Research letters
3 Chen YT, Lin AC, Siu LK et al. Sequence of closely related plasmids encoding blaNDM-1 in two unrelated Klebsiella pneumoniae isolates in Singapore. PLoS One 2012; 7: e48737. 4 Rimrang B, Chanawong A, Lulitanond A et al. Emergence of NDM-1- and IMP-14a-producing Enterobacteriaceae in Thailand. J Antimicrob Chemother 2012; 67: 2626– 30. 5 Poirel L, Walsh TR, Cuvillier V et al. Multiplex PCR for detection of acquired carbapenemase genes. Diagn Microbiol Infect Dis 2011; 70: 119– 23. 6 Carattoli A, Bertini A, Villa L et al. Identification of plasmids by PCR-based replicon typing. J Microbiol Meth 2005; 63: 219–28.
8 Picard B, Garcia JS, Gouriou S et al. The link between phylogeny and virulence in Escherichia coli extraintestinal infection. Infect Immun 1999; 67: 546–53. 9 Voulgari E, Zarkotou O, Ranellou K et al. Outbreak of OXA-48 carbapenemase-producing Klebsiella pneumoniae in Greece involving an ST11 clone. J Antimicrob Chemother 2013; 68: 84– 8. 10 Novais Aˆ, Rodrigues C, Branquinho R et al. Spread of an OmpK36-modified ST15 Klebsiella pneumoniae variant during an outbreak involving multiple carbapenem-resistant Enterobacteriaceae species and clones. Eur J Clin Microbiol Infect Dis 2012; 31: 3057–63.
J Antimicrob Chemother 2014 doi:10.1093/jac/dku260 Advance Access publication 7 July 2014
High tobramycin serum concentrations after tobramycin inhalation in a child with renal failure Femke de Velde1, Marieke Emonts2–4, Sascha Verbruggen5 and Heleen van der Sijs1* 1
Department of Hospital Pharmacy, Erasmus University Medical Centre, PO Box 2040, 3000 CA Rotterdam, The Netherlands; 2 Department of Paediatric Infectious Diseases and Immunology, Erasmus MC-Sophia Children’s Hospital, University Medical Centre, PO Box 2040, 3000 CA Rotterdam, The Netherlands; 3Paediatric Infectious Diseases and Immunology Department, Royal Victoria Infirmary, Great North Children’s Hospital, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK; 4Institute of Cellular Medicine, Newcastle University, 4th Floor, William Leech Building, Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK; 5 Paediatric Intensive Care Unit, Erasmus MC-Sophia Children’s Hospital, University Medical Centre, PO Box 2040, 3000 CA, Rotterdam, The Netherlands *Corresponding author. Tel: +31-10-7033202; Fax: +31-10-7032400; E-mail: [email protected]
Keywords: drug toxicity, drug adverse events, pharmacokinetics,
bioavailability, drug monitoring Sir, Inhaled tobramycin is used to treat chronic lung infections caused by Pseudomonas aeruginosa in cystic fibrosis. The advantages of
3163
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on February 10, 2015
7 Poirel L, Lagrutta E, Taylor P et al. Emergence of metallo-b-lactamase NDM-1-producing multidrug-resistant Escherichia coli in Australia. Antimicrob Agents Chemother 2010; 54: 4914–6.
