Daptomycin-induced eosinophilic pneumonia - a systematic review

Antimicrobial Resistance and Infection Control, Dec 2016

Purpose Eosinophilic pneumonia comprises a group of lung diseases in which eosinophils appear in increased numbers in the lungs and sometimes in the bloodstream. Several case reports link daptomycin use to this phenomenon. Summary We performed a systematic literature review to identify cases of eosinophilic pneumonia associated with daptomycin use. Relevant studies were identified by searching Pubmed/Medline, EMBASE, Google Scholar, Cochrane Database of Systematic Reviews, and Clin-Alert from inception to May 2016, and manual searches of reference lists. All case reports that include information regarding patient age, indication, clinical and objective findings, treatment and outcome were evaluated. Abstracts from conference proceedings as well as case reports not in English were excluded. Descriptive statistics were used to analyze the data. Thirty-five patient-cases were included in the final analysis. Patients most likely to be identified with daptomycin-induced eosinophilic pneumonia were male (83%) and elderly (mean age 65.4 ± 15 years). The dose for daptomycin ranged from 4 to 10 mg/kg/day, but included a large number of patients with renal dysfunction. The average duration of daptomycin therapy upon onset of EP symptoms was 2.8 ± 1.6 weeks. Majority of patients presented with dyspnea (94%), fever (57%) and were also found to have peripheral eosinophilia (77%) and infiltrates/opacities of CT/CXR (86%). Symptom improvement was seen after daptomycin discontinuation (24 h to 1 week). The majority of patients were also prescribed treatment with corticosteroids (66%). Conclusion Clinicians should be aware of daptomycin-induced eosinophilic pneumonia and its symptoms along with its presentation and treatment.

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Daptomycin-induced eosinophilic pneumonia - a systematic review

Uppal et al. Antimicrobial Resistance and Infection Control Daptomycin-induced eosinophilic pneumonia - a systematic review Priyasha Uppal 2 Kerry L. LaPlante 0 1 2 Melissa M. Gaitanis 1 2 Matthew D. Jankowich 1 2 Kristina E. Ward 0 0 Department of Pharmacy Practice, University of Rhode Island , 7 Greenhouse Rd, Suite 295 J, Kingston, RI 02881 , USA 1 Warren Alpert Medical School of Brown University , Providence, RI , USA 2 Providence Veterans Affairs Medical Center , Providence, RI , USA Purpose: Eosinophilic pneumonia comprises a group of lung diseases in which eosinophils appear in increased numbers in the lungs and sometimes in the bloodstream. Several case reports link daptomycin use to this phenomenon. Summary: We performed a systematic literature review to identify cases of eosinophilic pneumonia associated with daptomycin use. Relevant studies were identified by searching Pubmed/Medline, EMBASE, Google Scholar, Cochrane Database of Systematic Reviews, and Clin-Alert from inception to May 2016, and manual searches of reference lists. All case reports that include information regarding patient age, indication, clinical and objective findings, treatment and outcome were evaluated. Abstracts from conference proceedings as well as case reports not in English were excluded. Descriptive statistics were used to analyze the data. Thirty-five patient-cases were included in the final analysis. Patients most likely to be identified with daptomycin-induced eosinophilic pneumonia were male (83%) and elderly (mean age 65.4 ± 15 years). The dose for daptomycin ranged from 4 to 10 mg/kg/day, but included a large number of patients with renal dysfunction. The average duration of daptomycin therapy upon onset of EP symptoms was 2.8 ± 1.6 weeks. Majority of patients presented with dyspnea (94%), fever (57%) and were also found to have peripheral eosinophilia (77%) and infiltrates/opacities of CT/CXR (86%). Symptom improvement was seen after daptomycin discontinuation (24 h to 1 week). The majority of patients were also prescribed treatment with corticosteroids (66%). Conclusion: Clinicians should be aware of daptomycin-induced eosinophilic pneumonia and its symptoms along with its presentation and treatment. Daptomycin; Eosinophilia; Pneumonia - Background Eosinophilic pneumonia is a rare, but serious respiratory syndrome that occurs when eosinophils accumulate in the lungs [1, 2]. It has been associated