Necessity of Tobramycin trough Levels in Once Daily Iv-Treatment in Patients with Cystic Fibrosis

Abstract

Background Once daily intravenous (iv) treatment with tobramycin for Pseudomonas aeruginosa infection in patients with cystic fibrosis (pwCF) is frequently monitored by measuring tobramycin trough levels (TLs). Although the necessity of these TLs is recently questioned in pwCF without renal impairment, no study has evaluated this so far. The aim of this observational study was to evaluate the frequency of increased tobramycin TLs in pwCF treated with a once daily tobramycin dosing protocol.

Methods Patient records of all consecutive once daily iv tobramycin courses in 35 pwCF between 07/2009 and 07/2019 were analyzed for tobramycin level, renal function, co-medication and comorbidity.

Results Eight elevated TLs (2.9% of 278 courses) were recorded in four patients, two with normal renal function. One of these resolved without adjustment of tobramycin dosages suggesting a test timing or laboratory error. In the other patient the elevated tobramycin level decreased after tobramycin dosage adjustment. Six of the elevated levels occurred in two patients with chronic renal failure. In 15 other patients with reduced glomerular filtration rate (GFR) (36 courses) but normal range creatinine no case of elevated tobramycin trough levels was detected. Neither cumulative tobramycin dosages nor concomitant diabetes or nutritional status were risk factors for elevated TLs.

Conclusion Our data show that elevated tobramycin TLs are rare but cannot be excluded, so determination of tobramycin TLs is still recommended for safety.

Zusammenfassung

Hintergrund Die einmal tägliche intravenöse (iv) Gabe von Tobramycin zur Behandlung von Pseudomonas aeruginosa-Infektionen bei Patienten mit Cystischer Fibrose (pwCF) wird durch Messung des Tobramycin-Talspiegels (TL) überwacht. Obwohl die Notwendigkeit der Messung dieser TL bei pwCF ohne Nierenfunktionsstörung zuletzt in Frage gestellt wird, wurde dies bisher in keiner Studie untersucht. Ziel dieser Beobachtungsstudie war es, die Häufigkeit erhöhter Tobramycin-TL bei pwCF zu untersuchen, die mit einer einmal täglichen Tobramycin-Gabe behandelt wurden.

Methoden Retrospektive Datenanalyse der stationären, iv Tobramycin-Therapien von 07/2009–07/2019 bei 35 pwCF einschließlich Analyse von Nierenfunktion, Begleitmedikation und Komorbidität.

Ergebnisse Acht erhöhte Tobramycin-TL (2,9% von 278 Behandlungen) wurden bei vier Patienten festgestellt, zwei davon mit normaler Nierenfunktion. Bei einem der beiden normalisierte sich die erhöhten Werte ohne Anpassung der Tobramycin-Dosis, was auf einen Fehler beim Testzeitpunkt oder im Labor schließen lässt. Bei dem anderen Patienten ging der erhöhte Tobramycin-TL nach Anpassung der Tobramycin-Dosierung zurück. Sechs der erhöhten Werte traten bei zwei Patienten mit chronischem Nierenversagen auf. Bei 15 weiteren Patienten mit reduzierter glomerulärer Filtrationsrate (GFR), aber normwertigem Kreatinin, wurde während 36 Tobramycin-Therapien kein Fall von erhöhten TL festgestellt. Weder die kumulative Tobramycin-Dosis noch ein Diabetes oder der Ernährungszustand waren Risikofaktoren für erhöhte TL.

Schlussfolgerung Unsere Daten zeigen, dass erhöhte Tobramycin TL selten sind, aber nicht ausgeschlossen werden können, so dass die Bestimmung dieser aus Sicherheitsgründen weiterhin zu empfehlen ist.

