Skip to main content
SpringerLink
Log in

Clinical pharmacokinetics of antimicrobial drugs in cystic fibrosis.

  • Published:
Pharmacy World and Science Aims and scope Submit manuscript

Abstract

The disposition of many drugs in cystic fibrosis is abnormal compared with healthy individuals. In general, changes include an increased volume of distribution expressed in liters per kg bodyweight for highly hydrophilic drugs such as aminoglycosides, and, to a lesser extent, for penicillins and cephalosporins, together with an increased total body clearance. The main reason for the increased volume of distribution is the increased amount of lean tissue per kg bodyweight, since patients with CF are generally undernourished and have a paucity of adipose tissue. The reason for the increased renal clearance is less clear. Increased glomerular filtration and tubular secretion have been observed. Protein binding generally is unaltered in CF. The fluorquinolones and vancomycin show no altered pharmacokinetics in CF although gastro-intestinal absorption may be delayed for fluorquinolones. Sulphamethoxazole shows increased clearance due to an increased acetylation and, in the case of trimethoprim, renal clearance is increased compared with healthy individuals. As a consequence, drugs that show increased clearance, will lead to reduced serum concentrations and smaller AUCs and therefore CF patients require larger doses per kg bodyweight.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

References

  1. Boat TF, Welsh MJ, Beaudet AL. Cystic fibrosis. In: Scriver CL, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis of inherited disease. 6th ed. Vol. 2. New York: McGraw-Hill, 1989:2649-80.

    Google Scholar 

  2. Kate, LP ten. Erfelijkheid en vóórkomen van cystische fibrose. Maandschr Kindergeneeskunde 1975;43:316-28.

    Google Scholar 

  3. Elborn JS, Shale DJ, Britton JR. Cystic fibrosis: current survival and population estimates to the year 2000. Thorax 1991;46:881-5.

    PubMed  Google Scholar 

  4. Fiel SB. Clinical management of pulmonary disease in cystic fibrosis. Lancet 1993;341:1070-74.

    PubMed  Google Scholar 

  5. Veeze HJ. Pathophysiological aspects of cystic fibrosis. Thesis, Rotterdam, 1995.

  6. Webb AK. The difficulties of treating infection in adults with cystic fibrosis. Monaldi Arch Ches Dis 1993;6:657-61.

    Google Scholar 

  7. Frizell RA, Rechkemmer G, Shoemaker RL. Altered regulation of airway epithelial cell chloride channels in cystic fibrosis. Science 1986;233:558-60.

    PubMed  Google Scholar 

  8. Rommens JM, Ianuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 1989;245:1059-65.

    PubMed  Google Scholar 

  9. Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahei R, Grzeiczak Z, et al. Identification of the cystic fibrosis gene: cloning and characterization of the complementary DNA. Science 1989;245:1066-73.

    PubMed  Google Scholar 

  10. Welsh MJ, Smith AE. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell 1993;73:1251-4.

    PubMed  Google Scholar 

  11. Kuhn RJ, Nahata MC. Therapeutic management of cystic fibrosis. Clin Pharm 1985;4:555-65.

    PubMed  Google Scholar 

  12. De Groot R, Smith AL. Antibiotic pharmacokinetics in cystic fibrosis. Differences and clinical significance. Clin Pharmacokinet 1987;13:228-53.

    PubMed  Google Scholar 

  13. Prandota J. Clinical pharmacology of antibiotics and other drugs in cystic fibrosis. Drugs 1988;35:542-78.

    PubMed  Google Scholar 

  14. Horrevorts AM, Driessen O, Michel MF. Pharmacokinetics of antimicrobial drugs in cystic fibrosis. Chest 1988;94 (Suppl.):120-5.

