Abstract
There are considerable laboratory data and information from animal and continuous culture in vitro models to support continuous infusion therapy for penicillins and cephalosporins, but, as yet, the only existing clinical data relate to cephalosporins.
Penicillins do not exert concentration-dependent killing in the therapeutic range but have a post-antibiotic effect (PAE) against Gram-positive cocci but not Gram-negative rods. Animal models indicate the time (T) during which the serum concentrations exceed the minimum inhibitory concentration (MIC) of the pathogen [T > MIC] determines outcomes. Pharmacokinetic studies in humans indicate that continuous infusion with penicillins is possible but there are no clinical data on efficacy.
Cephalosporins have similar pharmacodynamic properties to penicillins; T > MIC determines outcome. Data related to ceftazidime indicate that the drug concentration at steady-state (Css) should exceed the pathogen MIC by >1-fold and perhaps by 4- to 5-fold or more. Human pharmacokinetics of ceftazidime administered by continuous infusion to a wide variety of patient groups indicates that Css of>20 mg/L can easily be achieved using conventional daily doses. Clinical data indicate increased effectiveness of a continuous regimen in neutropenic patients with Gram-negative infection. Furthermore cefuroxime administration by continuous infusion has resulted in lower doses and shorter course durations.
Little is known of the pharmacodynamics of monobactams and there are few clinical data on continuous infusion therapy.
Carbapenems have different pharmacodynamics to other β-lactams as they have concentration-dependent killing and a PAE with both Gram-positive and Gram-negative bacteria. While T > MIC has a role in determining outcomes, the proportion of the dosing interval for which serum drug concentrations should exceed the pathogen MIC is less than for other β-lactams. In vitro models have shown that continuous infusion is effective, as is less frequent dosing. There are few data on continuous infusion of carbapenems but some patients have been treated with once-daily dosing.
Clinically, continuous infusion therapy with penicillins and cephalosporins should be considered in patients infected with susceptible Gram-negative rods not responding to conventional therapy. As an approximation, the same total daily dose should be given but a bolus intravenous injection should be give at the start of continuous infusion to ensure Css is reached rapidly. The Css may be difficult to predict and determination of serum drug concentrations may be indicated. Ideally, the Css should be calculated based on the MIC of the potential pathogen and may be higher or lower than the Css achieved by a conventional daily dose.
Similar content being viewed by others
References
Bodey GP, Ketchel SJ, Rodriguez V. A randomised study of carbenicillin plus cefamandole or tobramycin in the treatment of febrile episodes in cancer patients. Am J Med 1979; 67: 608–16.
Eagle H, Musselman AD. The rate of bacterial action of penicillin in vitro as a function of its concentration, and its paradoxically reduced activity at high concentrations against certain organisms. JExp Med 1948; 88: 99–131.
Craig WA, Ebert SC. Killing and regrowth of bacteria in vitro: a review. Scand J Infect Dis 1991; Suppl. 74: 63–70.
Sabath LD, Lavadier N, Wheeler D, et al. A new type of penicillin resistance in Staphylococcus aureus. Lancet 1977: I; 443–7.
Tuomanen E, Durak DT, Tomasz A. Antibiotic tolerance among clinical isolates of bacteria. Antimicrob Agents Chemother 1986; 30: 521–7.
van Asselt GJ, Mouton RP, van Boven CPA. Penicillin tolerance and treatment failure in Group A streptococcal pharyngotonsillitis. Eur J Clin Microbiol Infect Dis 1996; 15 (2): 107–15.
Craig WA, Gudmundsson S. The post antibiotic effect. In: Lorian V, editor. Antibiotics in laboratory medicine. 3rd ed. Baltimore (MD): Williams and Wilkins, 1996: 296–329.
Sande MA, Korzeniowski OM, Allegro GM, et al. Intermittent or continuous therapy of experimental meningitis due to Streptococcus pneumoniae in rabbits: preliminary observations on the post antibiotic effect in vivo. Rev Infect Dis 1981; 3: 98–109.
Oshida T, Onta T, Nakaniski N, et al. Activity of subminimal inhibitory concentrations of aspoxicillin in prolonging the post antibiotic effect against Staphylococcus aureus. J Antimicrob Chemother 1990; 26: 29–38.
Odenholt I, Holm SE, Cars O. Effects of supra and sub-MIC benzyl penicillin concentrations on group A β haemolytic streptococci during the post antibiotic phase in vivo. J Antimicrob Chemother 1990; 26: 193–201.
