Optimizing Use of β-Lactam Antibiotics in the Critically Ill

ABSTRACT

The escalation of serious infections in critically ill patients over the past 25 years has continued despite advances in contemporary medicine. Ongoing research to reduce the high morbidity and mortality rates is mandated. β-lactam antibiotics are often used empirically in serious infections. The efficacy of these time-dependent antibiotics is correlated with the time that concentrations are maintained above the minimum inhibitory concentration of the infective pathogen. In critically ill patients, pathophysiological changes can reduce antibiotic concentrations and thus alternative modes of administration such as continuous infusion have been studied and shown to standardize β-lactam pharmacokinetics and meet pharmacodynamic targets. Clinical data supporting the efficacy of continuous infusion are currently scarce, but data continue to grow. Likewise antibiotic resistance continues to grow. Recent data suggest that poor dosing strategies may be contributing to this problem, which is exacerbated by a lack of development of alternate antibiotics. Suffice to say clinicians must use antibiotic regimens that optimally treat the individual patient and reduce the development of antibiotic resistance.

β-lactam - continuous infusion - critically ill - antibiotics - resistance

REFERENCES

• 1 Marshall J C. Inflammation, coagulopathy, and the pathogenesis of multiple organ dysfunction syndrome.  Crit Care Med. 2001;  29 S99-S106
• 2 Rice T W, Bernard G R. Therapeutic intervention and targets for sepsis.  Annu Rev Med. 2005;  56 225-248
• 3 Roberts J A, Lipman J. Antibiotic dosing in intensive care: pharmacokinetics, degree of disease and pharmacodynamics of sepsis.  Clin Pharmacokinet. 2006;  45 755-773
• 4 Garnacho-Montero J, Garnacho-Montero C, Cayuela A, Ortiz-Leyba C. Timing of adequate antibiotic therapy is more determinant of outcome than TNF and IL-10 polymorphisms in septic patients.  Crit Care. 2006;  10 R111
• 5 Talbot G H, Bradley J, Edwards Jr. J E, Gilbert D, Scheld M, Bartlett J G. Bad bugs need drugs: an update on the development pipeline from the Antimicrobial Availability Task Force of the Infectious Diseases Society of America.  Clin Infect Dis. 2006;  42 657-668
• 6 Roberts J A, Boots R, Rickard C M et al.. Is continuous infusion ceftriaxone better than once-a-day dosing in intensive care? A randomized controlled pilot study.  J Antimicrob Chemother. 2007;  59 285-291
• 7 Ali M Z, Goetz M B. A meta-analysis of the relative efficacy and toxicity of single daily dosing versus multiple daily dosing of aminoglycosides.  Clin Infect Dis. 1997;  24 796-809
• 8 Bailey T C, Little J R, Littenberg B, Reichley R M, Dunagan W C. A meta-analysis of extended-interval dosing versus multiple daily dosing of aminoglycosides.  Clin Infect Dis. 1997;  24 786-795
• 9 Wysocki M, Delatour F, Faurisson F. Continuous versus intermittent infusion of vancomycin in severe staphylococcal infections: prospective multicenter randomized study.  Antimicrob Agents Chemother. 2001;  45 2460-2467
• 10 Olofsson S K, Marcusson L L, Komp Lindgren P et al.. Selection of ciprofloxacin resistance in Escherichia coli in an in vitro kinetic model: relation between drug exposure and mutant prevention concentration.  J Antimicrob Chemother. 2006;  57 1116-1121
• 11 Tam V H, Schilling A N, Neshat S, Poole K, Melnick D A, Coyle E A. Optimization of meropenem minimum concentration/MIC ratio to suppress in vitro resistance of Pseudomonas aeruginosa .  Antimicrob Agents Chemother. 2005;  49 4920-4927
• 12 Thomas J K, Forrest A, Bhavnani S M et al.. Pharmacodynamic evaluation of factors associated with the development of bacterial resistance in acutely ill patients during therapy.  Antimicrob Agents Chemother. 1998;  42 521-527