inhalation over parenteral administration are direct endobronchial delivery and minimal systemic toxicity. Tobramycin inhalation is considered safe and effective.1 Serum levels in cystic fibrosis patients after inhalation are generally low (,1 mg/L),2,3 without evidence for drug accumulation in serum.2 Therefore, routine monitoring of systemic tobramycin levels after inhalation is not indicated. We report elevated serum tobramycin concentrations in a child with renal failure receiving inhaled tobramycin. An 11-year-old child was admitted to a paediatric intensive care unit for an out-of-hospital cardiac arrest. Resuscitation was complicated by bilateral pneumothorax. Extracorporeal membrane oxygenation was started on admission and continued for 4 days. Rhabdomyolysis on day 2 caused acute renal failure with oliguria. Continuous veno-venous haemofiltration (CVVH) was started on day 6. On day 8, atelectasis of the right superior lobe was detected. The patient received antimicrobials to successfully treat Staphylococcus aureus ventilator-associated pneumonia and systemic Candida albicans infection. In the fourth week intravenous ciprofloxacin was commenced to treat P. aeruginosa pneumonia. Because of increased diuresis and severe clotting of the line, CVVH was discontinued in the fifth week. The subsequent rise in creatinine decreased spontaneously after 5 days. One day after CVVH discontinuation, tobramycin for inhalation (TOBIw, Novartis Pharma, Basel, Switzerland) at 300 mg twice daily was started, delivered by a vibrating mesh nebulizer (Aeronebw Pro, Aerogen, Galway, Ireland), because of increased respiratory distress with oxygen requirement, fever and elevated C-reactive protein levels. Inhalation was preferred to intravenous infusion because of renal impairment. Ciprofloxacin was switched to meropenem because of resistance of P. aeruginosa. In the sixth week of admission a CT scan showed empyema, for which thoracoscopic surgery and drainage was performed. Seven days after starting tobramycin for inhalation the tobramycin serum level (13.8 mg/L 6 h after administration) was interpreted as a sampling error. The test was repeated after the weekend on day 10. The concentrations were 17.9 mg/L (trough) and 17.1 mg/L (1 h after administration). Tobramycin was discontinued on the 11th day. Concentrations after the last dose were 14.1 mg/L (after 1 h) and 13.4 mg/L (after 6 h). Five days after discontinuation the levels were ,0.5 mg/L and renal function improved accordingly (Figure 1). The patient’s respiratory condition gradually improved and subsequent cultures were negative. The patient recovered and was discharged to a rehabilitation centre 3 months after hospital admission. We obtained informed consent from both patient and parents to publish this report. Several possible causes for the high tobramycin levels were considered. Erroneous substitution of inhalation for intravenous therapy and medication with probable cross-reactivity of the tobramycin immunoassay were excluded. Skin contamination of fingerprick blood following nebulization of tobramycin4 was excluded because only arterial blood was drawn. A few case reports have described patients with renal dysfunction receiving tobramycin inhalation with high trough levels of 10.6,5 8.8,6 19.5,7 2.58 and 13.4 mg/L9 and a peak level of 2.1 mg/L.10 They received 80 – 300 mg twice daily,5 300 mg twice daily6 – 8,10 or 600 mg twice daily9 for 5 – 25 days. Four patients were ventilated,5,8 – 10 one had bronchopulmonary dysplasia,5 one was a lung transplant recipient6 and one had bronchiectasis.7 Two patients developed vestibular injury6,7 and one got hearing difficulties.9 We
Research letters
Tobramycin Creatinine
300
18
250
15
200
12
150
9
100
6
50
CVVH
0
10
20
30 40 Time (days)
50
Transparency declarations
0
None to declare.
60
Figure 1. Creatinine and tobramycin serum concentrations during the admission period. The patient was treated with CVVH on days 6 –14 and 16 – 31. Tobramycin (300 mg twice daily) was inhaled on days 32 – 42. TOB, tobramycin.
hypothesize that the high tobramycin levels in our case were caused by systemic accumulation resulting from renal dysfunction, but these levels are high compared with the previously reported cases.5 – 10 Possibly an inflammatory response after prolonged resuscitation, pneumothorax, atelectasis, empyema and mechanical ventilation contributed to increased absorption. We used the pharmacokinetic software tool MW\Pharm 3.5 (Mediware bv, Groningen, The Netherlands) to estimate the bioavailability of the inhaled tobramycin. The measured tobramycin concentrations in this case matched a dosage regimen of 120 mg of tobramycin intravenously twice daily (corresponding to 4 mg/kg twice daily), suggesting a bioavailability of 40%, .3-fold higher than usual (12%).2 The elimination half-life was prolonged to 1 day (normally 1.3–13 h).2 High serum tobramycin concentrations are related to nephrotoxicity and ototoxicity.2 The creatinine increase in our case was most probably attributable to CVVH discontinuation 1 day before starting tobramycin. Hearing loss was pre-existent in this patient due to bilateral tympanic membrane perforation. Audiological testing after tobramycin exposure showed hearing loss in both ears. It is not clear whether the hearing loss was worsened by tobramycin. Case reports show elevated tobramycin levels following inhalation in patients with renal insufficiency due to systemic accumulation. Respiratory-related disorders like mechanical ventilation or pneumothorax possibly contribute to increased systemic
3164
This study was carried out as part of our routine work.
