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Home , Diffuse panbronchiolitis, Pneumothorax

Case in Point Organizing and Associated With Daptomycin Use

James Prahl, MD; Michael Tripp, MD; and Christopher Stafford, MD

This case examines the rare association between the administration of daptomycin and pulmonary toxicity.

rganizing pneumonia sentences. On room air he ap- (OP) is a distinct peared cyanotic with clubbing pattern that may of his upper digits. Initial vital Ocomplicate a variety signs revealed a pulse rate of of collagen vascular diseases, 88, temperature of 100.8º F, re- bone marrow or -lung spiratory rate of 30, and pulse transplants, inflammatory saturation of 91% on bowel disease (IBD), inhala- 2 liters per minute of oxygen. tion of toxic gases, vasculitis, Pulmonary examination re- or medications. We report a vealed diffuse coarse case of OP complicated by a and rhonchi bilaterally. Cardiac spontaneous tension pneumo- and abdominal examinations that was temporally re- were normal. Examination of lated to a prolonged course of the extremities revealed club- daptomycin. bing and mild digital while the was on room INITIAL PRESENTATION Figure 1. showed mixed interstitial and air. Complete count AND EXAMINATION airspace opacities with upper lobe predominance. demonstrated anemia, throm- A 64-year-old man with a 40 bocytosis, and a leukocytosis pack-year history was of 12 x 103/µL with a differ- referred to the pulmonary service re- sively worsening. At baseline, the ential of 78% , 20% lym- porting cough, fever, and dyspnea. patient was very active and walked phocytes, and 2% eosinophils. Serum The patient had received 5 out of 6 regularly; however, on presenta- creatine was normal, albumin was weeks of treatment with daptomycin tion he was unable to walk up a sin- depressed, and the hepatic transami- for a septic right shoulder joint fol- gle flight of stairs without stopping nases were mildly elevated. Arterial lowing arthroscopic . Respira- due to significant dyspnea. He also blood gas obtained while breathing tory symptoms began 3 weeks before reported a 14-pound unexplained room air demonstrated a respira- presentation and had been progres- weight loss over this same time. tory alkalosis (pH of 7.51), Before his surgery he had been tak- (partial pressure of oxygen in arte-

Drs. Prahl, Tripp, and Stafford are physicians ing atenolol, atorvastatin, and escital- rial blood [Pao2] of 50 mm Hg), and in the Department of Internal Medicine and Criti- opram for many years without recent hypocapnea (partial pressure of car- cal Care Medicine, U.S. Naval Hospital Guam in changes to this regimen. The patient bon dioxide in arterial blood [Paco ] Agana Heights, Guam, and the Department of Pul- 2 monary and Critical Care Medicine, Naval Medical seemed to be in mild respiratory dis- of 30 mm Hg). The chest radiograph Center San Diego in San Diego, California. tress and able to speak in only short showed mixed interstitial and airspace

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opacities predominantly in the upper lobes (Figure 1). Computed tomog- raphy (CT) scan of the chest showed multifocal ground-glass opacities and areas of consolidation (Figures 2 and 3).

TREATMENT Due to the patient’s worsening respi- ratory status, he was admitted to the internal medicine service and treated with intravenous (IV) ciprofloxacin, piperacillin/tazobactam, and van- comycin for presumed pneumonia. Initial infectious disease workup in- cluded and blood cultures, Streptococcus pneumoniae and Legio- nella urine antigens, and serology for endemic fungi, all negative. Failure to improve on hospital day 4 prompted a fiberoptic with bron- Figure 2. Chest CT demonstrating bilateral upper lobe mixed airspace consolidation with choalveolar lavage (BAL), which re- associated ground-glass opacities. vealed normal airways. All bacterial, viral, and fungal cul- tures obtained from the BAL were negative. BAL showed 700 white blood cells of which 78% were neu- trophils and 22% ; no eosinophils were detected. Multiple transbronchial were ob- tained, and the histology showed an OP without infectious organisms (Figures 4 and 5). Daptomycin ther- apy was discontinued and 60 mg/d of prednisone and 250 mg/d of azithro- mycin were started, with rapid reso- lution of fever and improvement in . The patient was subsequently discharged 2 days after therapy was initiated; however, 10 days later he presented to the Emergency Depart- ment hypotensive with left-side . A tension pneumothorax was diagnosed, and a tube thoracos- tomy was performed. Due to a persis- tent air leak, the patient underwent Figure 3. Chest CT again demonstrating mixed airspace and ground-glass opacities with video-assisted thoracoscopic surgery. no evidence of pleural effusions or lymphadenopathy. Biopsies were obtained, which con- firmed the diagnosis of “OP.” The

