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54. A comparison between phenol exposure due to the inhalation of nebulized tobramycin and international occupational exposure limits
Supplement / The Netherlands Journal of Medicine 54 (1999) S3 –S84 receive tobramycin 10 mg / kg as a once daily dose, plus a B-lactam antibiotic, or tobramycin 3.3 mg / kg thrice daily plus a B-lactam antibiotic. Primary efficacy and safety endpoints were changes in respiratory function, and changes in renal function and hearing respectively. After 12 days treatment, the % improvement over baseline FVC and FEV1 were 8.3 [tds] vs. 22.4 [od], p , 0.05, and 20 [tds] vs. 17.5 [od], NS. The differences between the two groups for changes in clinical score, BMI, plasma viscosity, and c-reactive protein were not significant. Neither group showed any change in plasma creatinine from day 0 to day 12. One patient [tds group] showed bilateral impairment of 20 dB at one frequency in pure tone audiogram after treatment. Mean peak plasma tobramycin levels were 10.5 mg / l in the group receiving thrice daily tobramycin and 19.9 mg / l in the once daily group. Once daily tobramycin is at least as effective and safe as three times daily administration.
52. An open study to evaluate the safety and tolerance of Bolus IV Colistin in respiratory exacerbations. S Conway 1 , C. Etherington 1 , A. Whitehead 1 , M. Phillips 1 , J. Johnson 1 , A. Watson 1 , K. Pollard 1 , J. Munday 2 , M. Goldman 2 , M. Wootton 3 . 1 Seacroft Hospital, Leeds, UK, 2 Pharmax Ltd., Kent, UK, 3 Southmead Hospital, Bristol, UK. Colistin, 2 MU in 50 ml 0.9% NaCl, administered over 30 minutes 3 3 / day has been shown to be safe and effective treatment in patients with chronic PA infection. Bolus injections save time and expenditure on delivery systems used for home therapy. 12 patients with chronic PA infection with an acute respiratory exacerbation received 3 3 2 MU doses on day 1 by IV infusion in 50 ml 0.9% NaCl over 30 minutes. On days 2–4, 8 hourly bolus injections were given over 5 minutes, 2 MU in 20 ml (day 2), 15 ml (day 3), 10 ml (day 4). The latter dose was continued to day 12. If a dose was not tolerated, treatment reverted to the previous tolerated concentration. Patients were assessed daily. No clinically significant change occurred in observed laboratory parameters from day 1–12. Pre- and post-dose RFT showed no dose related bronchoconstriction. One patient reported intolerance on day 2 (mild incoordination and dizziness) and reverted to a regimen of 50 ml infusions with no problems. No serious adverse event occurred. All other patients continued 10 ml bolus injections from day 4–12. 2 patients with long lines had pain and inflammation at the injection site necessitating replacement of the line. Bolus Colistin 2 MU in 10 ml 0.9% NaCl administered over 5 minutes is safe and well tolerated but should be confined to patients with TIVAS in situ.
53. Inhaled anti-pseudomonal prophylaxis in cystic fibrosis. E. Eber, B. Heinzl, B. Oberwaldner, M.S. Zach. Respiratory and Allergic Disease Division, Dept. of Paediatrics, Univ. of Graz, Austria. Chronic Pseudomonas aeruginosa (PA) infection plays a central role for progression of lung disease in cystic fibrosis (CF). Thus, long-term inhalation of antibiotics to prevent PA-infection appears as a reasonable prophylactic strategy. Since 1985 such a strategy was applied to patients at special risk (meconium ileus, early
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RSV-infection, surgery, intensive care) in our CF centre. 28 subjects were judged to be such ‘‘high-risk’’ patients and received an inhaled prophylaxis (gentamicin or colistin). In 12 patients this prophylaxis was administered during the whole study period (1985–1998); there was no PA-infection in this group. In the remaining 16 patients inhaled antibiotics were stopped for various reasons including side effects (bronchospasm) and non-compliance. After such discontinuation of prophylaxis, 7 patients became chronically infected with PA. Overall, there were no PA-infections in 1461 months of prophylaxis but 7 infections in 676 months after discontinuation (p 5 0.003). Our data suggest that prophylactically administered inhaled antipseudomonal antibiotics can delay chronic PA-infection in ‘‘high risk’’ CF patients.