3 TOB
0
Funding
References 1 Pai VB, Nahata MC. Efficacy and safety of aerosolized tobramycin in cystic fibrosis. Pediatr Pulmonol 2001; 32: 314– 27. 2 Geller DE, Pitlick WH, Nardella PA et al. Pharmacokinetics and bioavailability of aerosolized tobramycin in cystic fibrosis. Chest 2002; 122: 219–26. 3 Barker AF, Couch L, Fiel SB et al. Tobramycin solution for inhalation reduces sputum Pseudomonas aeruginosa density in bronchiectasis. Am J Respir Crit Care Med 2000; 162: 481–5. 4 Redman S, Wainwright C, Stacey S et al. Misleading high tobramycin plasma concentrations can be caused by skin contamination of fingerprick blood following inhalation of nebulized tobramycin (TOBIw). Ther Drug Monit 2005; 27: 205–7. 5 Abdulhamid I, Wise TL, Andrews S et al. Elevated serum tobramycin concentrations after treatment with tobramycin inhalation in a preterm infant. Pharmacotherapy 2008; 28: 939–44. 6 Ahya VN, Doyle AM, Mendez JD et al. Renal and vestibular toxicity due to inhaled tobramycin in a lung transplant recipient. J Heart Lung Transplant 2005; 24: 932–5. 7 Edson RS, Brey RH, McDonald TJ et al. Vestibular toxicity due to inhaled tobramycin in a patient with renal insufficiency. Mayo Clin Proc 2004; 79: 1185– 91. 8 Kahler DA, Schowengerdt KO, Fricker FJ et al. Toxic serum trough concentrations after administration of nebulized tobramycin. Pharmacotherapy 2003; 23: 543–5. 9 Patatanian L. Inhaled tobramycin-associated hearing loss in an adolescent with renal failure. Pediatr Infect Dis J 2006; 25: 276–8. 10 Langley A, Cottingham L. Detectable serum tobramycin concentrations in a patient with renal dysfunction receiving tobramycin by inhalation. Am J Health Syst Pharm 2011; 68: 1385– 6.
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on February 10, 2015
CVVH
absorption of tobramycin in these patients. It is therefore recommended that tobramycin levels should be monitored in patients with renal dysfunction receiving tobramycin by inhalation.
21
Tobramycin (mg/L)
Creatinine (µmol/L)
350
3 Chen YT, Lin AC, Siu LK et al. Sequence of closely related plasmids encoding blaNDM-1 in two unrelated Klebsiella pneumoniae isolates in Singapore. PLoS One 2012; 7: e48737. 4 Rimrang B, Chanawong A, Lulitanond A et al. Emergence of NDM-1- and IMP-14a-producing Enterobacteriaceae in Thailand. J Antimicrob Chemother 2012; 67: 2626– 30. 5 Poirel L, Walsh TR, Cuvillier V et al. Multiplex PCR for detection of acquired carbapenemase genes. Diagn Microbiol Infect Dis 2011; 70: 119– 23. 6 Carattoli A, Bertini A, Villa L et al. Identification of plasmids by PCR-based replicon typing. J Microbiol Meth 2005; 63: 219–28.
8 Picard B, Garcia JS, Gouriou S et al. The link between phylogeny and virulence in Escherichia coli extraintestinal infection. Infect Immun 1999; 67: 546–53. 9 Voulgari E, Zarkotou O, Ranellou K et al. Outbreak of OXA-48 carbapenemase-producing Klebsiella pneumoniae in Greece involving an ST11 clone. J Antimicrob Chemother 2013; 68: 84– 8. 10 Novais Aˆ, Rodrigues C, Branquinho R et al. Spread of an OmpK36-modified ST15 Klebsiella pneumoniae variant during an outbreak involving multiple carbapenem-resistant Enterobacteriaceae species and clones. Eur J Clin Microbiol Infect Dis 2012; 31: 3057–63.