    Google Scholar 

  15. Kelly HW, Lovato C. Antibiotic use in cystic fibrosis. Drug Intell Clin Pharm 1984;18:772-83.

    PubMed  Google Scholar 

  16. Høiby N. Microbiology of cystic fibrosis. In: Hodson ME, Geddes DM, eds. Cystic fibrosis. London: Chapman and Hall Medical, 1995:75-98.

    Google Scholar 

  17. Johansen HK, Høiby N. Seasonal onset of initial colonisation and chronic infection with Pseudomonas aeruginosa in patients with cystic fibrosis in Denmark. Thorax 1992;47:109-11.

    PubMed  Google Scholar 

  18. Høiby N. Antibiotic therapy for chronic infection of Pseudomonas in the lung. Annu Rev Med 1993;44:1-10.

    PubMed  Google Scholar 

  19. Pitcher-Wilmott RW, Levinsky RJ, Gordon I, Turner MW, Matthew DJ. Pseudomonas infections, allergy and cystic fibrosis. Arch Dis Child 1982;57:582-6.

    PubMed  Google Scholar 

  20. Mouton JW, Kerrebijn KF. Antibacterial therapy in cystic fibrosis. Med Clin N Am 1990;74:837-50.

    PubMed  Google Scholar 

  21. Regelmann WE, Elliott GR, Warwick WJ, Clawson CC. Reduction of sputum Pseudomonas aeruginosa density by antibiotics improves lung function in cystic fibrosis more than do bronchodilators and chest physiotherapy alone. Am Rev Respir Dis 1990;141:914-21.

    PubMed  Google Scholar 

  22. Weaver LT, Green MR, Nicholson K, Mills J, Heeley ME, Kuzemko JA, et al. Prognosis in cystic fibrosis treated with continuous flucloxacillin from the neonatal period. Arch Dis Child 1994;70:84-9.

    PubMed  Google Scholar 

  23. Hodson ME. Maintenance treatment with antibiotics in cystic fibrosis patients. Sense or nonsense? Neth J Med 1995;46:288-92.

    PubMed  Google Scholar 

  24. Pleasant RA, Williams DM, Waltner WE, Knowles M. Influence of infusion method on tobramycin serum concentrations in adults with cystic fibrosis. Clin Pharm 1990;9:541-45.

    PubMed  Google Scholar 

  25. Jusko WJ, Mosovich LL, Gerbracht LM, Mattar ME, Yaffe SJ. Enhanced renal excretion of dicloxacillin in patients with cystic fibrosis. Pediatr 1975;56:1038-44.

    Google Scholar 

  26. Yaffe SJ, Gerbracht LM, Mosovich LL, Mattar ME, Danish M, Jusko WJ. Pharmacokinetics of methicillin in patients with cystic fibrosis. J Infect Dis 1977;135:828-31.

    PubMed  Google Scholar 

  27. Martini N, Agostini M, Barlocco G, Bozzini L, Castellani L, Messori A, et al. Serum and sputum concentrations of azlocillin, cefoperazone and ceftazidime in patients with cystic fibrosis. J Clin Hosp Pharm 1984;9:303-9.

    PubMed  Google Scholar 

  28. Bosso JA, Saxon BA, Herbst JJ, Matsen JM. Azlocillin pharmacokinetics in patients with cystic fibrosis. Antimicrob Agents Chemother 1984;25:630-2.

    PubMed  Google Scholar 

  29. De Groot R, Hack BD, Weber A, Chaffin D, Ramsey B, Smith AL. Pharmacokinetics of ticarcillin in patients with cystic fibrosis: A controlled prospective study. Clin Pharmacol Ther 1990;47:73-8.

    PubMed  Google Scholar 

  30. Spino M, Chai RP, Isles AF, Thiesen JJ, Teroso A, Gold R, et al. Cloxacillin absorption and disposition in cystic fibrosis. J Pediatrics 1984;105:829-35.

    Google Scholar 

  31. Malmborg AS, Alfredsson H, Kusoffsky E, Strandvik B. Azlocillin and gentamicin in respiratory tract infections with Pseudomonas aeruginosa in patients with cystic fibrosis. Scand J Infect Dis 1981;29 (suppl):64-9.

