The Leeds Method of Management. April, 2008. Nebulised antibiotics [online]. Leeds Regional Adult and Paediatric Cystic Fibrosis Units, St James's University Hospital, Leeds, UK. Available from http://www.cysticfibrosismedicine.com
The advantages of nebulised antibiotic therapy for Pseudomonas aeruginosa infection in CF have been recognised for over 30 years (Mearns, 1970). An antibiotic delivered directly to the site of infection should be most effective. The altered lung environment consequent on inadequate CFTR protein function may reduce drug accumulation by the bacteria, and aminoglycoside efficacy may be reduced by binding to the excess extracellular neutrophil DNA (Levy et al, 1983). Sputum concentrations 25 times greater than the minimum inhibitory concentration (MIC) may be necessary to achieve a bactericidal effect (Mendelman et al, 1985). These levels cannot be reached by intravenous administration without unacceptable risks of systemic toxicity, but can be realised by inhalation of aerosolised antibiotics which, because of their minimal systemic absorption are unlikely to cause ototoxicity or nephrotoxicity (Smith et al, 1989).
Patients should be assessed before and after a test dose of a nebulised antibiotic. In children chest auscultation and, where possible, respiratory function tests are performed. In adults pre and post respiratory function tests are performed. Some patients will develop bronchospasm and may benefit from bronchodilator inhalation given before the antibiotic (Dodd et al, 1997; Cunningham et al, 2001; Alothman et al, 2002). A mouthpiece is preferable to a mask to maximise pulmonary deposition.
Nebulised antibiotics should be taken after physiotherapy to ensure maximum deposition.
Tobramycin crosses the placenta and there is a theoretical risk of damage to the VIII cranial nerve and of nephrotoxicity. Avoidance of parenteral administration is recommended during pregnancy but the risks from nebulised administration are much less. A decision whether or not to continue nebulised antibiotic treatment during pregnancy should be made on an individual basis and in consultation with the patient. The minimal but theoretical risks to the baby of continued treatment should be weighed against the risks to the mother’s health of stopping treatment.
i) Delay or prevention of chronic infection with P. aeruginosa
ii) Prevention of clinical deterioration in patients chronically infected with P. aeruginosa
antibiotics reduce the rate of decline of respiratory function in patients
chronically infected with P. aeruginosa. In 1981, Hodson et
al compared six months of treatment with twice-daily nebulised gentamicin
(80mg) and carbenicillin (1gm) versus placebo (Hodson et al, 1981).
Treated patients had significantly improved respiratory function and a
non-significant trend towards fewer hospital admissions. Follow-up studies
confirmed the benefits of treatment for chronic pseudomonas infection;
improved lung function, a slower decline in lung function, fewer hospital
admissions, better clinical scores and weight, and decreased P. aeruginosa
density and virulence factors (Conway, 1999). There was no renal toxicity,
ototoxicity or increase in bacterial resistance (Touw et al, 1995;
Mukhopadhyay et al, 1996).
The Cochrane Review found insufficient evidence to claim superiority for either TOBI® or colistin. Eleven trials met the inclusion criteria. The review concluded that nebulised antibiotic treatment improves lung function and reduces the frequency of respiratory exacerbations. There was no evidence of clinically important adverse events (Ryan et al, 2003).
Long term treatment is effective with patients having fewer hospital admissions and intravenous antibiotic use, and better preservation of respiratory function (Moss, 2001). Long term treatment is generally very safe but patients show an unpredictable range of systemic antibiotic absorption. The possibility of toxic drug levels resulting from nebulised antibiotic delivery should be remembered. Acute renal failure after one week of TOBI® and concurrent ciprofloxacin, and reversible vestibular dysfunction in a patient receiving haemodialysis have been reported (Hoffmann et al, 2002; Edson et al, 2004). Following inhaled gentamicin children showed significantly raised, but reversible, urinary N-acetyl-b-D-glucosaminidase (NAG) activity indicating renal tubular damage, compared to control children who had never received inhaled gentamicin or who had discontinued the drug at least three months previously. There was a positive correlation between NAG levels and cumulative antibiotic dose (Ring et al, 1998).
There is no published evidence to support concern that nebulised antibiotics may be a health hazard to medical personnel or the hospital and home environment.
Some drug solutions/suspensions show physico-chemical compatibility and may be mixed in the nebuliser chamber for simultaneous inhalation (Kamin et al, 2006).