J Antimicrob Chemother 2014 doi:10.1093/jac/dku260 Advance Access publication 7 July 2014
High tobramycin serum concentrations after tobramycin inhalation in a child with renal failure Femke de Velde1, Marieke Emonts2–4, Sascha Verbruggen5 and Heleen van der Sijs1* 1
Department of Hospital Pharmacy, Erasmus University Medical Centre, PO Box 2040, 3000 CA Rotterdam, The Netherlands; 2 Department of Paediatric Infectious Diseases and Immunology, Erasmus MC-Sophia Children’s Hospital, University Medical Centre, PO Box 2040, 3000 CA Rotterdam, The Netherlands; 3Paediatric Infectious Diseases and Immunology Department, Royal Victoria Infirmary, Great North Children’s Hospital, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK; 4Institute of Cellular Medicine, Newcastle University, 4th Floor, William Leech Building, Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK; 5 Paediatric Intensive Care Unit, Erasmus MC-Sophia Children’s Hospital, University Medical Centre, PO Box 2040, 3000 CA, Rotterdam, The Netherlands *Corresponding author. Tel: +31-10-7033202; Fax: +31-10-7032400; E-mail: [email protected]
Keywords: drug toxicity, drug adverse events, pharmacokinetics,
bioavailability, drug monitoring Sir, Inhaled tobramycin is used to treat chronic lung infections caused by Pseudomonas aeruginosa in cystic fibrosis. The advantages of
3163
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on February 10, 2015
7 Poirel L, Lagrutta E, Taylor P et al. Emergence of metallo-b-lactamase NDM-1-producing multidrug-resistant Escherichia coli in Australia. Antimicrob Agents Chemother 2010; 54: 4914–6.
inhalation over parenteral administration are direct endobronchial delivery and minimal systemic toxicity. Tobramycin inhalation is considered safe and effective.1 Serum levels in cystic fibrosis patients after inhalation are generally low (,1 mg/L),2,3 without evidence for drug accumulation in serum.2 Therefore, routine monitoring of systemic tobramycin levels after inhalation is not indicated. We report elevated serum tobramycin concentrations in a child with renal failure receiving inhaled tobramycin. An 11-year-old child was admitted to a paediatric intensive care unit for an out-of-hospital cardiac arrest. Resuscitation was complicated by bilateral pneumothorax. Extracorporeal membrane oxygenation was started on admission and continued for 4 days. Rhabdomyolysis on day 2 caused acute renal failure with oliguria. Continuous veno-venous haemofiltration (CVVH) was started on day 6. On day 8, atelectasis of the right superior lobe was detected. The patient received antimicrobials to successfully treat Staphylococcus aureus ventilator-associated pneumonia and systemic Candida albicans infection. In the fourth week intravenous ciprofloxacin was commenced to treat P. aeruginosa pneumonia. Because of increased diuresis and severe clotting of the line, CVVH was discontinued in the fifth week. The subsequent rise in creatinine decreased spontaneously after 5 days. One day after CVVH discontinuation, tobramycin for inhalation (TOBIw, Novartis Pharma, Basel, Switzerland) at 300 mg twice daily was started, delivered by a vibrating mesh nebulizer (Aeronebw Pro, Aerogen, Galway, Ireland), because of increased respiratory distress with oxygen requirement, fever and elevated C-reactive protein levels. Inhalation was preferred to intravenous infusion because of renal impairment. Ciprofloxacin was switched to meropenem because of resistance of P. aeruginosa. In the sixth week of admission a CT scan showed empyema, for which thoracoscopic surgery and drainage was performed. Seven days after starting tobramycin for inhalation the tobramycin serum level (13.8 mg/L 6 h after administration) was interpreted as a sampling error. The test was repeated after the weekend on day 10. The concentrations were 17.9 mg/L (trough) and 17.1 mg/L (1 h after administration). Tobramycin was discontinued on the 11th day. Concentrations after the last dose were 14.1 mg/L (after 1 h) and 13.4 mg/L (after 6 h). Five days after discontinuation the levels were ,0.5 mg/L and renal function improved accordingly (Figure 1). The patient’s respiratory condition gradually improved and subsequent cultures were negative. The patient recovered and was discharged to a rehabilitation centre 3 months after hospital admission. We obtained informed consent from both patient and parents to publish this report. Several possible causes for the high tobramycin levels were considered. Erroneous substitution of inhalation for intravenous therapy and medication with probable cross-reactivity of the tobramycin immunoassay were excluded. Skin contamination of fingerprick blood following nebulization of tobramycin4 was excluded because only arterial blood was drawn. A few case reports have described patients with renal dysfunction receiving tobramycin inhalation with high trough levels of 10.6,5 8.8,6 19.5,7 2.58 and 13.4 mg/L9 and a peak level of 2.1 mg/L.10 They received 80 – 300 mg twice daily,5 300 mg twice daily6 – 8,10 or 600 mg twice daily9 for 5 – 25 days. Four patients were ventilated,5,8 – 10 one had bronchopulmonary dysplasia,5 one was a lung transplant recipient6 and one had bronchiectasis.7 Two patients developed vestibular injury6,7 and one got hearing difficulties.9 We
Research letters
Tobramycin Creatinine
300
18
250
15
200
12
150
9
100
6
50
CVVH
0
10
20
30 40 Time (days)
50
Transparency declarations
0
None to declare.