    Google Scholar 

  32. Leeder SJ, Spino M, Isles AF, Resoro AM, Gold R, MacLeod SM. Ceftazidime disposition in acute and stable cystic fibrosis. Clin Pharmacol Ther 1984;36:355-62.

    PubMed  Google Scholar 

  33. Padoan R, Brienza A, Crossignani RM, Lodi G, Giunta A, Assael BM, et al. Ceftazidime in treatment of acute pulmonary exacerbations in patients with cystic fibrosis. J Pediatrics 1983;103:320-4.

    Google Scholar 

  34. Permin H, Koch C, Høiby N, Christensen HO, Moller AF, Moller S. Ceftazidime treatment of chronic Pseudomonas aeruginosa respiratory tract infection in cystic fibrosis. J Antimicrob Chemother 1983;12 (suppl A):313-23.

    PubMed  Google Scholar 

  35. Turner A, Pedler SJ, Carswell F, Spencer GR, Speller DCE. Serum and sputum concentrations of ceftazidime in patients with cystic fibrosis. J Antimicrob Chemother 1984;14:521-27.

    PubMed  Google Scholar 

  36. Vinks AATMM, Touw DJ, Heijerman HGM, Danhof M, De Leede GPJ, Bakker W. Pharmacokinetics of ceftazidime in adult cystic fibrosis patients during continuous infusion and ambulatory treatment at home. Ther Drug Monit 1994;16:341-48.

    PubMed  Google Scholar 

  37. Reed MD, Stern RC, Yamashita TS, Ackers I, Myers CM, Blumer JL. Single-dose pharmacokinetics of cefsulodin in patients with cystic fibrosis. Antimicrob Agents Chemother 1984;25:579-81.

    PubMed  Google Scholar 

  38. Hedman A, Alvan G, Strandvik B, Arvidsson A. Increased renal clearance of cefsulodin due to higher glomerular filtration rate in cystic fibrosis. Clin Pharmacokinet 1990;18:168-75.

    PubMed  Google Scholar 

  39. Arguedas AG, Stutman HR, Zaleska M, Knupp CA, Marks MI, Nussbaum E. Cefepime. Pharmacokinetics and clinical response in patients with cystic fibrosis. Am J Dis Child 1992;146:797-802.

    PubMed  Google Scholar 

  40. Huls CE, Prince RA, Seilheimer DK, Bosso JA. Pharmacokinetics of cefepime in cystic fibrosis patients. Antimicrob Agents Chemother 1993;37:1414-16.

    PubMed  Google Scholar 

  41. Hamelin BA, Moore N, Knupp CA, Ruel M, Vallee F, LeBel M. Cefepime pharmacokinetics in cystic fibrosis. Pharmacotherapy 1993;13:465-70.

    PubMed  Google Scholar 

  42. Vinks AATMM, Rossem RN, Mathot RAA, Heijerman HGM, Bakker W. Pharmacokinetics of aztreonam after single dose compared to matched controls and during home treatment by continuous infusion in patients with cystic fibrosis. In: Vinks AATMM. Strategies for pharmacokinetic optimization of continuous infusion therapy of ceftazidime and aztreonam in patients with cystic fibrosis. Thesis, Leiden, 1996.

  43. Bergan T, Michalsen H, Malmborg AS, Pedersen SS, Pressler T, Storrosten OT, Strandvik B. Pharmacokinetic evaluation of imipenem combined with cilastatin in cystic fibrosis. Chemotherapy 1993;39:369-73.

    PubMed  Google Scholar 

  44. Richards DM, Brogden RN. Ceftazidime. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs 1985;29:105-61.

    PubMed  Google Scholar 

  45. Goldfarb J, Wormser GP, Inchiosa MA, Guideri G, Diaz M, Gandhi R, et al. Single-dose pharmacokinetics of oral ciprofloxacin in patients with cystic fibrosis. J Clin Pharmacol 1986;26:222-6.

