Hypersensitivity pneumonitis due to high-dose colistin aerosol therapy

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b Department of Pharmacy, Singapore General Hospital, Singapore. 1. Introduction ... She had a past medical history of long-standing ulcerative colitis treated ...

International Journal of Infectious Diseases 14 (2010) e1018–e1019

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Case Report

Hypersensitivity pneumonitis due to high-dose colistin aerosol therapy K.W. Leong a, S. Ong a, H.L. Chee a, W. Lee b, A.L. Kwa b,* a b

Department of Anesthesia and Surgical Intensive Care Unit, Singapore General Hospital, Singapore Department of Pharmacy, Singapore General Hospital, Singapore



Article history: Received 27 January 2010 Received in revised form 27 July 2010 Accepted 3 August 2010

We report a case of hypersensitivity pneumonitis, possibly due to aerosolized colistin therapy for severe multi-resistant Gram-negative pneumonia. Microbiological eradication was achieved with colistin therapy, which was stopped after 12 days in view of rising eosinophilia and possible lung fibrosis. The eosinophil count started to normalize 3 days after stopping colistin therapy and the patient was eventually weaned to minimal ventilatory support. ß 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Corresponding Editor: Craig Lee, Ottawa, Canada Keywords: Colistin Aerosol Pneumonitis Hypersensitive Resistance

1. Introduction We report a case of hypersensitivity pneumonitis due to aerosolized colistin (polymyxin E). 2. Case report A 69-year-old Indian woman was diagnosed with a localized perforation of the upper rectum. She underwent a total proctocolectomy with ileal pouch-anal anastomosis and a defunctioning loop ileostomy. She had a past medical history of long-standing ulcerative colitis treated with steroids, diabetes mellitus, and hyperlipidemia. Post-operatively, she was admitted to the surgical intensive care unit (SICU) for septic shock secondary to abdominal wound infection. During her admission to the SICU, she developed nosocomial pneumonia secondary to multi-resistant Acinetobacter baumannii (MRAB), which was only sensitive to gentamicin, polymyxins, trimethoprim–sulfamethoxazole, and minocycline. The MRAB pneumonia was treated with nebulized colistin. She received 1 million units (MU) of colistimethate sodium (prodrug of colistin), initially for 2 days, which was increased to 2 MU 8-hourly to facilitate rapid clearance and clinical improvement. During the

* Corresponding author. Tel.: +65 63213401; fax: +65 62202780. E-mail address: [email protected] (A.L. Kwa).

colistin therapy, the patient was hemodynamically stable without the need for inotropes. She was also not in overt positive fluid balance as she was supported with intermittent hemodialysis. A repeat sputum culture done on day 4 of therapy revealed clearance of the MRAB. However, a new organism, Stenotrophomonas maltophilia was isolated instead. This was thought to be a colonizer, selected out from high-dose nebulized colistin, hence no treatment was instituted. On day 5 of the colistin therapy, her ventilatory support increased significantly. Full blood counts (FBC) had also started to show eosinophilia that had not been present before (Figure 1). A high-resolution computed tomography (CT) scan of the chest done on day 9 of nebulized colistin therapy revealed bilateral groundglass opacities with increased interstitial lung markings and patchy air-space opacities, consistent with fibroproliferative changes on the background of bilateral pneumonia, as reported by the radiologist. The high-dose nebulized colistin therapy was stopped after 12 days in view of the rising eosinophilia and possible hypersensitivity pneumonitis. The eosinophil count started to normalize 3 days after stopping therapy (Figure 1). Ventilator support was also decreased and she was eventually weaned to pressure support mode with minimal pressure support from the ventilator 13 days after stopping colistin. During the nebulized colistin therapy, there was concomitant use of pantoprazole, noradrenaline, soluble insulin, meropenem, and fluconazole. We performed an extensive literature search and

1201-9712/$36.00 – see front matter ß 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijid.2010.08.001


K.W. Leong et al. / International Journal of Infectious Diseases 14 (2010) e1018–e1019

Nebulised colistin therapy

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Figure 1. Absolute eosinophil count and static lung compliance trends.