Keywords

tobramycin trough level - cystic fibrosis - GFR - renal insuffiency - toxicity - aminoglycoside

Schlüsselwörter

Cystische Fibrose - GFR - Niereninsuffizienz - Tobramycin Talspiegel. - Aminoglykoside - Toxizität

Publication History

Article published online:
29 January 2024

• References

• 1 Smyth A, Tan KH, Hyman-Taylor P. et al. Once versus three-times daily regimens of tobramycin treatment for pulmonary exacerbations of cystic fibrosis–the TOPIC study: a randomised controlled trial. Lancet 2005; 365: 573-578 DOI: 10.1016/S0140-6736(05)17906-9.
• 2 Burkhardt O, Lehmann C, Madabushi R. et al. Once-daily tobramycin in cystic fibrosis: better for clinical outcome than thrice-daily tobramycin but more resistance development?. J Antimicrob Chemother 2006; 58: 822-829 DOI: 10.1093/jac/dkl328.
• 3 Prescott WA, Nagel JL. Extended-interval once-daily dosing of aminoglycosides in adult and pediatric patients with cystic fibrosis. Pharmacotherapy 2010; 30: 95-108 DOI: 10.1592/phco.30.1.95.
• 4 Zobell JT, Epps K, Kittell F. et. al Tobramycin and Beta-Lactam Antibiotic Use in Cystic Fibrosis Exacerbations: A Pharmacist Approach. J Pediatr Pharmacol Ther 2016; 21: 239-246 DOI: 10.5863/1551-6776-21.3.239.
• 5 Sherwin CM, Zobell JT, Stockmann C. et al. Pharmacokinetic and pharmacodynamic optimisation of intravenous tobramycin dosing among children with cystic fibrosis. J Pharmacokinet Pharmacodyn 2014; 41: 71-79 DOI: 10.1007/s10928-013-9348-7.
• 6 Moore RD, Lietman PS, Smith CR. Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis 1987; 155: 93-99 DOI: 10.1093/infdis/155.1.93.
• 7 Bhatt J, Jahnke N, Smyth AR. Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic fibrosis. Cochrane Database of Systematic Reviews 2019; Art. No. CD002009 DOI: 10.1002/14651858.CD002009.pub7.
• 8 Larcombe R, Coulthard K, Eaton V. et al Is there a multinational consensus of tobramycin prescribing and monitoring for cystic fibrosis? Survey of current therapeutic drug monitoring practices in USA/Canada, UK/Ireland, and Australia/New Zealand. Eur J Hosp Pharm 2022; ejhpharm-2022-003545 DOI: 10.1136/ejhpharm-2022-003545.
• 9 Wilcock MJ, Ruddick A, Gyi KM. et al. Renal diseases in adults with cystic fibrosis: a 40 year single centre experience. J Nephrol 2015; 28: 585-591 DOI: 10.1007/s40620-015-0179-z.
• 10 Schwarz C, Schulte-Hubbert B, Bend J. et al. CF Lung Disease – a German S3 Guideline: Module 2: Diagnostics and Treatment in Chronic Infection with Pseudomonas aeruginosa. Pneumologie 2018; 72: 347-392
• 11 Ratjen F, Brockhaus F, Angyalosi G. Aminoglycoside therapy against Pseudomonas aeruginosa in cystic fibrosis: a review. J Cyst Fibros 2009; 8: 361-369 DOI: 10.1016/j.jcf.2009.08.004.
• 12 Prayle A, Smyth A. Aminoglycoside use in cystic fibrosis: therapeutic strategies and toxicity. Curr Opin Pulm Med 2010; 16: 604-610 DOI: 10.1097/MCP.0b013e32833eebfd.
• 13 Praet A, Bourguignon L, Vetele F. et al. Population pharmacokinetic modeling and dosing simulations of tobramycin in pediatric patients with cystic fibrosis. Antimicrob Agents Chemother 2021; 65: e00737-21 DOI: 10.1128/AAC.00737-21.
• 14 Hennig S, Norris R, Kirkpatrick CMJ. Target concentration intervention is needed for tobramycin dosing in paediatric patients with cystic fibrosis – a population pharmacokinetic study. J Clin Pharmacol 2007; 65: 502-510 DOI: 10.1111/j.1365-2125.2007.03045.x.