Thauvin C, Eliopoulos GM, Willey S, et al. Continuous-infusion ampicillin therapy of enterococcal endocarditis in rats. Antimicrob Agents Chemother 1987; 31: 139–43.
Gengo FM, Manmon TW, Nightingale CH, et al. Integration of pharmacokinetics and pharmacodynamics of methicillin in curative treatment of experimental endocarditis. J Antimicrob Chemother 1984; 14: 619–31.
Bakker-Woudenberg AJM, van den Berg JC, Fontijne P, et al. Efficacy of continuous versus intermittent administration of benzylpenicillin in Streptococcus pneumoniae in normal and immunodeficient rats. Eur J Clin Microbiol 1984; 3 (2): 131–5.
Vogelman B, Gudmundsson S, Leggett J, et al. Correlation of antimicrobial pharmaco-kinetic parameters with therapeutic efficacy in an animal model. J Infect Dis 1988; 158: 831–47.
Mordenti JJ, Quintiliani R, Nightingale CH. Combination antibiotic therapy: a comparison of constant infusion and intermittent bolus dosing in an experimental animal model. J Antimicrob Chemother 1995; 15 Suppl. A: 313–21.
White CA, Toothaker RD. Influence of ampicillin elimination half-life on in vitro bactericidal effect. J Antimicrob Chemother 1985; 15 Suppl. A: 257–60.
van Etta LL, Kravitz GR, Ross TE, et al. Effect of method of administration on extravascular penetration of four antibiotics. Antimicrob Agents Chemother 1982; 21 (6): 873–80.
Lavoie GY, Bergeron MG. Influence of four modes of administration on penetration of aztreonam, cefuroxime and ampicillin into interstitial fluid and fibrin clots and on in vivo efficacy against Haemophilus influenzae. Antimicrob Agents Chemother 1985; 28: 404–12.
Neftel KA, Waltz M, Spengler H, et al. Effect of storage of penicillin G solutions on sensitisation to penicillin G after intravenous administration. Lancet 1982: 1; 986–8.
Visser LG, Arnouts P, van Furth R, et al. Clinical pharmacokinetics of continuous intravenous administration of penicillins. Clin Infect Dis 1993; 17: 491–5.
Weinstein MP, Statton CW, Ackley A, et al. Multicenter collaborative evaluation of a standardised serum bactericidal test as a prognostic indicator in infective endocarditis. Am J Med 1985; 78: 262–9.
Jones BL, Ludland HA, Brown DFJ. High dose ampicillin for the treatment of high level aminoglycoside resistant enterococcal endocarditis. J Antimicrob Chemother 1994; 33: 891–2.
Koerner RJ, Nicol A, Reeves DS, et al. Ciprofloxacin resistant Serratia marcescens endocarditis in as a complication of non-Hodgkin’s lymphoma. J Infect 1994; 29: 73–6.
Mouton JW, Hollander JGD. Killing of Pseudomonas aeruginosa during continuous and intermittent infusion of ceftazidime in an in vitro pharmacokinetic model. Antimicrob Agents Chemother 1994; 38: 931–6.
Mouton JW, Vinks AATMM, Punt NC. Pharmacokinetic-pharmacodynamic modelling of activity of ceftazidime during continuous and intermittent infusion. Antimicrob Agents Chemother 1997; 41: 733–8.
Cappelletty DM, Kang SL, Palmer SM, et al. Pharmacodynamics of ceftazidime administered as continuous infusion or intermittent bolus along and in combination with a single daily dose amikacin against Pseudomonas aeruginosa in an in vitro model. Antimicrob Agents Chemother 1995; 33: 1797–801.
Manduru M, Mihm LB, White RL, et al. In vitro pharmacodynamics of ceftazidime against Pseudomonas aeruginosa isolates from cystic fibrosis patients. Antimicrob Agents Chemother 1997; 41: 2053–6.
Garrison MW, Malone CL, Eiland JE. Activity of once-daily cefpodoxime regimens against Haemophilus influenzae and Streptococcus pneumoniae with an in vitro pharmacodynamic chamber model. Antimicrob Agents Chemother 1996; 40: 1545–7.
Roosendaal R, Bakker-Woudenberg IAJM, van den Berg JC, et al. Therapeutic efficacy of continuous versus intermittent administration of ceftazidime in an experimental Klebsiella pneumoniae pneumonia in rats. J Infect Dis 1985; 152 (2): 281–92.