60
Figure 1. Creatinine and tobramycin serum concentrations during the admission period. The patient was treated with CVVH on days 6 –14 and 16 – 31. Tobramycin (300 mg twice daily) was inhaled on days 32 – 42. TOB, tobramycin.
hypothesize that the high tobramycin levels in our case were caused by systemic accumulation resulting from renal dysfunction, but these levels are high compared with the previously reported cases.5 – 10 Possibly an inflammatory response after prolonged resuscitation, pneumothorax, atelectasis, empyema and mechanical ventilation contributed to increased absorption. We used the pharmacokinetic software tool MW\Pharm 3.5 (Mediware bv, Groningen, The Netherlands) to estimate the bioavailability of the inhaled tobramycin. The measured tobramycin concentrations in this case matched a dosage regimen of 120 mg of tobramycin intravenously twice daily (corresponding to 4 mg/kg twice daily), suggesting a bioavailability of 40%, .3-fold higher than usual (12%).2 The elimination half-life was prolonged to 1 day (normally 1.3–13 h).2 High serum tobramycin concentrations are related to nephrotoxicity and ototoxicity.2 The creatinine increase in our case was most probably attributable to CVVH discontinuation 1 day before starting tobramycin. Hearing loss was pre-existent in this patient due to bilateral tympanic membrane perforation. Audiological testing after tobramycin exposure showed hearing loss in both ears. It is not clear whether the hearing loss was worsened by tobramycin. Case reports show elevated tobramycin levels following inhalation in patients with renal insufficiency due to systemic accumulation. Respiratory-related disorders like mechanical ventilation or pneumothorax possibly contribute to increased systemic
3164
This study was carried out as part of our routine work.
3 TOB
0
Funding
References 1 Pai VB, Nahata MC. Efficacy and safety of aerosolized tobramycin in cystic fibrosis. Pediatr Pulmonol 2001; 32: 314– 27. 2 Geller DE, Pitlick WH, Nardella PA et al. Pharmacokinetics and bioavailability of aerosolized tobramycin in cystic fibrosis. Chest 2002; 122: 219–26. 3 Barker AF, Couch L, Fiel SB et al. Tobramycin solution for inhalation reduces sputum Pseudomonas aeruginosa density in bronchiectasis. Am J Respir Crit Care Med 2000; 162: 481–5. 4 Redman S, Wainwright C, Stacey S et al. Misleading high tobramycin plasma concentrations can be caused by skin contamination of fingerprick blood following inhalation of nebulized tobramycin (TOBIw). Ther Drug Monit 2005; 27: 205–7. 5 Abdulhamid I, Wise TL, Andrews S et al. Elevated serum tobramycin concentrations after treatment with tobramycin inhalation in a preterm infant. Pharmacotherapy 2008; 28: 939–44. 6 Ahya VN, Doyle AM, Mendez JD et al. Renal and vestibular toxicity due to inhaled tobramycin in a lung transplant recipient. J Heart Lung Transplant 2005; 24: 932–5. 7 Edson RS, Brey RH, McDonald TJ et al. Vestibular toxicity due to inhaled tobramycin in a patient with renal insufficiency. Mayo Clin Proc 2004; 79: 1185– 91. 8 Kahler DA, Schowengerdt KO, Fricker FJ et al. Toxic serum trough concentrations after administration of nebulized tobramycin. Pharmacotherapy 2003; 23: 543–5. 9 Patatanian L. Inhaled tobramycin-associated hearing loss in an adolescent with renal failure. Pediatr Infect Dis J 2006; 25: 276–8. 10 Langley A, Cottingham L. Detectable serum tobramycin concentrations in a patient with renal dysfunction receiving tobramycin by inhalation. Am J Health Syst Pharm 2011; 68: 1385– 6.
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on February 10, 2015
CVVH
absorption of tobramycin in these patients. It is therefore recommended that tobramycin levels should be monitored in patients with renal dysfunction receiving tobramycin by inhalation.
21
Tobramycin (mg/L)
Creatinine (µmol/L)
350