• 13 Roosendaal R, Bakker-Woudenberg I A, Van den Berghe J C, van Raafe M, Michel M F. Continuous versus intermittent administration of ceftazidime in experimental Klebsiella pneumoniae pneumonia in normal and leukopenic rats.  Antimicrob Agents Chemother. 1986;  30 403-408
• 14 Olofsson S K, Geli P, Andersson D I, Cars O. Pharmacodynamic model to describe the concentration-dependent selection of cefotaxime-resistant Escherichia coli .  Antimicrob Agents Chemother. 2005;  49 5081-5091
• 15 Gugel J, Dos Santos Pereira A, Pignatari A C, Gales A C. Beta-Lactam MICs correlate poorly with mutant prevention concentrations for clinical isolates of Acinetobacter spp. and Pseudomonas aeruginosa .  Antimicrob Agents Chemother. 2006;  50 2276-2277
• 16 Firsov A A, Smirnova M V, Lubenko I Y, Vostrov S N, Portnoy Y A, Zinner S H. Testing the mutant selection window hypothesis with Staphylococcus aureus exposed to daptomycin and vancomycin in an in vitro dynamic model.  J Antimicrob Chemother. 2006;  58 1185-1192
• 17 Tsuji B, Rybak M. The influence of Staphylococcus aureus accessory gene regulator function on the development of glycopeptide hetero-resistance in an in vitro pharmacodynamic model. moxifloxacin.  In: 15th European Congress on Clinical Microbiology and Infectious Diseases. Copenhagen; Blackwell Publishing 2005: P-1590
• 18 Craig W. Pharmacokinetic and experimental data on beta-lactam antibiotics in the treatment of patients.  Eur J Clin Microbiol. 1984;  3 575-578
• 19 Craig W A. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men.  Clin Infect Dis. 1998;  26 1-10 quiz 11-12
• 20 Craig W A. Basic pharmacodynamics of antibacterials with clinical applications to the use of beta-lactams, glycopeptides, and linezolid.  Infect Dis Clin North Am. 2003;  17 479-501
• 21 Turnidge J D. The pharmacodynamics of beta-lactams.  Clin Infect Dis. 1998;  27 10-22
• 22 Drusano G L. Antimicrobial pharmacodynamics: critical interactions of “bug and drug”.  Nat Rev Microbiol. 2004;  2 289-300
• 23 Vogelman B, Craig W A. Kinetics of antimicrobial activity.  J Pediatr. 1986;  108 835-840
• 24 Vogelman B, Gudmundsson S, Leggett J, Turnidge J, Ebert S, Craig W A. Correlation of antimicrobial pharmacokinetic parameters with therapeutic efficacy in an animal model.  J Infect Dis. 1988;  158 831-847
• 25 Vogelman B S, Craig W A. Postantibiotic effects.  J Antimicrob Chemother. 1985;  15(Suppl A) 37-46
• 26 Bakker-Woudenberg I A, Roosendaal R. Impact of dosage schedule of antibiotics on the treatment of serious infections.  Intensive Care Med. 1990;  16(Suppl 3) S229-S234
• 27 Leggett J E, Fantin B, Ebert S. Comparative antibiotic dose-effect relations at several dosing intervals in murine pneumonitis and thigh-infection models.  J Infect Dis. 1989;  159 281-292
• 28 Schentag J J, Smith I L, Swanson D J et al.. Role for dual individualization with cefmenoxime.  Am J Med. 1984;  77 43-50
• 29 Mouton J W, Vinks A A, Punt N C. Pharmacokinetic-pharmacodynamic modeling of activity of ceftazidime during continuous and intermittent infusion.  Antimicrob Agents Chemother. 1997;  41 733-738
• 30 Mouton J W, den Hollander J G. Killing of Pseudomonas aeruginosa during continuous and intermittent infusion of ceftazidime in an in vitro pharmacokinetic model.  Antimicrob Agents Chemother. 1994;  38 931-936
• 31 Nuytinck H K, Offermans X J, Kubat K, Goris J A. Whole-body inflammation in trauma patients: an autopsy study.  Arch Surg. 1988;  123 1519-1524
• 32 Gosling P, Sanghera K, Dickson G. Generalized vascular permeability and pulmonary function in patients following serious trauma.  J Trauma. 1994;  36 477-481
