Semin Respir Crit Care Med 2007; 28(6): 596-603
DOI: 10.1055/s-2007-996406
© Thieme Medical Publishers

Optimizing Use of Aminoglycosides in the Critically Ill

Rhonda S. Rea1 , Blair Capitano1
  • 1Pharmacy and Therapeutics, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania
Further Information

Publication History

Publication Date:
20 December 2007 (online)

ABSTRACT

In the era of increasing bacterial resistance and a lack of development of new antimicrobials for the treatment of gram-negative infections, aminoglycosides (AGs) are more commonly used in combination with other antimicrobials for the treatment of life-threatening infections in the intensive care unit (ICU).

AGs display concentration-dependent killing activity; thus the rate and extent of bacterial killing increase with increasing peak (Cmax) drug concentrations. Optimizing AG dosing requires attainment of a pharmacodynamic target ratio (Cmax:minimal inhibitory concentration [MIC] ≥ 10) upon first dose, which is associated with a more rapid rate of resolution of infection. Extended-interval AG dosing has been shown to attain this target in the general patient population while decreasing the risk of nephrotoxicity compared with multiple daily dosing. However, ICU patients have pharmacokinetic differences compared with patients who are less ill, including increased volume of distribution and variable clearance, which may make attainment of this target difficult. The need for extended-interval aminoglycoside dosing with Cmax monitoring and MIC determination of the pathogen may be needed to optimally treat serious infections in the critically ill.