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patient was discharged in good con- dition 5 days later. On outpatient follow-up, he had returned to his pre- vious level of functioning, and radio- graphic abnormalities resolved after completing an 8-week tapering course of prednisone and azithromycin.

ABOUT OP OP is a rare lung injury pattern that presents with that mimic community-acquired pneumonia. The annual is reported to be < 1 in 100,000.1 OP is defined as an inflammatory process, characterized histologically by buds of granulation that occlude the lumen of distal airways and inflamma- tory cells that surround the associated Figure 4. Low-power view of transbronchial lung , demonstrating alveoli with anas- airways without disturbing the under- tomosing plugs of connective tissue with preserved underlying lung architecture. lying normal lung architecture.2,3 Clinically, present with subacute cough, fever, and malaise, which fail to resolve after multiple courses of . Imaging studies may show multifocal airspace opaci- ties, focal nodular opacities, or mixed interstitial and airspace , all of which can be migratory. can reveal a mild restrictive process.4 OP secondary to various etiologies, such as collagen vascular disease, in- fections, medications, neoplasm, for- eign body aspiration, hypersensitivity, and fume inhalation, is known as sec- ondary organizing pneumonia (SOP). Without a predisposing condition or insult, OP is known as cryptogenic organizing pneumonia (COP). Traditionally, a ob- tained via video-assisted thoraco- scopic surgery (VATS) has been the gold standard for diagnosis, but more recent literature suggests transbron- Figure 5. High-power view of lung biopsy, showing characteristic connective tissue plugs chial lung biopsy may, in some cases, within airspaces with multiple surrounding inflammatory cells. be adequate. One study using trans- bronchial lung biopsy showed a sen- tion, however, is that areas of OP can be missed on a transbronchial lung sitivity of 64% and a specificity of occur in association with other inter- biopsy; therefore, sampling errors 86% with a 94% positive predicted stitial lung diseases, such as eosino- are more likely with transbronchial value in diagnosing COP.5 One limita- philic pneumonia (EP), which may lung biopsy.

