Successful Conservative Treatment of Mycotic Pulmonary Artery Aneurysms Caused by MRSA Bacteremia Yoichi Iki, MD,a Atsuko Hata, MD, PhD,a Midori Fukuyama, MD,a Takakazu Yoshioka, MD, PhD,a Ken Watanabe, MD, PhD,a Seishi Asari, PhD,b Daisuke Hata, MD, PhDa

Mycotic pulmonary artery aneurysms (MPAAs) are rare and life-threatening abstract with currently no recommended treatment strategies. In this report, we describe a successfully treated case of ventricular septal defect in an 11- month-old girl who developed bacteremia, infective endocarditis, and MPAA caused by methicillin-resistant Staphylococcus aureus (MRSA). We first started vancomycin, gentamycin, and panipenem-betamipron for infective endocarditis but switched to teicoplanin and arbekacin on day 3 after initiating treatment because bacteremia persisted, and vancomycin minimum inhibitory concentration was relatively high at 2 mg/L. Although we added aDepartment of Pediatrics, Kitano Hospital, Tazuke Kofukai clindamycin on day 5 and fosfomycin on day 7, MRSA bacteremia persisted, Medical Research Institute, Osaka City, Osaka, Japan; and bGraduate School of Medicine, Osaka University, Suita City, and we finally added daptomycin at 10 mg/kg per day on day 8, whereupon Osaka, Japan the bacteremia subsided within a day. Although the bacteremia subsided, the Dr Iki conceptualized the study, collected data, and patient developed septic pulmonary embolisms and septic arthritis on her left drafted the initial manuscript; Dr A. Hata reviewed knee. We continued daptomycin but switched the concomitant drug to and revised the manuscript; Drs Fukuyama, linezolid, trimethoprim-sulfamethoxazole, and rifampicin on day 11. After Yoshioka, Watanabe, Asari, and D. Hata critically reviewed the manuscript; and all authors approved several repeats of puncture and lavage of her knee joint, she became afebrile the final manuscript as submitted and agree to be on day 16. Computed tomography scans taken on day 32 revealed right accountable for all aspects of the work. pulmonary artery MPAAs. She was treated with long-term multidrug therapy, DOI: https://doi.org/10.1542/peds.2019-0672 and MPAAs were absent on subsequent computed tomography scans on day Accepted for publication Aug 2, 2019 184. Multidrug therapy mainly based on daptomycin could be a possible Address correspondence to Atsuko Hata, Department salvage therapy for refractory MRSA bacteremia with high vancomycin of Infectious Diseases and Department of Pediatrics, minimum inhibitory concentration. Conservative treatment should be Division of Infectious Diseases, Kitano Hospital, Tazuke Kofukai Medical Research Institute, 2-4-20 selectively considered as a treatment option for clinically stable MPAA instead Ohgimachi, Kita-ku, Osaka 530-8480, Japan. E-mail: of surgical and endovascular treatment. [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). CASE REPORT Copyright © 2019 by the American Academy of We encountered a case Pediatrics of ventricular septal defect An 11-month-old girl FINANCIAL DISCLOSURE: The authors have indicated (VSD) in an 11-month-old girl presented with a 6-day history they have no financial relationships relevant to this who developed bacteremia, of fever, vomiting, and diarrhea. article to disclose. infective endocarditis (IE), and Her medical history revealed VSD, FUNDING: No external funding. mycotic pulmonary atopic dermatitis, and staphylococcal POTENTIAL CONFLICT OF INTEREST: The authors have artery aneurysm (MPAA) caused scalded skin syndrome caused indicated they have no potential conflicts of interest by methicillin-resistant Staphylococcus by MRSA for which she had to disclose. aureus (MRSA). The reported received vancomycin treatment mortality rate of MPAA is .50% 10 months before. The sensitivity To cite: Iki Y, Hata A, Fukuyama M, et al. and 100% if ruptured. Her MPAAs of MRSA to antibiotics was similar, Successful Conservative Treatment of Mycotic were resolved completely by but the susceptibility to arbekacin Pulmonary Artery Aneurysms Caused by MRSA Bacteremia. Pediatrics. 2019;144(5):e20190672 using conservative therapy. and vancomycin was previously higher