with several medications and chemicals, with antibiotics and nonsteroidal anti-inflammatory drugs among the most common [3, 4]. The pathophysiology of acute eosinophilic pneumonia is thought to be caused by detection of an antigen by alveolar macrophages which leads to recruitment of T-helper 2 lymphocytes and subsequent release of interleukin 5. Interleukin 5 promotes eosinophil production and migration to the lung. Additionally, eotaxin (a potent eosinophil chemoattractant) production by alveolar macrophages, pulmonary endothelial cells, airway smooth muscle cells, and alveolar epithelial cells leads to further accumulation of eosinophils in the lungs [5]. Daptomycin is a cyclic lipopeptide antibiotic derived from the fermentation of Streptomyces roseosporus. Daptomycin has activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) [6]. In 2007, pulmonary eosinophilia was added to the “Adverse Reactions, Post-Marketing Experience” section of the product label for daptomycin [2]. A review of the literature and the US FDA Adverse Event Reporting System database in 2012 revealed 7 definite, 13 probable, and 38 possible cases of daptomycin-induced eosinophilic pneumonia [1]. While the mechanism of daptomycin’s pulmonary toxicity is not known, the drug undergoes conformational change through interaction with calcium which allows binding to the cytoplasmic membrane, increased membrane permeability, and intracellular ion escape [7]. The antibacterial activity of daptomycin is decreased because of its binding to pulmonary surfactant. Some have speculated two potential mechanisms for daptomycin’s pulmonary toxicity: 1) chronic daptomycin administration results in drug accumulation near the epithelial alveolar surface causing epithelial injury and pneumonia and 2) the daptomycin-surfactant interaction could alter lipid integrity which may stimulate an inflammatory response [3, 7, 8]. Per the FDA guidance, eosinophilic pneumonia is attributed to daptomycin when the following criteria are met: 1) concurrent exposure to daptomycin, 2) fever, 3) dyspnea with increased oxygen requirement or requiring mechanical ventilation, 4) new infiltrates on chest x-ray or computed tomography (CT) scan, 5) bronchoalveolar lavage (BAL) with > 25% eosinophils, and 6) clinical improvement following daptomycin withdrawal [2]. Solomon and Schwartz [4] have also developed criteria for drug- or toxin-induced eosinophilic pneumonia that is similar and includes 1) presence of simple, acute, or chronic eosinophilic pneumonia by diagnostic criteria which includes excess of eosinophils either on lung biopsy or BAL (usually ≥25%) in the setting of parenchymal infiltrates 2) presence of a potential candidate drug or toxin in an appropriate time frame 3) no other cause of eosinophilic pneumonia such as fungal or parasitic infection 4) clinical improvement after cessation of the drug or toxin, and 5) recurrence of eosinophilic pneumonia with re-challenge to the drug or toxin. However, re-challenge is often not recommended as it can be dangerous [4, 5]. Although the mechanism of daptomycin-induced eosinophilic pneumonia is unknown, some have speculated that daptomycin may bind to human surfactant and accumulate in the alveolar space causing injury to the epithelium with resulting inflammation [7, 8]. The purpose of this review is to systematically evaluate the published literature describing daptomycin-induced eosinophilic pneumonia. Methods All relevant cases and studies were identified by systematically searching of the PubMed, EMBASE, Google Scholar, Cochrane Database of Systematic Reviews, and Clin-Alert databases by two reviewers from inception through May 2016. The truncated terms “daptomycin”, “eosinophil*”, and “pneumon*” were searched in each database. All case reports that included information regarding patient age, indication, clinical and objective findings, treatment, and outcome were evaluated. Reports not published in English were excluded as well as abstracts from conference proceedings. Descriptive analysis was used to present pooled demographic information and other data where applicable. Results No clinical or observational trials assess daptomycininduced eosinophilic pneumonia; only case reports and case series are published. In 2012, Kim et al. identified 7 definite, 13 probable, and 38 possible cases of daptomycin-induced eosinophilic pneumonia via