There are no trials
showing that nebulised antibiotics are as effective as intravenous antibiotics
for treating infective exacerbations, or that they are useful adjuncts
to intravenous therapy (Stephens et al, 1983; Schaad et al,
1987; Semsarian, 1990).
Twice daily inhaled gentamicin in a small group of very young children prevented chronic infection for a mean of 78 months (Heinzl et al, 2002). Regular use of nebulised TOBI®, colistin, injectable forms of tobramycin or amikacin are associated with a chronic P. aeruginosa infection rate of <3% in Belgian children (Lebecque et al, 2006). There are, however, important negative effects to be considered before adopting this proactive approach, e.g. the increased risks of bacterial resistance, the risk of emergence of fungal organisms, the potential toxicity of treatment and the impact on daily life of long term nebulised antibiotic treatments. We can also prevent chronic P. aeruginosa infection in the majority of children with less invasive protocols aimed at eradicating new P. aeruginosa infection.
We recommend that specific treatment should be considered for patients who are smear positive, and for those with persistent positive cultures and symptoms despite routine antibiotic treatment.
Nebulised amikacin is part of the complex and long term antibiotic regimens for the treatment of the “rapid growers” e.g. M. abscessus (Cullen et al, 2000). There is no evidence base for dosage but 500mg bd is recommended. This may need reducing to 250mg bd in younger children. The injectable preparation (250mg/ml) should be used and made up to 4mls with sodium chloride 0.9%.
The role of nebulised vancomycin remains uncertain. There are anecdotal reports of efficacy in eradicating MRSA from the respiratory tract of patinets with CF (Maiz et al, 1998), but there are concerns regarding the possible impact of widespread and longer term use on the emergence of resistance.
Alothman GA, Alsaadi MM, Ho BL, et al. Evaluation of bronchial constriction in children with cystic fibrosis after inhaling two different preparations of tobramycin. Chest 2002; 122: 930-934. [PubMed]
Burns JL, Van Dalfsen JM, Shawar RM, et al. Effect of chronic intermittent administration of inhaled tobramycin on respiratory microbiological flora in patients with cystic fibrosis. J Infect Dis 1999; 179: 1190-1196. [PubMed]
Conway SP. Evidence for using nebulised antibiotics in cystic fibrosis. Arch Dis Child 1999; 80: 307-309. [PubMed]
Cullen AR, Cannon CL, Mark EJ, et al. Mycobacterium abscessus infection in CF: colonisation or infection? Am J Respir Crit Care Med 2000; 161: 641-645. [PubMed]
Cunningham S, Prasad A, Collyer L, et al. Bronchoconstriction following nebulised colistin in cystic fibrosis. Arch Dis Child 2001; 84: 432-433. [PubMed]
Denton M, Kerr K, Mooney L, et al. Transmission of colistin-resistant Pseudomonas aeruginosa between patients attending a pediatric cystic fibrosis center. Pediatr Pulmonol 2002; 34: 257-261. [PubMed]
Dodd ME, Abbott J, Maddison J, et al. Effect of tonicity of nebulised colistin on chest tightness and pulmonary function in adults with cystic fibrosis. Thorax 1997; 52: 656-658. [PubMed]
Edson RS, Brey RH, McDonald TJ, et al. Vestibular toxicity due to inhaled tobramycin in a patient with renal insufficiency. Mayo Clinc Proc 2004; 79: 1185-1191. [PubMed]
Govan JR. Insights into cystic fibrosis microbiology from the European tobramycin trial in cystic fibrosis. J Cyst Fibros 2002; 1(Suppl 2): 203-208. [PubMed]
Heinzl B, Eber E, Oberwaldner B, et al. Effects of inhaled gentamicin prophylaxis on acquisition of Pseudomonas aeruginosa in children with cystic fibrosis: a pilot study. Pediatr Pulmonol 2002; 33: 32-37. [PubMed]
Hodson ME, Penketh ARL, Batten JC. Aerosol carbenicillin and gentamicin treatment of Pseudomonas aeruginosa in patients with cystic fibrosis. Lancet 1981; i: 1137-1139. [PubMed]