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 144, number 5, November 2019:e20190672 CASE REPORT when she had staphylococcal scalded cultures grew Gram-positive cocci in both days 5 and 9, the results of her skin syndrome (minimum inhibitory several hours. Consequently, IE was blood cultures were positive every concentration [MIC] of arbekacin: confirmed by evidence of active day. Ventilation settings were ,16; MIC of vancomycin: ,2). valvulitis and bacteremia. increased to maximum because of her worsening oxygen saturation. We She developed breathing difficulty on At admission, she was mentally alert administered clindamycin at a dosage day 3. Chest radiography revealed but irritable, with a body temperature of 30 mg/kg per day on day 5, diffuse infiltration in bilateral lung of 40.0°C, blood pressure of 105/57 fosfomycin at a dosage of 150 mg/kg fields. She met the diagnostic criteria mm Hg, pulse rate of 200 beats per per day on day 7, and daptomycin at of acute respiratory difficulty minute, respiratory rate of 50 breaths a dosage of 10 mg/kg per day on syndrome and was administered per minute, and peripheral oxygen day 8. saturation of 98% in room air. intubation and mechanical ventilator Physical examination revealed support. On the same day, her blood The results of cultures of blood taken a grade 2/6 systolic murmur on the cultures grew MRSA. Sensitivities to on day 9 were negative, but she had left sternal border and petechiae of several antibiotics became apparent a persistent fever. A computed skin. She had no right heart failure (Table 1) on the basis of MIC. The tomography (CT) scan taken on day symptoms such as hepatomegaly or MRSA isolates were not susceptible to 11 revealed multiple septic splenomegaly. gentamicin but were susceptible to pulmonary embolisms and septic vancomycin. However, her serum arthritis on her left knee, but MPAAs A hematologic study revealed a white trough concentration of vancomycin were absent then. The combination blood cell count of 6800 cells per was 5.9 µg/mL (target 15–20 mg/L). drugs with daptomycin were 3 mm with 62% neutrophils, Furthermore, peripheral blood switched to intravenous linezolid at hemoglobin concentration of 10.3 g/ cultures from day 2 and 3 grew a dosage of 30 mg/kg per day, oral dL, platelet count of 22 000 platelets MRSA. Although vancomycin serum trimethoprim-sulfamethoxazole at 3 per mm , and C-reactive protein level concentration could have been a dosage of 8 mg/kg per day of 11.5 mg/dL. Transthoracic adjusted to the serum trough of 15 to (trimethoprim component), and oral echocardiography revealed normal 20 mg/L, we changed antibiotics on rifampicin at a dosage of 10 mg/kg left ventricular function and 7.0 mm the basis of susceptibility test results per day. Additionally, we performed vegetation on the tricuspid valve, that revealed vancomycin MIC was repeated puncture and lavage of her with slight tricuspid regurgitation high in the susceptible range and in knee joint. Thereafter, her fever (Fig 1). consideration of her clinical course subsided gradually, and her deterioration. We started arbekacin at respiratory condition improved. On Treatment was started with a dosage of 6 mg/kg per day targeting day 15, she was extubated, and on intravenous vancomycin at 60 mg/kg a serum peak of 15 to 20 mg/L and day 16, she became afebrile. On day per day, panipenem-betamipron at teicoplanin targeting a serum trough 22, we changed linezolid to 160 mg/kg per day, gentamicin at of 15 to 20 mg/L at a dosage of intravenous clindamycin to prevent 7 mg/kg per day (Fig 2), and 10 mg/kg every 12 hours for 2 doses bone marrow suppression including immunoglobulin. Three sets of blood and subsequently at 10 mg/kg every neutropenia and thrombocytopenia. 24 hours. During the course of antibiotic Although her serum trough therapy, the vegetation regressed, but concentrations of teicoplanin were a chest radiograph revealed a nodular 31.6 and 15.9 µg/mL, respectively, on shadow (Fig 3). A contrasted CT