    PubMed  Google Scholar 

  46. Smith MJ, White LO, Bowyer H, Willis J, Hodson ME, Batten JC. Pharmacokinetics and sputum penetration of ciprofloxacin in patients with cystic fibrosis. Antimicrob Agents Chemother 1986;30:614-6.

    PubMed  Google Scholar 

  47. LeBel M, Bergeron MG, Vallee F, Fiset C, Chasse G, Bigonesse P, et al. Pharmacokinetics and pharmacodynamics of ciprofloxacin in cystic fibrosis patients. Antimicob Agents Chemother 1986;30:260-6.

    Google Scholar 

  48. Davis RL, Koup JR, Williams-Warren J, Weber A, Heggen L, Stempel D, Smith AL. Pharmacokinetics of ciprofloxacin in cystic fibrosis. Antimicrob Agents Chemother 1987;31:915-19.

    PubMed  Google Scholar 

  49. Reed MD, Stern RC, Myers C, Yamashita TS, Blumer JL. Lack of unique ciprofloxacin pharmacokinetic characteristics in patients with cystic fibrosis. J Clin Pharmacol 1988;28:691-9.

    PubMed  Google Scholar 

  50. Mimeault J, Vallee F, Seelman R, Sorgel F, Ruel M, LeBel M. Altered disposition of fleroxacin in patients with cystic fibrosis. Clin Pharmacol Ther 1990;47:618-28.

    PubMed  Google Scholar 

  51. Contrepois A, Brion N, Garaud JJ, Faurisson F, Delatour F, Levy JC, et al. Renal disposition of gentamicin, dibekacin, tobramycin, netilmicin, and amikacin in humans. Antimicrob Agents Chemother 1985;27:520-4.

    PubMed  Google Scholar 

  52. Ansorg R, Muller K-D, Wiora J. Comparison of inhibitory and bactericidal activity of antipseudomonal antibiotics against Pseudomonas aeruginosa isolates from cystic fibrosis patients. Chemotherapy 1990;36:222-9.

    PubMed  Google Scholar 

  53. Bergogne-Berezin E. Pharmacokinetics of antibiotics in cystic fibrosis patients with particular reference to the bronchopulmonary tree (Review). Infection 1987;15:288-94.

    PubMed  Google Scholar 

  54. Fick RB, Stillwell PC. Controversies in the management of pulmonary disease due to cystic fibrosis. Chest 1989;1319-27.

  55. Pottter JL, Matthews LW, Spector S, Lemm J. Complex formation between basic antibiotics and deoxyribonucleic acid in human pulmonary secretions. Pediatrics 1965,36:714-20.

    PubMed  Google Scholar 

  56. Hunt BE, Weber A, Berger A, Ramsey B, Smith AL. Macromolecular mechanisms of sputum inhibition of tobramycin activity. Antimicrob Agents Chemother 1995;39:34-9.

    PubMed  Google Scholar 

  57. Kelly HW, Menendez R, Fan L, Murphy S. Pharmacokinetics of tobramycin in cystic fibrosis. J Pediatr 1982;100:318-21.

    PubMed  Google Scholar 

  58. Kearns GL, Hilman BC, Wilson JT. Dosing implications of altered gentamicin disposition in patients with cystic fibrosis. J Pediatrics 1982;100:312-8.

    Google Scholar 

  59. Bauer LA, Piecoro JJ, Wilson D, Blouin RA. Gentamicin and tobramycin pharmacokinetics in patients with cystic fibrosis. Clin Pharmacy 1983;2:262-4.

    Google Scholar 

  60. Hsu M-C, Aguila HA, Schmidt VL, Munzenberger PJ, Kauffman RE, Polgar G. Individualization of tobramycin dosage in patients with cystic fibrosis. Ped Infect Dis 1984;3:526-9.