REFERENCES

  • 1 Bryant R E, Hood A F, Hood C E, Koenig M G. Factors affecting mortality of gram-negative rod bacteremia.  Arch Intern Med. 1971;  127 120-128
  • 2 Freid M A, Vosti K L. The importance of underlying disease in patients with gram-negative bacteremia.  Arch Intern Med. 1968;  121 418-423
  • 3 Young L S, Meyer R D, Weinstein R J, Anderson E T. Gram-negative rod bacteremia: microbiologic, immunologic, and therapeutic considerations.  Ann Intern Med. 1977;  86 456-471
  • 4 Georges B, Conil J M, Dubouix A et al.. Risk of emergence of Pseudomonas aeruginosa resistance to beta-lactam antibiotics in intensive care units.  Crit Care Med. 2006;  34 1636-1641
  • 5 National Nosocomial Infections Surveillance System . National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 to June 2002.  Am J Infect Control. 2002;  30 458-475
  • 6 Flamm R K, Weaver M K, Thornsberry C et al.. Factors associated with relative rates of antibiotic resistance in Pseudomonas aeruginosa isolates tested in clinical laboratories in the United States from 1999 to 2002.  Antimicrob Agents Chemother. 2004;  48 2431-2436
  • 7 Spellberg B, Powers J H, Brass E P, Miller L G, Edwards J E. Trends in antimicrobial drug development: implications for the future.  Clin Infect Dis. 2004;  38 1279-1286
  • 8 Kollef M H. Gram-negative bacterial resistance: evolving patterns and treatment paradigms.  Clin Infect Dis. 2005;  40 S85-S88
  • 9 Craig W A. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men.  Clin Infect Dis. 1998;  26 1-10 quiz 1-2
  • 10 Moore R D, Lietman P S, Smith C R. Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration.  J Infect Dis. 1987;  155 93-99
  • 11 Kashuba A D, Nafziger A N, Drusano G L, Bertino J S. Optimizing aminoglycoside therapy for nosocomial pneumonia caused by gram-negative bacteria.  Antimicrob Agents Chemother. 1999;  43 623-629
  • 12 Burgess D S. Use of pharmacokinetics and pharmacodynamics to optimize antimicrobial treatment of Pseudomonas aeruginosa infections.  Clin Infect Dis. 2005;  40 S99-S104
  • 13 Gilbert D N. Aminoglycosides. In: Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 5th ed. Philadelphia; Churchill Livingstone 2000: 307-336
  • 14 Feld R, Rachlis A, Tuffnell P G et al.. Empiric therapy for infections in patients with granulocytopenia: continuous v interrupted infusion of tobramycin plus cefamandole.  Arch Intern Med. 1984;  144 1005-1010
  • 15 Feld R, Valdivieso M, Bodey G P, Rodriguez V. A comparative trial of sisomicin therapy by intermittent versus continuous infusion.  Am J Med Sci. 1977;  274 179-188
  • 16 Reiner N E, Bloxham D D, Thompson W L. Nephrotoxicity of gentamicin and tobramycin given once daily or continuously in dogs.  J Antimicrob Chemother. 1978;  4(Suppl A) 85-101
  • 17 Urban A W, Craig W A. Daily dosage of aminoglycosides.  Curr Clin Top Infect Dis. 1997;  17 236-255
  • 18 Craig W A. Post-antibiotic effects in experimental infection models: relationship to in-vitro phenomena and to treatment of infections in man.  J Antimicrob Chemother. 1993;  31(Suppl D) 149-158
  • 19 Craig W A, Redington J, Ebert S C. Pharmacodynamics of amikacin in vitro and in mouse thigh and lung infections.  J Antimicrob Chemother. 1991;  27(Suppl C) 29-40
  • 20 Fisman D N, Kaye K M. Once-daily dosing of aminoglycoside antibiotics.  Infect Dis Clin North Am. 2000;  14 475-487
  • 21 Kapusnik J E, Hackbarth C J, Chambers H F, Carpenter T, Sande M A. Single, large, daily dosing versus intermittent dosing of tobramycin for treating experimental pseudomonas pneumonia. [erratum appears in J Infect Dis 1988;158:911].  J Infect Dis. 1988;  158 7-12
  • 22 Barclay M L, Begg E J, Hickling K G. What is the evidence for once-daily aminoglycoside therapy?.  Clin Pharmacokinet. 1994;  27 32-48
  • 23 Davies J, Wright G D. Bacterial resistance to aminoglycoside antibiotics.  Trends Microbiol. 1997;  5 234-240
  • 24 Miller G H, Sabatelli F J, Hare R S et al.. The most frequent aminoglycoside resistance mechanisms-changes with time and geographic area: a reflection of aminoglycoside usage patterns? Aminoglycoside Resistance Study Groups.  Clin Infect Dis. 1997;  24(Suppl 1) S46-S62
  • 25 Jana S, Deb J K. Molecular understanding of aminoglycoside action and resistance.  Appl Microbiol Biotechnol. 2006;  70 140-150
  • 26 Daikos G L, Lolans V T, Jackson G G. First-exposure adaptive resistance to aminoglycoside antibiotics in vivo with meaning for optimal clinical use.  Antimicrob Agents Chemother. 1991;  35 117-123