54. A comparison between phenol exposure due to the inhalation of nebulized tobramycin and international occupational exposure limits. S. Wolz, A.B. Montgomery. PathoGenesis Corp., Seattle, WA, USA. Intravenous formulations of tobramycin (TOB) contain phenol (PHE) as a preservative. Although these formulations have been used for aerosol therapy, they have not undergone rigorous safety testing usually required for licensure. Inhalation of TOB containing PHE is known to cause bronchospasm in cystic fibrosis patients. PHE is recognized as toxic, causing pulmonary inflammation and death in rodent inhalation studies. It is an irritant of the eyes, mucus membranes, skin and respiratory tract. Systemic absorption can occur via all routes of exposure. The US National Institute for Occupation Safety and Health recommends a 15minute short-term exposure limit (STEL) to PHE for workers of 15.6 ppm. Many other countries, such as the UK, Switzerland, Germany, Finland, Sweden, and Hungary, have adopted STELs of # 10 ppm for healthy workers, based on toxicologic and epidemiologic data. An average 70 kg worker, inhaling a concentration of PHE equivalent to the STEL (10 ppm for 15 min.) would receive a dose of 0.04 mg / kg PHE. From a 2 mL vial of TOB containing 0.5% PHE, 80% is fully nebulized. 50% of this solution will be deposited in the lungs and upper airways, and the remainder exhaled. Since PHE is readily absorbed through the skin and mucus membranes, any deposits on the patient’s airways will contribute to the total exposure. The patient is thus receiving at least 4 mg PHE per vial. A 50 kg cystic fibrosis patient, treated with 80 mg of nebulized TOB is being exposed to 0.08 mg / kg PHE, or twice the STEL. Patients use 2 to 8 vials TOB per day. In conclusion, treatment with phenol-containing TOB exceeds widely accepted occupational exposure limits designed to protect the health of healthy adult workers, and can cause pulmonary inflammation when used to treat cystic fibrosis patients.
55. Pilot study on toleration of inhalation with a new high¨ concentrated tobramycin solution. G. Huls, Ch. Beyes, P. Bittner-Dersch, H. Lindemann. CF-Working Group, Univ. of Giessen, Germany. Aim of this pilot study was to examine the acceptance of a new high concentrated tobramycin solution for inhalation therapy in patients with cystic fibrosis (CF).
52. An open study to evaluate the safety and tolerance of Bolus IV Colistin in respiratory exacerbations. S Conway 1 , C. Etherington 1 , A. Whitehead 1 , M. Phillips 1 , J. Johnson 1 , A. Watson 1 , K. Pollard 1 , J. Munday 2 , M. Goldman 2 , M. Wootton 3 . 1 Seacroft Hospital, Leeds, UK, 2 Pharmax Ltd., Kent, UK, 3 Southmead Hospital, Bristol, UK. Colistin, 2 MU in 50 ml 0.9% NaCl, administered over 30 minutes 3 3 / day has been shown to be safe and effective treatment in patients with chronic PA infection. Bolus injections save time and expenditure on delivery systems used for home therapy. 12 patients with chronic PA infection with an acute respiratory exacerbation received 3 3 2 MU doses on day 1 by IV infusion in 50 ml 0.9% NaCl over 30 minutes. On days 2–4, 8 hourly bolus injections were given over 5 minutes, 2 MU in 20 ml (day 2), 15 ml (day 3), 10 ml (day 4). The latter dose was continued to day 12. If a dose was not tolerated, treatment reverted to the previous tolerated concentration. Patients were assessed daily. No clinically significant change occurred in observed laboratory parameters from day 1–12. Pre- and post-dose RFT showed no dose related bronchoconstriction. One patient reported intolerance on day 2 (mild incoordination and dizziness) and reverted to a regimen of 50 ml infusions with no problems. No serious adverse event occurred. All other patients continued 10 ml bolus injections from day 4–12. 2 patients with long lines had pain and inflammation at the injection site necessitating replacement of the line. Bolus Colistin 2 MU in 10 ml 0.9% NaCl administered over 5 minutes is safe and well tolerated but should be confined to patients with TIVAS in situ.