Roosendaal R, Bakker-Woudenberg IAJM, van den Berghe-van Raffe M, et al. Impact of the dosage schedule on the efficacy of ceftazidime, gentamicin and ciprofloxacin in Klebsiella pneumoniae, pneumonia and septicaemia in leukopenic rats. Eur J Clin Microbiol Infect Dis 1989; 8 (10): 878–87.
Leggett JE, Fantin B, Ebert S, et al. Comparative antibiotic dose-effect relations at several dosing intervals in murine pneumonitis and thigh-infection models. J Infect Dis 1989; 159 (2): 281–92.
Livingston DM, Wang MT. Continuous infusion of cefazolin is superior to intermittent dosing in decreasing infection after haemorrhagic shock. Am J Surg 1993; 165: 203–7.
Onyeji CO, Nicolau DP, Nightingale CH, et al. Optimal times above MICs of ceftibuten and cefaclor in experimental intraabdominal infections. Antimicrob Agents Chemother 1994; 38: 1112–7.
Bergeron MG, Simard P. Influence of three modes of administration on the penetration of latamoxef into interstital fluid and fibrin clots and its in vivo activity against Haemophilus influenzae. J Antimicrob Chemother 1986; 17: 775–84.
Miglioli PA, Xerri L, Palatini P. Influence of the mode of intravenous administration on the penetration of ceftazidime into tissues and pleural exudate of rats. Pharmacology 1991; 43: 242–6.
Mouton JW, Horrevorts AM, Mulder PGH, et al. Pharmacokinetics of ceftazidime in serum and suction blister fluid during continuous and intermittent infusions in healthy volunteers. Antimicrob Agents Chemother 1990; 34: 2307–11.
Vinks AATMM, Touw DJ, Heijerman HEM, et al. Pharmacokinetics of ceftazidime in adult cystic fibrosis patients during continuous infusion and ambulatory treatment at home. Ther Drug Monit 1994; 16: 341–8.
Vinks AATM, Brimicombe RW, Heijerman HGM, et al. Continuous infusion of ceftazidime in cystic fibrosis patients during home treatment: clinical outcome, microbiology and pharmacokinetics. J Antimicrob Chemother 1997; 40: 125–33.
Kuzemko J, Crawford C. Continuous infusion of ceftazidime in cystic fibrosis. Lancet 1989; II: 385.
David TJ, Devlin J. Continuous infusion of ceftazidime in cystic fibrosis. Lancet 1989; I: 1454–5.
Daenen S, Erjavec Z, Uges DRA, et al. Continuous infusion of ceftazidime in febrile neutropenic patients in acute myeloid leukaemia. Eur J Clin Microbiol Infect Dis 1995; 14: 188–92.
Akkerman SR, Dix SP, Lamposona V, et al. Pharmacokinetic of continuous infusion ceftazidime in febrile neutropenic bone marrow transplant patients. Pharmacotherapy 1992; 12: 506.
Rio Y, Leroy F, Humber G, et al. Comparative ceftazidime serum concentrations during continuous infusion in healthy subjects and sever burns patients [abstract A13]. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1994 Oct 4–7; Orlando. Washington, DC: American Society for Microbiology, 1994: 16.
Castela N, Taburet AM, Carlet J, et al. Pharmacokinetics of ceftazidime during continuous infusion in intensive care patients [abstract All]. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1994 Oct 4–7; Orlando. Washington, DC: American Society for Microbiology, 1994: 16.
Benko AS, Cappelletty DM, Kruse JA, et al. Continuous infusion versus intermittent administration of ceftazidime in critically ill patients with suspected Gram-negative infections. Antimicrob Agents Chemother 1996; 40: 691–5.
Lagast H, Meunier-Carpentier F, Klastersky J. Treatment of Gram-negative bacillary septicaemia with cefoperazone. Eur J Clin Microbiol 1983; 2 (6): 554–8.
Schentag JJ, Smith IL, Swanson DJ, et al. Role of dual individualisation with cefmenoxime. Am J Med 1984; 77 Suppl. 6A: 43–50.
Schentag JJ. Correlation of pharmacokinetic parameters to efficacy of antibiotics: relationships between serum concentrations, MIC values and bacterial eradication in patients with Gram-negative pneumonia. Scand J Infect Dis 1991; Suppl. 74: 218–34.