Hodson ME, Gallagher CG, Govan JR. A randomised clinical trial of nebulised tobramycin or colistin in cystic fibrosis. Eur Resp J 2002; 20:658-664. [PubMed]
Hoffman IM, Rubin BK, Iskandar SS, et al. Acute renal failure in cystic fibrosis: Associated with inhaled tobramycin. Pediatr Pulmonol 2002; 34: 375-377. [PubMed]
Kamin W, Schwabe A, Kramer I. Inhalation solutions – which ones are allowed to be mixed? Physico-chemical compatibility of drug solutions in nebulisers. J Cyst Fibros 2006; 5: 205-213. [PubMed]
Lang BJ, Arron SD, Ferris SW, et al. Multiple combination bactericidal antibiotic testing for patients with cystic fibrosis infected with multiresistant strains of Pseudomonas aeruginosa. Am J Respir Crit Care Med 2000; 162: 2241-2245. [PubMed]
Lebecque P, Leal T, Zylberberg K, et al. Towards zero prevalence of chronic Pseudomonas aeruginosa infection in children with cystic fibrosis. J Cyst Fibros 2006; 5: 237-244. [PubMed]
Levy J, Smith AL, Kenny MA, et al. Bioactivity of gentamicin in purulent sputum from patients with cystic fibrosis or bronchiectasis: comparison with activity in serum. J Infect Dis 1983; 148: 1069-1076. [PubMed]
Maiz L, Canton R, Mir N, et al. Aerosolized vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infection in cystic fibrosis. Pediatr Pulmonol 1998; 26: 287-289. [PubMed]
Mearns MB. Aerosol therapy in cystic fibrosis. Arch Dis Child 1970; 45: 605 - 607. [PubMed]
Mendelman PM, Smith AL, Levy J, et al. Aminoglycoside penetration, inactivation, and efficacy in cystic fibrosis sputum. Am Rev Respir Dis. 1985; 132: 761-765. [PubMed]
Moss RB. Administration of aerosolised antibiotics in cystic fibrosis patients. Chest 2001; 120: 107S-113S. [PubMed]
Moss RB. Long term benefits of inhaled tobramycin in adolescent patients with cystic fibrosis. Chest 2002: 121; 55-63. [PubMed]
Mukhopadhyay S, Singh M, Cater JI, et al. Nebulised anti-Pseudomonal antibiotic therapy in cystic fibrosis: a meta-analysis of benefits and risks. Thorax 1996; 51: 364-368. [PubMed]
Ramsey BW, Pepe MS, Quan JM, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N Engl J Med 1999 Jan7; 340(1): 23-30. [PubMed]
Ratjen F, Doring G, Nikolaizik WH. Effect of inhaled tobramycin on early Pseudomonas aeruginosa colonisation in patients with cystic fibrosis. Lancet 2001; 348: 983-984. [PubMed]
Ring E, Eber E, Erwa W, et al. Urinary N-acetyl-beta-D-glucosaminidase in patients with cystic fibrosis on long term gentamicin inhalation. Arch Dis Child 1998; 78: 540-543. [PubMed]
Ryan G, Mukhopadhyay S, Singh M. Nebulised anti-pseudomonal antibiotics for cystic fibrosis. Cochrane Database Syst Rev 2003; 3: CD001021. [PubMed]
Saiman L, Mehar F, Niu WW, et al. Antibiotics susceptibility of multiply resistant Pseudomonas aeruginosa isolated from patients with cystic fibrosis, including candidates for transplantation. Clin Infect Dis 1996; 23: 532-537. [PubMed]
Schaad UB, Wedgwood-Krucko J, Suter S, et al. Efficacy of inhaled amikacin as an adjunct to intravenous combination therapy (ceftazidime and amikacin) in cystic fibrosis. J Pediatr 1987; 111: 599-605. [PubMed]
Semsarian C. Efficacy of inhaled tobramycin in cystic fibrosis. J Paediatr Child Health 1990; 26: 110-111. [PubMed]
Smith AL, Ramsey BW, Hedges DL, et al. Safety of aerosol tobramycin administration for 3 months to patients with cystic fibrosis. Pediatr Pulmonol 1989; 7: 265-271. [PubMed]
Stephens D, Garey N, Isles A, et al. Efficacy of inhaled tobramycin in the treatment of pulmonary exacerbations in children with cystic fibrosis. Pediatr Infect Dis 1983; 2: 209-211. [PubMed]
Touw DJ, Brimicombe RW, Hodson ME, et al. Inhalation of antibiotics in cystic fibrosis. Eur Respir J 1995; 8: 1594-1604. [PubMed]
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