FIGURE 1 Transthoracic echocardiography on adminis- tration. LV, left ventricle; RA, right atrium; RV, FIGURE 2 right ventricle; TV, tricuspid valve. Use of antibiotics in acute phase and blood culture results.

Downloaded from www.aappublications.org/news by guest on September 28, 2021 2 YOICHI et al TABLE 1 Susceptibility of MRSA in This Patient to Antibiotics and MIC Breakpoints for MRSA knowledge, this is the only reported Antibiotics MIC of MRSA in This MIC Breakpoint, mg/L case of a child with MPAA caused by Patient, mg/L (Sensitive) MRSA that was cured solely by 4–8 Vancomycin =2 #2 conservative treatment. Gentamicin .8 #4 Panipenem-betamipron No data No data The major causes of pulmonary Teicoplanin ,2 #8 artery aneurysm are infections (eg, Arbekacin ,1 #16 IE, pneumonia, lung abscess).1 Here, Clindamycin ,0.5 #0.5 MPAA appeared after IE, together , # Fosfomycin 1 4 with septic pulmonary embolisms. Daptomycin No data #1 Trimethoprim-sulfamethoxazole ,1 #2 Common causative organisms for IE Rifampicin ,1 #1 in children are Staphylococcus Linezolid =2 #4 species, mainly S aureus,9 with half of Erythromycin ,0.5 #0.5 Staphylococci resistant to We used the MIC interpretive standard of the Clinical and Laboratory Standards Institute for all except fosfomycin. methicillin.10 Because the Clinical and Laboratory Standards Institute does not have an MIC interpretive standard for fosfomycin, we used the standard of Beckman Coulter, Inc, instead. Recent guidelines for MRSA treatment recommend vancomycin revealed MPAAs of the right intraoperatively. No abnormal for IE.11,12 However, authors of some pulmonary artery on day 32 (Fig 4). findings were obtained from head studies suggest that even if the CT findings revealed further MRI conducted at discharge. She had vancomycin MIC is considered regressed MPAAs on day 40 and day no disease recurrence and has susceptible by current standards, 47. We chose conservative therapy developed normally without sequelae a high probability of treatment failure instead of either surgical or in the succeeding 5 years. We are still exists if it is high in the susceptible endovascular therapy. After managing her. range (MIC of $1.5 mg/L by Etest or confirming the aneurysm regression, $1 mg/L by broth microdilution), as we carefully withdrew antibiotics. We in our case.13,14 In our case, it was DISCUSSION stopped clindamycin on day 54 and difficult to decide when to change the rifampicin on day 84. On day 184, MPAA is rare and life-threatening,1,2 treatment. The American guideline contrasted CT revealed that the especially in children.3,4 To our states that the threshold to change MPAAs had disappeared completely. Finally, trimethoprim- sulfamethoxazole was stopped on day 220. Subsequently, her condition stabilized without relapse. She underwent surgical VSD closure on day 341. At the time of VSD surgical repair, the pulmonary artery was normal in appearance

FIGURE 3 FIGURE 4 Chest radiograph taken on day 31. A nodular CT-scan performed on day 32 (A), day 65 (B), day 95 (C), and day 184 (D). MPAAs (white arrow), shadow (white arrow) was visible in the right measuring 15 3 20 mm and 10 3 10 mm, gradually reduced and disappeared. LA, left atrium; LV, left lung field. ventricle; RA, right atrium; RV, right ventricle.