• 15 Paviour P, Hennig S, Staatz CE. Usage and monitoring of intravenous tobramycin in cystic fibrosis in Australia and the UK. J Pharm Pract Res 2016; 46: 15-21 21 DOI: 10.1002/jppr.1145.
• 16 Hennig S, Holthouse F, Staatz CF. Comparing dosage adjustment methods for once-daily tobramycin in paediatric and adolescent patients with cystic fibrosis. Clin Pharmacokinet 2015; 54: 409-421 DOI: 10.1007/s40262-014-0211-9.
• 17 Barras MA, Serisier D, Hennig S. et al. Bayesian Estimation of Tobramycin Exposure in Patients with Cystic Fibrosis. Antimicrob Agents Chemother 2016; 60: 6698-6702 DOI: 10.1128/AAC.01131-16.
• 18 Gao Y, Hennig S, Barras M. Monitoring of Tobramycin Exposure: What is the Best Estimation Method and Sampling Time for Clinical Practice?. Clinical Pharmacokinetics 2019; 58: 389-399 DOI: 10.1007/s40262-018-0707-9.
• 19 Coulthard KP, Peckham DG, Conway SP. et al. Therapeutic drug monitoring of once daily tobramycin in cystic fibrosis – caution with trough concentrations. Journal of Cystic Fibrosis 2007; 6: 125-130 DOI: 10.1016/j.jcf.2006.05.015.
• 20 Pedersen SS, Jensen T, Osterhammel D. et al. Cumulative and acute toxicity of repeated high-dose tobramycin treatment in cystic fibrosis. Antimicrob Agents Chemother 1987; 31: 594-599 DOI: 10.1128/aac.31.4.594.
• 21 Vic P, Ategbo S, Turck D. et al. Efficacy, tolerance, and pharmacokinetics of once daily tobramycin for pseudomonas exacerbations in cystic fibrosis. Arch Dis Child 1998; 78: 536-539 DOI: 10.1136/adc.78.6.536.
• 22 Zobell JT, Epps K, Kittell F. et al. Tobramycin and Beta-Lactam Antibiotic Use in Cystic Fibrosis Exacerbations: A Pharmacist Approach. J Pediatr Pharmacol Ther 2016; 21: 239-246 DOI: 10.5863/1551-6776-21.3.239.
• 23 Drusano GL, Ambrose PG, Bhavnani SM. et al. Back to the future: using aminoglycosides again and how to dose them optimally. Clin Infect Dis 2007; 45: 753-760 DOI: 10.1086/520991.
• 24 Imburgia TA, Seagre RN, Christensen H. et al. Review of Tobramycin Dosing in Pediatric Patients With Cystic Fibrosis. J Pediatr Pharmacol Ther 2023; 28: 63-70 DOI: 10.5863/1551-6776-28.1.63.
• 25 Bloomfield C, Staatz CE, Unwin S. et al. Assessing predictive performance of published population pharmacokinetic models of intravenous tobramycin in pediatric patients. Antimicrob Agents Chemother 2016; 60: 3407-3414 DOI: 10.1128/AAC.02654-15.
• 26 Santoro D, Postorino A, Lucanto C. et al. Cystic Fibrosis: A Risk Condition for Renal Disease. J Ren Nutr 2017; 27: 470-473 DOI: 10.1053/j.jrn.2017.05.006.
• 27 Berg KH, Ryom L, Faurholt-Jepsen D. et al. Prevalence and characteristics of chronic kidney disease among Danish adults with cystic fibrosis. J Cyst Fibros 2018; 17: 478-483 DOI: 10.1016/j.jcf.2017.11.001.
• 28 Al-Aloul M, Miller H, Alapati S. et al. Renal impairment in cystic fibrosis patients due to repeated intravenous aminoglycoside use. Pediatr Pulmonol 2005; 39: 15-20 DOI: 10.1097/FTD.0b013e31822c78e9.
• 29 Bertenshaw C, Watson AR, Lewis S. et al. Survey of acute renal failure in patients with cystic fibrosis in the UK. Thorax 2007; 62: 541-545 DOI: 10.1136/thx.2006.067595.
• 30 Crass RL, Pai MP. Optimizing Estimated Glomerular Filtration Rate to Support Adult to Pediatric Pharmacokinetic Bridging Studies in Patients with Cystic Fibrosis. Clinical Pharmacokinetics 2019; 58: 1323-1332 DOI: 10.1007/s40262-019-00761-5.
• 31 Anasemon S, McKenzie R, Young BS. et al. Incidence of nephrotoxicity with prolonged aminoglycoside exposure in patients with cystic fibrosis. Ped Pulmonol 2020; 55: 3384-3390 DOI: 10.1002/ppul.25066.