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Our patient had an open lung bi- change secondary to inactivation of cient to cause rupture.21 The incidence opsy that confirmed the initial clini- daptomyocin by pulmonary surfac- of pneumothorax following a bron- cal and histological diagnosis of OP. tant.18 choscopic lung biopsy is reported to Pneumothorax has been associated Daptomycin did not demonstrate be between 1% and 6% in nonme- with OP, but this condition is not a significant pulmonary toxicity dur- chanically ventilated patients.22,23 Al- major clinical feature.6 OP is gener- ing the trials leading to its approved though we can’t definitely rule out ally treated with tapering doses of use; however, EP and 1 other case of an iatrogenic pneumothorax from corticosteroids, although in the case OP have been subsequently reported the patient’s transbronchial biopsy, it of SOP, any suspected causes, such with daptomycin.19 In July 2010, the seems unlikely as our patient’s pneu- as radiation, environmental expo- U.S. Food and Drug Administration mothorax presented 10 days after his sure, or infection, must be addressed (FDA) issued safety information re- procedure. Review of the literature de- first. The use of such as garding the risk of developing EP scribes 5 days as the latest reported azithromycin has shown promise during the use of daptomycin. The pneumothorax following a transbron- when added to the use of corticoste- FDA reviewed 7 likely cases of EP. All chial biopsy.24 We believe that the roids.7-10 Macrolides are believed to of the reported cases occurred 2 to 4 daptomycin initiated an OP that sub- have anti-inflammatory effects and weeks after therapy was initiated.20 sequently lead to a pneumothorax. have been shown to suppress the re- Although areas of OP may occur in lease of pro-inflammatory cytokines, EP, we were able to exclude this with CONCLUSION such as tumor factor alpha an open lung biopsy. Daptomycin use has only rarely been (TNF-), interleukins 1 and 8, and Also, our patient was unlikely to associated with pulmonary toxicity, the expression of adhesion molecules have EP as he did not have eosino- including OP. To our knowledge, this necessary for migration phils in his BAL or peripheral smear. is the second case of OP associated and activation.11-15 The prognosis of Possible interaction of daptomycin with daptomycin and the first case patients who receive treatment with with surfactant has been postulated complicated by a pneumothorax. It steroids is overall very good with to be the underlying pathophysiology is unknown at this time whether OP complete recovery in up to 80% of behind the drug’s pulmonary toxic- is dose related or an idiosyncratic patients within 3 months.4 Recur- ity, allowing the accumulation of dap- complication of daptomycin. Provid- rence can be seen in up to 58% of tomycin in the alveolar spaces and ers who use this , particu- cases and seems to occur equally subsequent injury to the epithelium larly for prolonged courses of therapy, in both secondary and cryptogenic and formation of OP.19 It is unknown should be aware of potential lung tox- cases.16 at this time whether OP could be a icities. l dose-related complication of daptom- Induced OP ycin or idiosyncratic. Our patient had Author disclosures SOP has been associated with vari- extended therapy with daptomycin The authors report no actual or poten- ous antimicrobial agents, including and improved following cessation of tial conflicts of interest with regard to nitrofurantoin, , ampho- the medication, although he was also this article. tericin, and several cephalosporins.2 treated with oral corticosteroids and OP may occur months to years after therapy. Disclaimer a medication has been started and The opinions expressed herein are those may recur when the medication is Pneumothorax of the authors and do not necessar- restarted.2 Daptomycin is a novel li- Rarely, OP can present or be compli- ily reflect those of Federal Practitio- popeptide derived from Streptomy- cated by a pneumothorax. One case ner, Quadrant HealthCom Inc., Naval ces with the mechanism of action via report describes a complication oc- Medical Center San Diego, the U.S. depolarization of cell membranes of curring due to “air leak syndrome.”21 Navy, the Department of Defense, the gram-positive . Daptomycin We hypothesize regional peripheral U.S. Government, or any of its agen- is not recommended for treatment obstruction by fibrous plugs that sec- cies. This article may discuss unla- of gram-positive pneumonia due to ondarily led to a ball-valve effect and beled or investigational use of certain questions concerning different mech- distal overinflation of airways. Severe drugs. Please review complete prescrib- anisms in lung tissue.17 Some postu- coughing that causes overpressuriza- ing information for specific drugs or late that the drug’s mechanism may tion of the distal alveoli may be suffi- drug combinations—including indica-