Warren JW, Miller EH, Fitzpatrick B, et al. A randomised controlled trial of cefperazone vs cefamandole-tobramycin in the treatment of putative, severe infections with Gram-negative bacilli. Rev Infect Dis 1983; 5 Suppl. 1: S173–80.
Drusano GL. Human pharmacodynamics of beta-lactams, aminoglycosides and their combinations. Scand J Infect Dis 1991; Suppl. 74: 235–48.
Zeisler JA, McCarthy JD, Richelieu WA, et al. Cefuroxime by continuous infusion: a new standard of care? Infect Med 1992; 9: 54–60.
Miglioli PA, Ragazzi E, Pwerani M, et al. Penetration of carumonam into pleural fluid: comparison of intravenous bolus and constant infusion in rats with experimentally induced pleurisy. Int J Antimicrob Agents 1993; 3: 65–9.
Nicolau DP, Nightingale CH, Quintiliani R. Continuous infusion β lactams: a pharmaco-dynamic approach. Infect Dis Clin Pract 1996; 5 (7): 432–4.
Bowker KE, Holt HA, Reeves DS, et al. Bactericidal activity, post antibiotic effect and modified controlled effective regrowth time of meropenem at high concentrations. J Microb Chemother 1996; 38: 1055–9.
Hanberger H, Svensson E, Nilsson LE, et al. Pharmacodynamic effects of meropenem on Gram-negative bacteria. Eur J Clin Microbiol Infect Dis 1995; 14: 383–90.
Hanberger H. Pharmacodynamic effects of antibiotics: studies on bacterial morphology, initial killing, post antibiotic effect and regrowth time. Scand J Infect Dis 1992; Suppl. 81: 1–52.
Keil S, Wiedemann B. Antimicrobial effects of continuous versus intermittent administration of carbapenem antibiotics in an in vitro dynamic model. Antimicrob Agents Chemother 1997; 41: 1215–9.
Bowker KE, Holt HA, Reeves DS, et al. Pharmacodynamics of meropenem explored by use of single compartment in vitro continuous bacterial culture model [abstract A46]. 36th Interscience Conference of Antimicrobial Agents and Chemotherapy; 1996 Sep 15–18; Orlando. Washington, DC: American Society for Microbiology, 1996.
Maggiolo F, Taras A, Frontespezi S, et al. Bactericidal activity of two different dosage regimens of imipenem in an in vitro dynamic model. J Antimicrob Chemother 1993; 32: 295–300.
Fluckiger U, Segessenmann C, Gerber AU. Integration of pharmacokinetics and pharmacodynamics of imipenem in a humanadapted mouse model. Antimicrob Agents Chemother 1991; 35: 1905–10.
Fuentes F, Martin MM, Izquierdo J, et al. In vivo and in vitro study of several pharmacodynamic effects of meropenem. Scand J Infect Dis 1995; 27: 469–75.
Walker R, Andes D, Conklin R, et al. Pharmacodynamic activities of meropenem in an animal infection model [abstract A91]. 34th Interscience Congress on Antimicrobial Agents and Chemotherapy; 1994 Oct 4–7; Orlando. Washington, DC: American Society for Microbiology, 1994.
Mouton JW, Michel MF. Pharmacokinetics of meropenem in serum and suction blister fluid during continuous and intermittent infusion. J Antimicrob Chemother 1991; 28: 911–8.
Edwards JR. Meropenem: a microbiological overview. J Antimicrob Chemother 1995; 36 Suppl. A: 1–17.
MacGowan AP, Bowker KE, Lovering AM, et al. Once-a-day carbapenem therapy. J Antimicrob Chemother 1996; 38: 327–8.
Ebert SC, Craig WA. Retain intermittent dosing of carbapenems: author’s reply. Antimicrob Agents Chemother 1994; 38: 159–61.
Mathot RAA, de Graaf AI, Vinks AATMM. Stability of meropenem in a portable pump reservoir. Clin Microbiol Infect 1997; 88 (3 Suppl. 2): 393.
Craig W, Ebert S, Watanabe Y. Differences in time above MIIC (T > MIC) required for efficacy of β lactams in animal infection models [abstract 86]. 33rd Interscience Congress on Antimicrobial Agents and Chemotherapy; 1993 Oct 16–19; New Orleans.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
MacGowan, A.P., Bowker, K.E. Continuous Infusion of β-Lactam Antibiotics. Clin Pharmacokinet 35, 391–402 (1998). https://doi.org/10.2165/00003088-199835050-00004
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-199835050-00004