jacobs MR. How can we predict bacterial eradication? Int J Infect Dis. 2003 Mar;7 Suppl 1:S13-20.
[21] Craig WA. Choosing an antibiotic on the basis of pharmacodynamics. Ear Nose Throat J. 1998 Jun;77(6 Suppl):7-11; discussion 11-2.
[22] Garton AM, Rennie RP, Gilpin J, Marrelli M, Shafran SD. Comparison of dose doubling with probenecid for sustaining serum cefuroxime levels. J Antimicrob Chemother. 1997 Dec;40(6):903-6.
[23] Sarasola P, McKellar QA. Effect of probenecid on disposition kinetics of ampicillin in horses. Vet Rec. 1992 Aug 22;131(8):173-5.
[24] Schentag JJ. Antimicrobial action and pharmacokinetics/pharmacodynami- cs: the use of AUIC to improve efficacy and avoid resistance. J Chemother. 1999 Dec;11(6):426-39.
[25] Schentag JJ, Birmingham MC, Paladino JA, Carr JR, Hyatt JM, Forrest A, Zimmer GS, Adelman MH, Cumbo TJ. In nosocomial pneumonia, optimizing antibiotics other than aminoglycosides is a more important determinant of successful clinical outcome, and a better means of avoiding resistance. Semin Respir Infect. 1997 Dec;12(4):278-93.
[26] Cazzola M, Matera MG, Noschese P. Parenteral antibiotic therapy in the treatment of lower respiratory tract infections. Strategies to minimize thedevelopment of antibiotic resistance. Pulm Pharmacol Ther. 2000;13(6):249-56.
[27] Nawaz M, Hafeez M, Khan FH, Nawaz R, Iqbal T. Bioavailability, disposition kinetics and renal clearance of ampicillin following three routes of administration in sheep. Zentralbl Veterinarmed A. 1989 Feb;36(2):84-9.
[28] Frimodt-Moller N. How predictive is PK/PD for antibacterial agents? Int J Antimicrob Agents. 2002 Apr;19(4):333-9.
[29] Nicolau DP, Quintiliani R. Choosing between the new cephalosporin antibiotics: a pharmacodynamic approach. Pharmacoeconomics. 1994;5(Suppl 2):34-9.
[30] Song JH. Introduction: the goals of antimicrobial therapy. Int J Infect Dis. 2003 Mar;7 Suppl 1:S1-4.
[31] Turnidge JD. The pharmacodynamics of beta-lactams. Clin Infect Dis 1998; 27(1): 10-22.
[32] Levison ME. Pharmacodynamics of antibacterial drugs. Infect Dis Clin North Am 2000; 14(2): 281-91, vii.
[33] Vogelman B, Gudmundsson S, Leggett J, Turnidge J, Ebert S, Craig WA. Correlation of antimicrobial pharmacokinetic parameters with therapeutic efficacy in an animal model. J Infect Dis 1988; 158(4): 831-47.
[34] de Hoog M, Mouton JW, van den Anker JN. New dosing strategies for antibacterial agents in the neonate. Semin Fetal Neonatal Med 2005 Apr; 10(2): 185-94.
[35] Drusano GL. Role of pharmacokinetics in the outcome of infections. Antimicrob Agents Chemother 1988; 32: 289-97.
[36] Jacobs MR. How can we predict bacterial eradication?. Int J Infect Dis 2003 Mar;7 Suppl 1:S13-20.
[37]Auckenthaler R. Pharmacokinetics and pharmacodynamics of oral beta-lactam antibiotics as a two-dimensional approach to their efficacy. J Antimicrob Chemother 2002; 50 Suppl: 13-7.
[38] Frimodt-Moller N. How predictive is PK/PD for antibacterial agents?. Int J Antimicrob Agents 2002; 19(4): 333-9.
[39] Jacobs MR. Building in efficacy: developing solutions to combat drug-resistant S. pneumoniae. Clin Microbio Infect 2004; 10 Suppl 2:18-27.
[40] MacGowan AP. Pharmacokinetic and pharmacodynamic profile of linezolid in healthy volunteers and patients with Gram-positive infections. J Antimicrob Chemother 2003; 51 Suppl 2:ii17-25.
[41] Burnell JM, Kirby WM. Effectiveness of a new compound, benemid, inelevating serum penicillin concentrations. J Clin Invest 1951 Jul; 30(7): 697-700.