53. Inhaled anti-pseudomonal prophylaxis in cystic fibrosis. E. Eber, B. Heinzl, B. Oberwaldner, M.S. Zach. Respiratory and Allergic Disease Division, Dept. of Paediatrics, Univ. of Graz, Austria. Chronic Pseudomonas aeruginosa (PA) infection plays a central role for progression of lung disease in cystic fibrosis (CF). Thus, long-term inhalation of antibiotics to prevent PA-infection appears as a reasonable prophylactic strategy. Since 1985 such a strategy was applied to patients at special risk (meconium ileus, early
S37
RSV-infection, surgery, intensive care) in our CF centre. 28 subjects were judged to be such ‘‘high-risk’’ patients and received an inhaled prophylaxis (gentamicin or colistin). In 12 patients this prophylaxis was administered during the whole study period (1985–1998); there was no PA-infection in this group. In the remaining 16 patients inhaled antibiotics were stopped for various reasons including side effects (bronchospasm) and non-compliance. After such discontinuation of prophylaxis, 7 patients became chronically infected with PA. Overall, there were no PA-infections in 1461 months of prophylaxis but 7 infections in 676 months after discontinuation (p 5 0.003). Our data suggest that prophylactically administered inhaled antipseudomonal antibiotics can delay chronic PA-infection in ‘‘high risk’’ CF patients.
54. A comparison between phenol exposure due to the inhalation of nebulized tobramycin and international occupational exposure limits. S. Wolz, A.B. Montgomery. PathoGenesis Corp., Seattle, WA, USA. Intravenous formulations of tobramycin (TOB) contain phenol (PHE) as a preservative. Although these formulations have been used for aerosol therapy, they have not undergone rigorous safety testing usually required for licensure. Inhalation of TOB containing PHE is known to cause bronchospasm in cystic fibrosis patients. PHE is recognized as toxic, causing pulmonary inflammation and death in rodent inhalation studies. It is an irritant of the eyes, mucus membranes, skin and respiratory tract. Systemic absorption can occur via all routes of exposure. The US National Institute for Occupation Safety and Health recommends a 15minute short-term exposure limit (STEL) to PHE for workers of 15.6 ppm. Many other countries, such as the UK, Switzerland, Germany, Finland, Sweden, and Hungary, have adopted STELs of # 10 ppm for healthy workers, based on toxicologic and epidemiologic data. An average 70 kg worker, inhaling a concentration of PHE equivalent to the STEL (10 ppm for 15 min.) would receive a dose of 0.04 mg / kg PHE. From a 2 mL vial of TOB containing 0.5% PHE, 80% is fully nebulized. 50% of this solution will be deposited in the lungs and upper airways, and the remainder exhaled. Since PHE is readily absorbed through the skin and mucus membranes, any deposits on the patient’s airways will contribute to the total exposure. The patient is thus receiving at least 4 mg PHE per vial. A 50 kg cystic fibrosis patient, treated with 80 mg of nebulized TOB is being exposed to 0.08 mg / kg PHE, or twice the STEL. Patients use 2 to 8 vials TOB per day. In conclusion, treatment with phenol-containing TOB exceeds widely accepted occupational exposure limits designed to protect the health of healthy adult workers, and can cause pulmonary inflammation when used to treat cystic fibrosis patients.
55. Pilot study on toleration of inhalation with a new high¨ concentrated tobramycin solution. G. Huls, Ch. Beyes, P. Bittner-Dersch, H. Lindemann. CF-Working Group, Univ. of Giessen, Germany. Aim of this pilot study was to examine the acceptance of a new high concentrated tobramycin solution for inhalation therapy in patients with cystic fibrosis (CF).