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8. Epler GR, Colby TV, McLoud TC, Carrington CB, pneumonia. Int J Tuberc Lung Dis. 2007;11(6):689- tions, contraindications, warnings, and Gaensler EA. obliterans organizing 694. adverse effects—before administering pneumonia. N Engl J Med. 1985;312(3):152-158. 17. Cubicin [package insert]. Lexington, MA: Cubist 9. Arbetter KR, Prakash UB, Tazelaar HD, Douglas Pharmaceuticals; 2010. pharmacologic therapy to patients. WW. Radiation-induced in the “nonir- 18. Silverman JA, Mortin LI, Vanpraagh AD, Li T, Alder radiated” lung. Mayo Clin Proc. 1999;74(1):27-36. J. Inhibition of daptomycin by pulmonary surfac- REFERENCES 10. Ichikawa Y, Ninomiya H, Katsuki M, Hotta M, tant: In vitro modeling and clinical impact. J Infect Tanaka M, Oizumi K. Low-dose/long-term eryth- Dis. 2005;191(12):2149-2152. 1. Gudmundsson G, Sveinsson O, Isaksson HJ, Jons- romycin for treatment of bronchiolitis obliterans 19. Cobb E, Kimbrough RC, Nugent KM, Phy MP. Or- son S, Frodadottir H, Aspelund T. Epidemiol- organizing pneumonia (BOOP). Kurume Med J. ganizing pneumonia and pulmonary eosinophilic ogy of organising pneumonia in Iceland. Thorax. 1993;40(2):65-67. infiltration associated with daptomycin. Ann Phar- 2006;61(9):805-808. 11. Sakito O, Kadota J, Kohno S, Abe K, Shirai R, Hara macother. 2007;41(4):696-701. 2. Epler GR. Drug-induced bronchiolitis obliterans or- K. Interleukin 1 beta, tumor necrosis factor alpha, 20. Federal Drug Administration. U.S. Food and Drug ganizing pneumonia. Clin Chest Med. 2004;25(1):89- and in fluid Administration website. FDA Drug Safety Commu- 94. of patients with : A poten- nication: associated with 3. Schlesinger C, Koss MN. The organizing pneumo- tial mechanism of macrolide therapy. . the use of Cubicin (daptomycin). http://www.fda nias: An update and review. Curr Opin Pulm Med. 1996;63(1):42-48. .gov/Safety/MedWatch/SafetyInformation/Safety 2005;11(5):422-430. 12. Wales D, Woodhead M. The anti-inflammatory ef- AlertsforHumanMedicalProducts/ucm220499.htm. 4. Drakopanagiotakis F, Polychronopoulos V, Jud- fects of macrolides. Thorax. 1999;54(suppl 2):S58- Updated July 29, 2010. Accessed June 28, 2012. son MA. Organizing pneumonia. Am J Med Sci. S62. 21. Iwanaga T, Hirota T, Ikeda T. Air leak syndrome as 2008;335(1):34-39. 13. Rubin BK, Henke MO. Immunomodulatory activity one of the manifestations of bronchiolitis obliterans 5. Poletti V, Cazzato S, Minicuci N, Zompatori M, Burzi and effectiveness of macrolides in chronic airway organizing pneumonia. Intern Med. 2000;39(2):163- M, Schiattone ML. The diagnostic value of bron- disease. Chest. 2004;125(suppl 2):70S-78S. 165. choalveolar lavage and transbronchial lung biopsy 14. Labro MT, el Benna J, Abdelghaffar H. Modulation of 22. Wang K-P, Mehta AC, Turner JF Jr, eds. Flexible in cryptogenic organizing pneumonia. Eur Respir J. human polymorphonuclear neutrophil function by Bronchoscopy. 2nd ed. Malden, MA: Blackwell Pub- 1996;9(12):2513-2516. macrolides: Preliminary data concerning dirithromy- lishing, Inc; 2004. 6. Lee PC, Lin JH, Lin CH, Chien ST, Hsu JY, Feng NH. cin. J Antimicrob Chemother. 1993;31(suppl C):51- 23. Izbicki G, Shitrit D, Yarmolovsky A, et al. Is rou- Spontaneous pneumothorax after steroid treatment 64. tine chest radiography after transbronchial biopsy in a patient with bronchiolitis obliterans organizing 15. Ianaro A, Ialenti A, Maffia P, et al. Anti-inflammatory necessary?: A prospective study of 350 cases. Chest. pneumonia. J Formos Med Assoc. 2005;104(3):190- activity of macrolide antibiotics. J Pharmacol Exp 2006;129(6):1561-1564. 193. Ther. 2000;292(1):156-163. 24. Levy H, Kallenbach JM, Feldman C, Pincus P, Hur- 7. Stover DE, Mangino D. Macrolides: A treatment 16. Sveinsson OA, Isaksson HJ, Sigvaldason A, Yn- witz M. Delayed pneumothorax after transbronchial alternative for bronchiolitis obliterans organizing gvason F, Aspelund T, Gudmundsson G. Clinical lung biopsy. Thorax. 1986;41(8):647-648. pneumonia? Chest. 2005;128(5):3611-3617. features in secondary and cryptogenic organising

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