review of literature and FDA Adverse Event Reporting System Reports (AERS) as defined in Table 1 [1]. Details regarding the 38 possible cases reported through AERS were not described. Of the 20 cases that were identified as definite or probable, 9 have been published in the literature, the remaining 11 were summarized by Kim [1, 3, 9–13]. We also identified 39 additional cases of eosinophilic pneumonia attributed to daptomycin for a total of 59 cases described in the literature [7, 14–24]. Of those, 21 were excluded from this systematic review because they were abstract presentations at international meetings and did not go through the peer review publishing process [25–41]. Another three were excluded because they were not published in English [42–44]. Currently available data on a total of 35 cases of daptomycin-induced eosinophilic pneumonia is summarized in Table 2. Concurrent exposure to daptomycin Concurrent exposure to daptomycin Concurrent exposure to daptomycin All other cases that did not meet criteria Dyspnea with increased oxygen requirement or requiring mechanical ventilation New infiltrates on CXR or CT Dyspnea with increased oxygen requirement or requiring mechanical ventilation New infiltrates on chest x-ray or CT BAL with > 25% eosinophils Clinical improvement following daptomycin withdrawal BAL with ≤ 25% eosinophils OR peripheral eosinophilia Clinical improvement following daptomycin withdrawal Adapted from references 1 and 2 Abbreviation: BAL bronchoalveolar lavage; CT computed tomography; CXR chest x-ray New infiltrates on CXR or CT Clinical improvement following daptomycin withdrawal OR the patient died Kim [1] (2012) 63/F MSSA spinal osteomyelitis Clinical Findings Objective Findings Treatment Cobb [6] (2007) Osteomyelitis with bacteremia MRSA bacteremia MRSA osteomyelitis MSSA bacteremia MRSA diabetic foot infection 77/F Bacteremia (enterococcal) MRSA endocarditis Prosthetic joint infection 81/F MRSA paraspinal abscess Infection of left knee prosthesis Fever, cough, night sweats Dyspnea requiring MV Dyspnea requiring MV BAL = 60–70% Peripheral eosinophilia Elevated CPK BAL = 44% Peripheral eosinophilia Pulmonary infiltrates BAL = 9–13% Peripheral eosinophilia CT = ground glass opacities Lung biopsy = eosinophilic pneumonitis BAL not performed Peripheral eosinophilia Pulmonary infiltrates Eosinophils in tracheal aspirate Pleuritic pain Hypoxia requiring BAL not performed Peripheral eosinophilia CT = bilateral infiltrates Dyspnea requiring O2 Hematemesis Dyspnea requiring O2 Dyspnea requiring O2 Dyspnea requiring MV Fever Dyspnea requiring MV Dyspnea requiring MV Fatigue Weakness BAL with eosinophils (not quantified) Peripheral eosinophilia Peripheral eosinophilia CXR = pneumonitis Peripheral eosinophilia CT = bilateral ground glass appearance BAL = 2% (s/p corticosteroid)a CXR = bilateral mid-lung infiltrates DAP d/c Corticosteroids DAP d/c Corticosteroids DAP d/c Given NSAIDs, meperidine DAP d/c Corticosteroids DAP d/c DAP d/c Corticosteroids DAP d/c Corticosteroids DAP d/c Corticosteroids DAP d/c Corticosteroids DAP d/c Outcome Recovered Recovered Improved Improved Residual infiltrates on CT s/p 4 wks Recovered Improved Improved Improved within 2 weeks Kakish [8] (2008) Shinde [9] (2009) 54/ M MRSA vertebral osteomyelitis, epidural abscess Complicated inguinal hernia repair Lal [10] (2010) Prosthetic joint infection Miller [11] (2010) 60/ M MSSA prosthetic hip infection Kalogeropoulous 78/ [12] (2011) M Endocarditis Prosthetic knee infection MRSA osteomyelitis, septic arthritis Diskitis of lumbar spine Hayes [7] (2007) MSSA endocarditis DAP d/c Corticosteroids DAP d/c Corticosteroids DAP d/c Corticosteroids DAP d/c Corticosteroids DAP d/c Rechallenged, DAP d/c Corticosteroids DAP d/c DAP d/c Corticosteroids Improved within 24 h Normal CT at 4 weeks Improved within 48 h Rechallenge failed within 24 h Resolution within 96 h Recurrence with rechallenge at 5 months Resolution within 24 h Fever, rigors, diaphoresis Required MV Low-grade fever Dyspnea requiring MV Hypoxemia Dyspnea, dry cough requiring Cough, fever Hypoxia requiring Fever, chills, diaphoresis, Hypoxemia requiring O2 BAL 16% initially BAL 26% after rechallenge CRP elevated BAL = 33% Peripheral eosinophilia Lung biopsy revealed eosinophils Peripheral eosinophilia CT = bilateral airspace, peripheral predominance, small bilateral effusions Lung biopsy = many eosinophils BAL = 14% Peripheral eosinophilia CT = patchy bilateral infiltrates BAL = 81% after rechallenge Peripheral eosinophilia CT = bilateral scattered ground-glass opacities Lung biopsy = acute fibrinous and organizing pneumonia, reactive alveolar and interstitial epithelial changes BAL = 13% Peripheral eosinophilia CT = diffuse ground-glass, reticular opacities Lung biopsy = acute organizing pneumonia, eosinophilia, chronic inflammation, fibro-inflammatory changes Non-productive Peripheral eosinophilia cough, dyspnea CT = patchy peripheral Low-grade fevers, nodular/ground-glass chills Phillips [15] 2014) 48/ M Yusuf [17] (2014) 64/ M Osteomyelitis MRSA bacteremia Prosthetic joint infection Prosthetic joint infection Chiu [18] (2015) Osteomyelitis Roux [21] (2015) 74/F Infected hip reconstruction 67/F MRSA diabetic foot ulcer MSSA prosthetic hip infection Spondylo-discitis with lumbar epidural and bilateral psoas abscesses Patel [14] (2014) 61/F Osteomyelitis Dry cough Dyspnea requiring MV Fever Dyspnea Low grade fever Hypoxia Fever Fever Dyspnea requiring MV Pleuritic chest pain Dyspnea Cough with mild hypoxemia Cough, dyspnea requiring BPAP Fever, fatigue, decreased appetite Dry cough, hypoxemia BAL = 30% Peripheral eosinophilia CT = bilateral pleural effusion, diffuse bilateral patchy infiltrate BAL = 74% Peripheral eosinophilia CT = diffuse multi-lobar infiltrates CT = bilateral ground glass opacities Sputum negative for eosinophils CXR – bilateral airspace disease Peripheral eosinophilia Elevated CRP CT = consolidation in peripheral field of right upper lobe Peripheral eosinophilia Elevated CRP CT = right lobe infiltration BAL = 10% Peripheral eosinophilia DAP d/c Corticosteroids DAP d/c Corticosteroids DAP d/c Corticosteroids Improved within 24 h Improved within 72 h Improved DAP d/c Corticosteroids Resolution within 1 week DAP d/c Improved Improved within 24 h DAP d/c Improved within 24 h DAP d/c Corticosteroids DAP d/c DAP d/c Inhaled corticosteroids DAP d/c Corticosteroids Improved within 24 h Resolved within 6 weeks Improved within 72 h Improved within 96 h DAP was d/c 1 day Improved within 60 h before symptoms Corticosteroids Wojtaszczyk [22] (2015) Akcaer [23] (2016) Septic arthritis and pacemaker vegetation MSSA post-amputation abscess Dyspnea Tachypnea, hypoxia requiring CT = diffuse alveolar and interstitial opacities BAL = 58% Elevated CRP CT = bilateral ground glass opacity, patchy consolidation Peripheral eosinophilia Elevated CRP Elevated ESR HRCT = right pleural effusion, bilateral tree-in-bud pattern, bilateral scattered ground-glass opacities DAP d/c Corticosteroids Resolved within 72 h DAP d/c Resolved within 72 h Age(years), mean ± SD Daptomycin indication, n (%) Osteomyelitis/diabetic foot infection Prosthetic joint infection Daptomycin dose (mg/kg/day), mean ± SD Treatment duration at symptom onset (weeks), mean ± SD Clinical findings, n (%) Table 3 Compilation of available data on 35 cases of daptomycin-induced eosinophilic pneumonia Sex, n (%) Analysis of the 35 cases shows eosinophilic pneumonia resulting from daptomycin use is most likely to be reported in males with a mean age of 65.4 ± 15 years and a mean length of therapy of 2.8 ± 1.6 weeks at symptom onset. The most common indication for daptomycin use was osteomyelitis and/or diabetic foot infection closely followed by prosthetic joint infection. Daptomycin dose ranged from 4 to 10 mg/kg/day depending on renal function; therefore, the adverse effect does not appear to be dose dependent, but time dependent exposure. The most common symptoms of eosinophilic pneumonia included fever and dyspnea often requiring either oxygen supplementation or mechanical ventilation. Other clinical findings included malaise, elevated ESR (4/35 cases), or elevated C-reactive protein (11/35 cases). Peripheral eosinophilia was also present in approximately 77% (27/35 cases) of patients. Many cases also had computed tomography scans or chest x-rays which revealed opacities (12/35 cases) and bilateral infiltrates (13/35 cases). Symptom improvement was seen within 24 h through one week after daptomycin discontinuation. The majority of patients were also prescribed treatment with corticosteroids (23/35 cases); however, all patients were reported to recover (See Table 3). Discussion While the criteria developed by Solomon and Schwartz differ from the FDA guidance, they