• 33 Joukhadar C, Frossard M, Mayer B X et al.. Impaired target site penetration of beta-lactams may account for therapeutic failure in patients with septic shock.  Crit Care Med. 2001;  29 385-391
• 34 Parrillo J E, Parker M M, Natanson C et al.. Septic shock in humans: advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy.  Ann Intern Med. 1990;  113 227-242
• 35 Parrillo J E. Pathogenetic mechanisms of septic shock.  N Engl J Med. 1993;  328 1471-1477
• 36 Pea F, Porreca L, Baraldo M, Furlanut M. High vancomycin dosage regimens required by intensive care unit patients cotreated with drugs to improve haemodynamics following cardiac surgical procedures.  J Antimicrob Chemother. 2000;  45 329-335
• 37 Di Giantomasso D, May C N, Bellomo R. Norepinephrine and vital organ blood flow.  Intensive Care Med. 2002;  28 1804-1809
• 38 Di Giantomasso D, May C N, Bellomo R. Norepinephrine and vital organ blood flow during experimental hyperdynamic sepsis.  Intensive Care Med. 2003;  29 1774-81
• 39 Di Giantomasso D, Bellomo R, May C N. The haemodynamic and metabolic effects of epinephrine in experimental hyperdynamic septic shock.  Intensive Care Med. 2005;  31 454-462
• 40 Livornese L L, Slavin D, Benz R L, Ingerman M J, Santoro J. Use of antibacterial agents in renal failure.  Infect Dis Clin North Am. 2001;  15 983-1002
• 41 Livornese L L, Slavin D, Gilbert B, Robbins P, Santoro J. Use of antibacterial agents in renal failure.  Infect Dis Clin North Am. 2004;  18 551-579
• 42 Trotman R L, Williamson J C, Shoemaker D M, Salzer W L. Antibiotic dosing in critically ill adult patients receiving continuous renal replacement therapy.  Clin Infect Dis. 2005;  41 1159-1166
• 43 Roberts J A, Paratz J D, Paratz E, Krueger W A, Lipman J. Continuous infusion of beta-lactam antibiotics in severe infections: a review of its role.  Int J Antimicrob Agents. 2007;  30 11-18
• 44 Lipman J, Wallis S C, Rickard C M, Fraenkel D. Low cefpirome levels during twice daily dosing in critically ill septic patients: pharmacokinetic modelling calls for more frequent dosing.  Intensive Care Med. 2001;  27 363-370
• 45 Lipman J, Wallis S C, Rickard C. Low plasma cefepime levels in critically ill septic patients: pharmacokinetic modeling indicates improved troughs with revised dosing.  Antimicrob Agents Chemother. 1999;  43 2559-2561
• 46 Lodise Jr T P, Lomaestro B, Drusano G L. Piperacillin-tazobactam for Pseudomonas aeruginosa infection: clinical implications of an extended-infusion dosing strategy.  Clin Infect Dis. 2007;  44 357-363
• 47 Roos J F, Bulitta J, Lipman J, Kirkpatrick C M. Pharmacokinetic-pharmacodynamic rationale for cefepime dosing regimens in intensive care units.  J Antimicrob Chemother. 2006;  58 987-993
• 48 Benko A S, Cappelletty D M, Kruse J A, Rybak M J. Continuous infusion versus intermittent administration of ceftazidime in critically ill patients with suspected gram-negative infections.  Antimicrob Agents Chemother. 1996;  40 691-695
• 49 Buijk S L, Gyssens I C, Mouton J W, Van Vliet A, Verbrugh H A, Bruining H A. Pharmacokinetics of ceftazidime in serum and peritoneal exudate during continuous versus intermittent administration to patients with severe intra-abdominal infections.  J Antimicrob Chemother. 2002;  49 121-128
• 50 Hanes S D, Wood G C, Herring V et al.. Intermittent and continuous ceftazidime infusion for critically ill trauma patients.  Am J Surg. 2000;  179 436-440
• 51 Roberts J A, Roberts M S, Dalley A, Cross S E, Lipman J. Exposure and predicted antimicrobial efficacy in critically ill patients: piperacillin. Paper presented at: Queensland Branch Conference, Society of Hospital Pharmacists of Australia October 20-22, 2006 Brisbane, Australia;