    Google Scholar 

  61. Levy J, Smith AL, Koup JR, Williams-Warren J, Ramsey B. Disposition of tobramycin in patients with cystic fibrosis: a prospective controlled study. J Pediatr 1984;105:117-24.

    PubMed  Google Scholar 

  62. Horrevorts AM, Degener JE, Dzoljic-Danilovic G, Michel MF, Kerrebijn KF, Driessen O, et al. Pharmacokinetics of tobramycin in patients with cystic fibrosis: implications for the dosing interval. Chest 1985;88:260-4.

    PubMed  Google Scholar 

  63. Michalsen H, Bergan T. Pharmacokinetics of netilmicin in children with and without cystic fibrosis. Antimicrob Agents Chemother 1981;19:1029-31.

    PubMed  Google Scholar 

  64. Bosso JA, Townsend PL, Herbst JJ, Matsen JM. Pharmacokinetics and dosage requirements of netilmicin in cystic fibrosis patients. Antimicrob Agents Chemother 1985;28:829-31.

    PubMed  Google Scholar 

  65. Mann HJ, Canafax DM, Cipolle RJ, Daniels CE, Zaske DE, Warwick WJ. Increased dosage requirements of tobramycin and gentamicin for treating Pseudomonas pneumonia in patients with cystic fibrosis. Pediatr Pulmonol 1985;1:238-43.

    PubMed  Google Scholar 

  66. MacDonald NE, Anas NG, Peterson RG, Schwartz RH, Brooks JG, Powell KR. Renal clearance of gentamicin in cystic fibrosis. J Pediatr 1983;103:985-90.

    PubMed  Google Scholar 

  67. Touw DJ, Vinks AATMM, Heijerman HGM, Bakker W. Validation of tobramycin monitoring in adolescent and adult patients with cystic fibrosis. Ther Drug Monit 1993;15:52-9.

    PubMed  Google Scholar 

  68. Touw DJ, Vinks AATMM, Heijerman HGM, Hermans J, Bakker W. Suggestions for the optimization of the initial tobramycin dose in adolescent and adult patients with cystic fibrosis. Ther Drug Monit 1994;16:125-31.

    PubMed  Google Scholar 

  69. Touw DJ, Vinks AATMM, Heijerman HGM, Bakker W. Prospective evaluation of a dose prediction algorithm for intravenous tobramycin in adolescent and adult patients with cystic fibrosis. Ther Drug Monit 1996;18:118-23.

    PubMed  Google Scholar 

  70. MacDonald NE, Morris RF, Peterson RG. Disease sevirity as a factor in elimination of tobramycin (tobra) in patients with cystic fibrosis (CF) [abstract]. Pediatr Res 1987;21:238A.

    Google Scholar 

  71. Horner GW, Stempel DA. Tobramycin elimination rate change from first to later doses in older cystic fibrosis patients. Drug Intell Clin Pharm 1987;21:276-8.

    PubMed  Google Scholar 

  72. Autret E, Marchand S, Breteau M, Grenier B. Pharmacokinetics of amikacin in cystic fibrosis: a study of bronchial diffusion. Eur J Clin Pharmacol 1986;31:79-83.

    PubMed  Google Scholar 

  73. Canis F, Husson MO, Turck D, Vic P, Launay V, Ategbo S, et al. Pharmacokinetics and bronchial diffusion of single daily dose amikacin in cystic fibrosis patients. J Antimicrob Chemother 1997;39:431-3.

    PubMed  Google Scholar 

  74. Bosso JA, Relling MV, Townsend PL, Herbst JJ, Matsen JM. Intra-patient variability in aminoglycoside disposition in cystic fibrosis. Clin Pharmacokinet 1987;6:54-8.

    Google Scholar 

  75. Touw DJ, Vinks AATMM, Jacobs F, Heijerman HGM, Bakker W. Creatinine clearance as predictor of tobramycin elimination in adult patients with cystic fibrosis. Ther Drug Monit 1996;18:562-9.