are largely similar in that an offending agent (here, daptomycin) must be present, >25% eosinophils are present, and that clinical improvement is seen after discontinuation of the drug. The FDA guidance also includes some measures of symptomatology such as fever and dyspnea [2, 4]. Overall, dyspnea was the most common documented symptom associated with eosinophilic pneumonia followed by the presence of either pulmonary infiltrates or opacities on chest x-ray or CT. A total of 10 cases specifically mentioned the characteristic finding of ground glass opacities on CT. A potential limitation of this review is that some of the daptomycin-induced eosinophilic pneumonia used lung biopsy in place of BAL as part of the diagnostic criteria which is not part of the FDA guidance, but is included in the Solomon and Schwartz criteria. In addition, since some patients had BAL < 25% eosinophils but lung biopsy revealed eosinophilia [1, 13], a 25% cut off may be too strict in certain situations. Corticosteroids are believed to be beneficial at halting clinical manifestations of daptomycin-induced eosinophilic pneumonia and were used in the majority of reported cases. Steroids exert action through eosinophilic apoptosis and through accelerating intracellular signaling involved in eosinophil death [45]. No dose or length of Requiring oxygen Requiring mechanical ventilation Infiltrates/opacities of CT/CXR, n (%) BAL eosinophils %, mean ± SD Peripheral eosinophilia, n (%) Lung biopsy consistent with AEP, n (%) Treatment, n (%) Daptomycin discontinued only Daptomycin discontinued plus corticosteroid AEP acute eosinophilic pneumonia, BAL bronchoalveolar lavage, CT computed tomography, CXR chest x-ray, SD standard deviation corticosteroid treatment is established in guidelines for eosinophilic pneumonia; however, a commonly employed regimen is intravenous methylprednisolone 60–125 mg every 6 h, with conversion to prednisone 40–60 mg oral daily and taper over 2–6 weeks. Use of a 2- or 4-week course appears to have similar time to resolution of clinical symptoms and radiological abnormalities [46]. Conclusion As use of daptomycin continues to increase, it is important for clinicians to recognize and appropriately manage daptomycin-induced eosinophilic pneumonia. Although symptoms may resolve upon discontinuation of daptomycin, use of corticosteroid may be beneficial for recovery. Further research is needed to determine the exact mechanism of daptomycin-induced eosinophilic pneumonia and identify the optimal treatment course. 65.4 ± 15 32 ± 22.4 Abbreviations AERS: Aderverse Event Reporting System; BAL: Bronchoalveolar lavage; CT: Computed tomography; CXR: Chest x-ray; EP: Eosinophilic pneumonia; ESR: Erythrocyte sedimentation rate; FDA: Food and Drug Administration; MRSA: Methicillin resistant Staphylococcus aureus; VRE: Vancomycin resistant enterococcus Acknowledgements Not applicable. Funding The views expressed are those of the authors and do not necessarily reflect the position or policy of the United States Department of Veterans Affairs. This material is based upon work supported, in part, by the Office of Research and Development, Department of Veterans Affairs. Availability of data and materials Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. Authors’ contributions PU initiated the project, participated in review of literature, and was a major contributor in writing of the manuscript. KL provided analysis of intellectual content, writing of the manuscript, and critical revision. MG and MJ provided analysis of intellectual content and writing the manuscript. KW participated in review of literature, writing of the manuscript, and critical revision. All authors read and approved the final manuscript. Competing interests The views expressed are those of the authors and do not necessarily reflect the position or policy of the United States Department of Veterans Affairs. Kerry L. LaPlante has received research funding or acted as an advisor, or consultant for Cubist, Davol, Forest, and Pfizer Inc. Kristina Ward has received research funding from Pfizer Inc. 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Priyasha Uppal, Kerry LaPlante, Melissa Gaitanis, Matthew Jankowich, Kristina Ward. Daptomycin-induced eosinophilic pneumonia - a systematic review, Antimicrobial Resistance and Infection Control, 2016, 55, DOI: 10.1186/s13756-016-0158-8