  • 27 Maglio D, Nightingale C H, Nicolau D P. Extended interval aminoglycoside dosing: from concept to clinic.  Int J Antimicrob Agents. 2002;  19 341-348
  • 28 Streit J M, Jones R N, Sader H S, Fritsche T R. Assessment of pathogen occurrences and resistance profiles among infected patients in the intensive care unit: report from the SENTRY Antimicrobial Surveillance Program (North America, 2001).  Int J Antimicrob Agents. 2004;  24 111-118
  • 29 Jones R N, Sader H S, Beach M L. Contemporary in vitro spectrum of activity summary for antimicrobial agents tested against 18569 strains non-fermentative gram-negative bacilli isolated in the SENTRY Antimicrobial Surveillance Program (1997-2001).  Int J Antimicrob Agents. 2003;  22 551-556
  • 30 Mathai D, Lewis M T, Kugler K C et al.. Antibacterial activity of 41 antimicrobials tested against over 2773 bacterial isolates from hospitalized patients with pneumonia: I-results from the SENTRY Antimicrobial Surveillance Program (North America, 1998). [erratum appears in Diagn Microbiol Infect Dis 2001;39:275].  Diagn Microbiol Infect Dis. 2001;  39 105-116
  • 31 Schmitz F J, Verhoef J, Fluit A C. Prevalence of aminoglycoside resistance in 20 European university hospitals participating in the European SENTRY Antimicrobial Surveillance Programme.  Eur J Clin Microbiol Infect Dis. 1999;  18 414-421
  • 32 Friedland I, Gallagher G, King T, Woods G L. Antimicrobial susceptibility patterns in Pseudomonas aeruginosa: data from a multicenter Intensive Care Unit Surveillance Study (ISS) in the United States.  J Chemother. 2004;  16 437-441
  • 33 Obritsch M D, Fish D N, MacLaren R, Jung R. National surveillance of antimicrobial resistance in Pseudomonas aeruginosa isolates obtained from intensive care unit patients from 1993 to 2002.  Antimicrob Agents Chemother. 2004;  48 4606-4610
  • 34 Eagle H, Fleischman R, Levy M. “Continuous” vs. “discontinuous” therapy with penicillin; the effect of the interval between injections on therapeutic efficacy.  N Engl J Med. 1953;  248 481-488
  • 35 Eagle H, Fleischman R, Musselman A D. The effective concentrations of penicillin in vitro and in vivo for streptococci, pneumococci, and Treponema pallidum .  J Bacteriol. 1950;  59 625-643
  • 36 Eagle H, Fleischman R, Musselman A D. Effect of schedule of administration on the therapeutic efficacy of penicillin: importance of the aggregate time penicillin remains at effectively bactericidal levels.  Am J Med. 1950;  9 280-299
  • 37 Craig W A, Ebert S C. Killing and regrowth of bacteria in vitro: a review.  Scand J Infect Dis Suppl. 1990;  74 63-70
  • 38 Noone P, Pattison J R, Davies D G. The effective use of gentamicin in life-threatening sepsis.  Postgrad Med J. 1974;  50(Suppl 7) 9-16
  • 39 Moore R D, Smith C R, Lietman P S. Association of aminoglycoside plasma levels with therapeutic outcome in gram-negative pneumonia.  Am J Med. 1984;  77 657-662
  • 40 Moore R D, Smith C R, Lietman P S. The association of aminoglycoside plasma levels with mortality in patients with gram-negative bacteremia.  J Infect Dis. 1984;  149 443-448
  • 41 Kashuba A D, Bertino Jr J S, Nafziger A N. Dosing of aminoglycosides to rapidly attain pharmacodynamic goals and hasten therapeutic response by using individualized pharmacokinetic monitoring of patients with pneumonia caused by gram-negative organisms.  Antimicrob Agents Chemother. 1998;  42 1842-1844
  • 42 Blaser J, Stone B B, Groner M C, Zinner S H. Comparative study with enoxacin and netilmicin in a pharmacodynamic model to determine importance of ratio of antibiotic peak concentration to MIC for bactericidal activity and emergence of resistance.  Antimicrob Agents Chemother. 1987;  31 1054-1060
  • 43 Karlowsky J A, Zhanel G G, Davidson R J, Hoban D J. Once-daily aminoglycoside dosing assessed by MIC reversion time with Pseudomonas aeruginosa .  Antimicrob Agents Chemother. 1994;  38 1165-1168
  • 44 Nicolau D P, Freeman C D, Belliveau P P et al.. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients.  Antimicrob Agents Chemother. 1995;  39 650-655
  • 45 Freeman C D, Nicolau D P, Belliveau P P, Nightingale C H. Once-daily dosing of aminoglycosides: review and recommendations for clinical practice.  J Antimicrob Chemother. 1997;  39 677-686
  • 46 Rea R S, Bigos K, Bies R, Capitano B, Smith R. Suboptimal aminoglycoside dosing in critically ill patients.  Crit Care Med. 2005;  33(12, Suppl) A171