• 52 Jaruratanasirikul S, Sriwiriyajan S, Ingviya N. Continuous infusion versus intermittent administration of cefepime in patients with gram-negative bacilli bacteraemia.  J Pharm Pharmacol. 2002;  54 1693-1696
• 53 Lipman J, Gomersall C D, Gin T, Joynt G M, Young R J. Continuous infusion ceftazidime in intensive care: a randomized controlled trial.  J Antimicrob Chemother. 1999;  43 309-311
• 54 Young R J, Lipman J, Gin T, Gomersall C D, Joynt G M, Oh T E. Intermittent bolus dosing of ceftazidime in critically ill patients.  J Antimicrob Chemother. 1997;  40 269-273
• 55 Boselli E, Breilh D, Rimmele T et al.. Plasma and lung concentrations of ceftazidime administered in continuous infusion to critically ill patients with severe nosocomial pneumonia.  Intensive Care Med. 2004;  30 989-991
• 56 Alou L, Aguilar L, Sevillano D et al.. Is there a pharmacodynamic need for the use of continuous versus intermittent infusion with ceftazidime against Pseudomonas aeruginosa? An in vitro pharmacodynamic model.  J Antimicrob Chemother. 2005;  55 209-213
• 57 Mariat C, Venet C, Jehl F et al.. Continuous infusion of ceftazidime in critically ill patients undergoing continuous venovenous haemodiafiltration: pharmacokinetic evaluation and dose recommendation.  Crit Care. 2006;  10 R26
• 58 Rafati M R, Rouini M R, Mojtahedzadeh M et al.. Clinical efficacy of continuous infusion of piperacillin compared with intermittent dosing in septic critically ill patients.  Int J Antimicrob Agents. 2006;  28 122-127
• 59 Tam V H, Louie A, Lomaestro B M, Drusano G L. Integration of population pharmacokinetics, a pharmacodynamic target, and microbiologic surveillance data to generate a rational empiric dosing strategy for cefepime against Pseudomonas aeruginosa .  Pharmacotherapy. 2003;  23 291-295
• 60 Georges B, Conil J M, Cougot P et al.. Cefepime in critically ill patients: continuous infusion vs. an intermittent dosing regimen.  Int J Clin Pharmacol Ther. 2005;  43 360-369
• 61 Angus B J, Smith M D, Suputtamongkol Y et al.. Pharmacokinetic-pharmacodynamic evaluation of ceftazidime continuous infusion vs intermittent bolus injection in septicaemic melioidosis.  Br J Clin Pharmacol. 2000;  50 184-191
• 62 Lau W K, Mercer D, Itani K M et al.. Randomized, open-label, comparative study of piperacillin-tazobactam administered by continuous infusion versus intermittent infusion for treatment of hospitalized patients with complicated intra-abdominal infection.  Antimicrob Agents Chemother. 2006;  50 3556-3561
• 63 Lorente L, Lorenzo L, Martin M M, Jimenez A, Mora M L. Meropenem by continuous versus intermittent infusion in ventilator-associated pneumonia due to gram-negative bacilli.  Ann Pharmacother. 2006;  40 219-223
• 64 McNabb J J, Nightingale C H, Quintiliani R, Nicolau D P. Cost-effectiveness of ceftazidime by continuous infusion versus intermittent infusion for nosocomial pneumonia.  Pharmacotherapy. 2001;  21 549-555
• 65 Buijs J, Dofferhoff A SM, Mouton J W, van der Meer J WM. Continuous administration of PBP-2- and PBP-3-specific beta-lactams causes higher cytokine responses in murine Pseudomonas aeruginosa and Escherichia coli sepsis.  J Antimicrob Chemother. 2007;  59 926-933
• 66 Wiedemann B. An international perspective on antimicrobial resistance.  Am J Med. 1995;  99 19S-20S
• 67 Fantin B, Ebert S, Leggett J, Vogelman B, Craig W A. Factors affecting duration of in-vivo postantibiotic effect for aminoglycosides against gram-negative bacilli.  J Antimicrob Chemother. 1991;  27 829-836
• 68 Odenholt I, Gustafsson I, Lowdin E, Cars O. Suboptimal antibiotic dosage as a risk factor for selection of penicillin-resistant Streptococcus pneumoniae: in vitro kinetic model.  Antimicrob Agents Chemother. 2003;  47 518-523