hypersensitivity pneumonitis was due to the conversion of the prodrug to the biologically active form of colistin. It has been reported that in a single-dose aerosol exposure, the active colistin sulfate is much less likely to be tolerated than its prodrug.4 In water, phosphate buffer, and plasma, there is rapid conversion from prodrug to colistin within 24 to 48 h at 37 8C.5 After 48 h, more than 60% of the prodrug is converted to the active form at 37 8C.5 Airway reactivity after colistin aerosol therapy is not uncommon, but this is easily treated with nebulized salbutamol before colistin aerosol therapy.6 However, McCoy7 reported the development of ARDS in a clinically stable cystic fibrosis patient. The patient developed ARDS after a 5-week old pharmacy-compounded premixed colistin solution was used in his aerosol therapy. As a result of this fatal episode, the Food and Drug Administration (FDA) has submitted a warning for this treatment. In this case, we were unable to ascertain the time interval between drug reconstitution and nebulization, though in our practice colistin is usually only reconstituted just prior to administration. 4. Conclusions

were unable to find any evidence to suggest that these concomitant medications can cause hypersensitivity pneumonitis or a similar type of hyper-reactive reaction in the lungs. Unfortunately, a month later, she died as a result of a bleed from the rectal stump. 3. Discussion The prevalence of multi-drug resistance among Gram-negative bacteria is rising at an alarming rate, rendering many antimicrobial agents ineffective, except polymyxins. Nebulized colistin has been used successfully for the treatment of respiratory tract infections due to multidrug-resistant Gram-negative bacilli, with minimal reported complications.1,2 For our patient, nebulized colistin was deemed to have successfully eradicated the MRAB by day 4 of therapy. However, from day 5 onwards, increased ventilatory requirements were observed. We postulated that this turn of events was likely due to the development of hypersensitive pneumonitis as a result of, or exacerbated by, prolonged nebulization of colistin despite the achievement of early microbiological eradication. This was demonstrated by a sudden increase in ventilatory requirements during the early course of treatment, which reduced once colistin was stopped. Airway pressure release ventilation, an effective safe alternative for difficult-to-oxygenate patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS), has to be instituted as a result of the increased ventilatory requirements. We do not think that the increased ventilatory support was caused by a worsening pneumonia as there was no progression in the serial chest X-rays or clinically worsening sepsis as manifested by either a rising white cell count and/or unstable hemodynamics. Moreover, the increasing trend of absolute eosinophil counts appeared to correlate with the increasing ventilatory support, suggesting hypersensitive pneumonitis, which we postulate is likely to have been caused by colistin aerosol therapy. An increased eosinophil count during polymyxin treatment has previously been reported.3 In addition, when the Naranjo adverse drug reaction (ADR) probability scale was applied, the overall score was 7, which means ‘probable’. Nebulized colistin is often administered in the form of its prodrug, i.e., colistimethate sodium (previously known as colistin sulfomethate or colistin sodium). For our patient, we think that the

We have reported the development of a possible hypersensitivity pneumonitis as a result of high-dose colistin aerosol therapy in the background of nosocomial pneumonia. Hence, we recommend that for aerosol therapy requiring colistin: (1) the prodrug colistimethate sodium should be reconstituted just before administration in order to avoid excessive conversion to biologically active colistin, which can cause airway or alveolar injury; (2) the duration of colistin aerosol therapy for the treatment of pneumonia due to multidrug-resistant Gramnegative bacilli may be reduced to less than the recommended 2week duration in cases of rapid microbiological eradication. However, further clinical and pharmacokinetic studies are needed to prove this. Conflict of interest All authors declare that they have no conflict of interest in the areas of financial and personal relationships with other people or organizations that could inappropriately influence (bias) their work. References 1. Michalopoulos A, Fotakis D, Virtzili S, Vletsas C, Raftopoulou S, Mastora Z, Falagas ME. Aerosolized colistin as adjunctive treatment of ventilator-associated pneumonia due to multidrug-resistant Gram-negative bacteria: a prospective study. Respir Med 2008;102:407–12. 2. Kwa AL, Loh C, Low JG, Kurup A, Tam VH. Nebulized colistin in the treatment of pneumonia due to multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa. Clin Infect Dis 2005;41:754–7. 3. Falagas ME, Kasiakou SK. Toxicity of polymyxins: a systematic review of the evidence from old and recent studies. Crit Care 2006;10:R27. 4. Westerman EM, Le Brun PP, Touw DJ, Frijlink HW, Heijerman HG. Effect of nebulized colistin sulphate and colistin sulphomethate on lung function in patients with cystic fibrosis: a pilot study. J Cyst Fibros 2004;3:23–8. 5. Li J, Milne RW, Nation RL, Turnidge JD, Coulthard K. Stability of colistin and colistin methanesulfonate in aqueous media and plasma as determined by highperformance liquid chromatography. Antimicrob Agents Chemother 2003; 47:1364–70. 6. Michalopoulos A, Kasiakou SK, Mastora Z, Rellos K, Kapaskelis AM, Falagas ME. Aerosolized colistin for the treatment of nosocomial pneumonia due to multidrug-resistant Gram-negative bacteria in patients without cystic fibrosis. Crit Care 2005;9:R53–9. 7. McCoy KS. Compounded colistimethate as possible cause of fatal acute respiratory distress syndrome. N Engl J Med 2007;357:2310–1.

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