  • 47 Dasta J F, Armstrong D K. Variability in aminoglycoside pharmacokinetics in critically ill surgical patients.  Crit Care Med. 1988;  16 327-330
  • 48 Dager W E. Aminoglycoside pharmacokinetics: volume of distribution in specific adult patient subgroups.  Ann Pharmacother. 1994;  28 944-951
  • 49 Rivers E, Nguyen B, Haystad S et al.. Early goal-directed therapy in the treatment of severe sepsis and septic shock.  N Engl J Med. 2001;  345 1368-1377
  • 50 Wolfe T A, Dasta J. Comment: once-daily aminoglycoside dosing in critically ill patients.  Ann Pharmacother. 1998;  32 1109-1110
  • 51 Tang G J, Tang J J, Lin B S, Kong C W, Lee T Y. Factors affecting gentamicin pharmacokinetics in septic patients.  Acta Anaesthesiol Scand. 1999;  43 726-730
  • 52 Barletta J F, Johnson S B, Nix D E, Nix L C, Erstad B L. Population pharmacokinetics of aminoglycosides in critically ill trauma patients on once-daily regimens.  J Trauma. 2000;  49 869-872
  • 53 Buijk S E, Mouton J W, Gyssens I C, Verbrugh H A, Bruining H A. Experience with a once-daily dosing program of aminoglycosides in critically ill patients.  Intensive Care Med. 2002;  28 936-942
  • 54 Tholl D A, Shikuma L R, Miller T Q et al.. Physiologic response of stress and aminoglycoside clearance in critically ill patients.  Crit Care Med. 1993;  21 248-251
  • 55 Hatala R, Dinh T, Cook D J. Once-daily aminoglycoside dosing in immunocompetent adults: a meta-analysis. [see comment].  Ann Intern Med. 1996;  124 717-725
  • 56 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. [see comment].  Clin Infect Dis. 1997;  24 796-809
  • 57 Hyatt J M, McKinnon P S, Zimmer G S, Schentag J J. The importance of pharmacokinetic/pharmacodynamic surrogate markers to outcome: focus on antibacterial agents.  Clin Pharmacokinet. 1995;  28 143-160
  • 58 Roberts J A, Lipman J. Antibacterial dosing in intensive care: pharmacokinetics, degree of disease and pharmacodynamics of sepsis.  Clin Pharmacokinet. 2006;  45 755-773
  • 59 Finnell D L, Davis G A, Cropp C D, Ensom M H. Validation of the Hartford nomogram in trauma surgery patients.  Ann Pharmacother. 1998;  32 417-421
  • 60 Bauer L A, Blouin R A, Griffen Jr W O, Record K E, Bell R M. Amikacin pharmacokinetics in morbidly obese patients.  Am J Hosp Pharm. 1980;  37 519-522
  • 61 Wolfe T A, Dasta J F. Comment: once-daily aminoglycoside dosing in critically ill patients.  Ann Pharmacother. 1998;  32 1109-1110
  • 62 Xuan D, Nicolau D P, Nightingale C H. Population pharmacokinetics of gentamicin in hospitalized patients receiving once-daily dosing.  Int J Antimicrob Agents. 2004;  23 291-295
  • 63 Paterson D L, Robson J M, Wagener M M. Risk factors for toxicity in elderly patients given aminoglycosides once daily.  J Gen Intern Med. 1998;  13 735-739
  • 64 Bertino Jr J S, Booker L A, Franck P A et al.. Incidence of and significant risk factors for aminoglycoside-associated nephrotoxicity in patients dosed by using individualized pharmacokinetic monitoring. [see comment].  J Infect Dis. 1993;  167 173-179
  • 65 Rybak M J, Albrecht L M, Boike S C, Chandrasekar P H. Nephrotoxicity of vancomycin, alone and with an aminoglycoside.  J Antimicrob Chemother. 1990;  25 679-687
  • 66 Giuliano R A, Verpooten G A, Verbist L, Wedeen R P, De Broe M E. In vivo uptake kinetics of aminoglycosides in the kidney cortex of rats.  J Pharmacol Exp Ther. 1986;  236 470-475
  • 67 De Broe M E, Verbist L, Verpooten G A. Influence of dosage schedule on renal cortical accumulation of amikacin and tobramycin in man.  J Antimicrob Chemother. 1991;  27(Suppl C) 41-47
  • 68 Verpooten G A, Giuliano R A, Verbist L, Eestermans G, De Broe M E. Once-daily dosing decreases renal accumulation of gentamicin and netilmicin.  Clin Pharmacol Ther. 1989;  45 22-27
  • 69 Brummett R E, Fox K E, Bendrick T W, Himes D L. Ototoxicity of tobramycin, gentamicin, amikacin and sisomicin in the guinea pig.  J Antimicrob Chemother. 1978;  4(Suppl A) 73-83
  • 70 Snavely S R, Hodges G R. The neurotoxicity of antibacterial agents.  Ann Intern Med. 1984;  101 92-104
  • 71 Wong J, Brown G. Does once-daily dosing of aminoglycosides affect neuromuscular function?.  J Clin Pharm Ther. 1996;  21 407-411

Rhonda S ReaPharm.D. 

Pharmacy and Therapeutics, University of Pittsburgh, School of Pharmacy

200 Lothrop St., 302 Scaife Hall, Pittsburgh, PA 15213

Email: rhonda_rea@yahoo.com

    >