Case in Point Organizing Pneumonia and Pneumothorax 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 lung peared cyanotic with clubbing injury 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 heart-lung spiratory rate of 30, and pulse transplants, inflammatory oxygen 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 crackles case of OP complicated by a and rhonchi bilaterally. Cardiac spontaneous tension pneumo- and abdominal examinations thorax that was temporally re- were normal. Examination of lated to a prolonged course of the extremities revealed club- daptomycin. bing and mild digital cyanosis while the patient was on room INITIAL PRESENTATION Figure 1. Chest radiograph showed mixed interstitial and air. Complete blood 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 smoking history was of 12 x 103/µL with a differ- referred to the pulmonary service re- sively worsening. At baseline, the ential of 78% neutrophils, 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 surgery. 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), hypoxia 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 AUGUST 2012 • FEDERAL PRACTITIONER • 23 CASE IN POINT 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 sputum 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 bronchoscopy 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% lymphocytes; no eosinophils were detected. Multiple transbronchial biopsies 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 hypoxemia. The patient was subsequently discharged 2 days after therapy was initiated; however, 10 days later he presented to the Emergency Depart- ment hypotensive with acute left-side chest pain. 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 24 • FEDERAL PRACTITIONER • AUGUST 2012 CASE IN POINT 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 signs and symptoms that mimic community-acquired pneumonia. The annual incidence is reported to be < 1 in 100,000.1 OP is defined as an inflammatory process, characterized histologically by buds of granulation tissue that occlude the lumen of distal airways and inflamma- tory cells that surround the associated Figure 4. Low-power view of transbronchial lung biopsy, 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, patients present with subacute cough, fever, and malaise, which fail to resolve after multiple courses of antibiotics. Imaging studies may show multifocal airspace opaci- ties, focal nodular opacities, or mixed interstitial and airspace lesions, all of which can be migratory. Spirometry 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 lung biopsy 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. AUGUST 2012 • FEDERAL PRACTITIONER • 25 CASE IN POINT 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 macrolides 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 necrosis 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 neutrophil 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.