    PubMed  Google Scholar 

  76. Thomassen MJ, Demko CA, Doershuk CF. Cystic fibrosis: a review of pulmonary infections and interventions. Pediatr Pulmonol 1987;3:334-51.

    PubMed  Google Scholar 

  77. Hutabarat RM, Unadkat JD, Sahajwalla C, McNamara S, Ramsey B, Smith AL. Disposition of drugs in cystic fibrosis. I. Sulphamethoxazole and trimethoprim. Clin Pharmacol Ther 1991;49:402-9.

    PubMed  Google Scholar 

  78. Pleasant RA, Michalets EL, Williams DM, Samuelson WM, Rehm JR, Knowles MR. Pharmacokinetics of vancomycin in adult cystic fibrosis. Antimicrob Agents Chemother 1996;40:186-90.

    PubMed  Google Scholar 

  79. Boeckh M, Lode K, Borner K, Hoffken G, Hoffken J, Wagner J, et al. Pharmacokinetics and serum bactericidal activity of vancomycin alone and in combination with ceftazidime in healthy volunteers. Antimicrob Agents Chemother 1988;32:92-5.

    PubMed  Google Scholar 

  80. Healy DP, Polk RE, Garson ML, Roek DT, Comstock TJ. Comparison of steady-state pharmacokinetics of two dosage regimens of vancomycin in normal volunteers. Antimicrob Agents Chemother 1987;31:393-7.

    PubMed  Google Scholar 

  81. Spino M. Pharmacokinetics of drugs in cystic fibrosis. In: Gershwin E, ed. Clinical reviews in allergy, vol 9: Cystic Fibrosis. The Humana Press Inc, 1991;169-210.

  82. Mattie H. Pharmacokinetics of antimicrobial drugs in cystic fibrosis. β-Lactam antibiotics. Discussion. Chest 1998;94 (Suppl.):119S-20S.

    Google Scholar 

  83. Touw DJ, Optimization of tobramycin treatment in cystic fibrosis. Thesis, Leiden, 1996.

  84. Wang J-P, Unadkat JD, Al-Habet SMH, O'sullivan TA, Williams-Warren J, Smith AL, Ramsey B. Disposition of drugs in cystic fibrosis. IV. Mechanisms for enhanced renal clearance of ticarcillin. Clin Pharmacol Ther 1993;54:293-302.

    PubMed  Google Scholar 

  85. Spino M, Chai RP, Isles AF, Balfe JW, Brown RG, Thiesen JJ, et al. Assessment of glomerular filtration rate and effective renal plasma flow in cystic fibrosis. J Pediatrics 1985;107:64-70.

    Google Scholar 

  86. Hedman A, Adan-Abdi Y, Alvan G, Strandvik B, Arvidsson A. Influence of the glomerular filtration rate on renal clearance of ceftazidime in cystic fibrosis. Clin Pharmacokinet 1988;15:57-65.

    PubMed  Google Scholar 

  87. Prandota J. Drug disposition in cystic fibrosis: progress in understanding pathophysiology and pharmacokinetics. Pediatr Infect Dis J 1987;6:1111-26.

    PubMed  Google Scholar 

  88. Stenvinkel P, Hjelte L, Alvan G, Hedman A, Hultman E, Strandvik B. Decreased renal clearance of sodium in cystic fibrosis. Acta Paediatr Scand 1991;80:194-8.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacy, University Hospital Vrije Universiteit, P.O. Box 7057, NL‐1007 MB, Amsterdam, The Netherlands

    D.J. Touw

Authors
  1. D.J. Touw
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Touw, D. Clinical pharmacokinetics of antimicrobial drugs in cystic fibrosis.. Pharm World Sci 20, 149–160 (1998). https://doi.org/10.1023/A:1008634911114

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1008634911114

Search

Navigation