[42] Lepsy CS, Guttendorf RJ, Kugler AR, Smith DE. Effects of organic anion, organic cation, and dipeptide transport inhibitors on cefdinir in the isolated perfused rat kidney. Antimicrob Agents Chemother. 2003 Feb; 47(2): 689-96.
[43] Overbosch D, Van Gulpen C, Hermans J, Mattie H. The effect of probenecid on the renal tubular excretion of benzylpenicillin. Br J Clin Pharmacol. 1988 Jan;25(1):51-8.
[44] Mattie H. Clinical pharmacokinetics of aztreonam. Clin Pharmacokinet. 1988 Mar;14(3):148-55.
[45] Itoh T, Ishida M, Onuki Y, Tsuda Y, Shimada H, Yamada H. Stereoselective renal tubular secretion of carbenicillin. Antimicrob Agents Chemother. 1993 Nov;37(11):2327-32.
[46] Schrogie JJ, Rogers JD, Yeh KC, Davies RO, Holmes GI, Skeggs H, Martin CM. Pharmacokinetics and comparative pharmacology of cefoxitin and cephalosporins. Rev Infect Dis. 1979 Jan-Feb;1(1):90-8.
[47] Bergan T. Pharmacokinetic properties of the cephalosporins. Drugs. 1987;34 Suppl 2:89-104.
[48] Shiba K, Yoshida M, Shimada J, Saito A, Matsubayashi K, Hashimoto S, Yoshida K, Osada Y, Sakai O. Effect of probenecid on the pharmacokinetics of DQ-2556, a new 3-quaternary ammonium cephalosporin antibiotic, in humans. Chemotherapy. 1992;38(6):369-75.
[49]Tjandramaga TB, Mullie A, Verbesselt R, De Schepper PJ, Verbist L. Piperacillin: human pharmacokinetics after intravenous and intramuscular administration. Antimicrob Agents Chemother. 1978;14(6):829-37.
[50] Goodwin CS, Raftery EB, Goldberg AD, Skeggs H, Till AE, Martin CM. Effects of rate of infusion and probenecid on serum levels, renal excretion, and tolerance of intravenous doses of cefoxitin in humans: comparison with cephalothin. Antimicrob Agents Chemother. 1974; 6(3): 338-46.
[51] Liu C, Hinthorn DR, Hodges GR, Harms JL, Couchonnal G, Dworzack DL. Penetration of cefoxitin into cerebrospinal fluid:comparison with cefamandole, ampicillin and penicillin. Rev Infect Dis 1979 ;1(1):127-31.
[52] Garton AM, Rennie RP, Gilpin J, Marrelli M, Shafran SD. Comparison of dose doubling with probenecid for sustaining serum cefuroxime levels. J Antimicrob Chemother 1997; 40(6): 903-6.
[53] Paulsen O, Hoglund P, Schalen C. Pharmacokinetic comparison of two models of endocarditis prophylaxis with amoxycillin. Scand J Infect Dis1989; 21(6): 669-73.
[54] Allen MB, Fitzpatrick RW, Barratt A, Cole RB. The use of probenecid to increase the serum amoxycillin levels in patients with bronchiectasis. Respir Med 1990; 84(2): 143-6.
[55] Ko H, Cathcart KS, Griffith DL, Peters GR, Adams WJ. Pharmacokinetics of intravenously administered cefmetazole and cefoxitin and effects of probenecid on cefmetazole elimination. Antimicrob Agents Chemother. 1989 Mar;33(3):356-61.
[56] Baddour LM, Busby L, Shapiro E, Cox KB, Glassco S, Johnson JK. Evaluation of treatment with single-dose ampicillin/sulbactam with probenecid or ceftriaxone in patients with uncomplicated gonorrhea. Sex Transm Dis. 1992 Nov-Dec;19(6):341-5.
[57] Massarotti EM, Luger SW, Rahn DW, Messner RP, Wong JB, Johnson RC, Steere AC. Treatment of early Lyme disease. Am J Med. 1992 Apr;92(4):396-403.
[58] Dattwyler RJ, Volkman DJ, Conaty SM, Platkin SP, Luft BJ. Amoxycillin plus probenecid versus doxycycline for treatment of erythema migrans borreliosis. Lancet. 1990 Dec 8;336(8728):1404-6.
[60] 林志彬,金有豫 主编.医用药理学(第四版).世界图书公司北京公司,1998: 324-348.
[61] 王镜岩,朱圣庚,徐长法 主编.生物化学(第三版)(上册).高等教育出版社, 2002: 523-549.
[62] 刘定远 主编. 医药数理统计方法(第三版). 北京:人民卫生出版社,1999: 205-208.