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 144, number 5, November 2019 3 from vancomycin may be earlier if the patient’s clinical condition is worsening despite adequate debridement and removal of infection Course of Treatment right-sided aneurysms aneurysms were stable both aneurysms foci or if the vancomycin MIC is Regression of the Not described Regression of the 2 mg/L, particularly in critically ill patients.11 For successful treatment with vancomycin, a serum trough of 15 to 20 mg/L or a 24-hour area Therapy right-sided aneurysm detail gentamycin under the concentration-time curve Vancomycin for Antibiotics Both-sided Not described in Penicillin G and and/or MIC .400 is recommended

ow on the basis of pharmacokinetics and fl pharmacodynamics.15 However, some studies have revealed similar treatment failure rates between aneurysms the conduit vegetation in right ventricular out of the patent ductus arteriosus vancomycin treatments with troughs Surgical revision of Surgical removal of .15 mg/dL and those ,15 mg/dL.15,16 We therefore opted to administer other antibiotics instead on the basis of susceptibility test results and in consideration of her clinical course deterioration and poor vancomycin susceptibility. After we added daptomycin, her bacteremia subsided over the next day. Although with right ventricle to pulmonary artery conduit), IE, septic pulmonary embolisms central venous catheter, IE recent European guidelines state that VSD, IE Left upper lobectomy, VSD (postrepair) Not described Cephalosporin Failure Tetralogy of Fallot (postrepaired Esophageal atresia, long-term Patent ductus arteriosus, IE Division and suture daptomycin is superior to vancomycin for methicillin-sensitive S sides side sides sides sides Both Both aureus and MRSA bacteremia with vancomycin MIC .1 mg/L,15 we

3 hesitated to use daptomycin because 3.5 of concerns about lung penetrance. 3cm 3 diameter 4cm Maximum 4 Not described Right Not described Both Maximum Not described Both After the bacteremia subsided, she developed arthritis, and we were concerned about bacteremia relapse. The combination drugs were switched from teicoplanin, chills, and tachycardia cough cramps, and poor oral intake hemoptysis dyspnea; hemoptysis Fever, chills, and Fever, leg Fever and Fever and clindamycin, and fosfomycin to linezolid, trimethoprim- sulfamethoxazole, and rifampicin to S make the combination drugs more favorable for tissue transfer. sensitive aureus Streptococcus - a Candida Candida lusitaniae The course of this case was complicated by MPAA. For patients Female Not detectedFemale Fever, malaise, Female Female Methicillin- Male with rupture symptoms such as hemoptysis, endovascular 6y 9y 7y old old old old old 16 y 2mo embolization or surgical resection might be required2,17 because the 6 reported mortality rate of MPAA is . 2,3

4 5 7 8 50% and 100% if ruptured. Apart from adult pulmonary artery et al, 2002 2016 2017 2003 2014 Summary of Pediatric Patients With MPAA Treated Conservatively aneurysm and MPAA, in general, pulmonary artery aneurysm dilation 3 Lertsapcharoen 5 Walasangikar et al, 1 Knowles et al, Case Reference Age Sex Pathogen Symptoms Size Location Underlying Condition Invasive Therapy Conservative 2 Bozkurt et al, 4 Toganel et al,

TABLE 2 (absolute diameter $5.5 cm),

Downloaded from www.aappublications.org/news by guest on September 28, 2021 4 YOICHI et al aneurysm diameter increase, CONCLUSIONS 7. Toganel R, Benedek T, Benedek I. Giant mycotic pulmonary artery aneurysms adjunct structure compression, MPAA due to MRSA with high thrombus formation in the in a newborn. Eur Heart J Cardiovasc vancomycin MIC is rare and life- Imaging. 2014;15(8):885 aneurysm sack, valvular pathologies threatening. Multidrug therapy fl or shunt ow, and pulmonary mainly based on daptomycin could be 8. Walasangikar V, Dey AK, Sharma R, et al. Pulmonary mycotic pseudo- artery hypertension may also a possible salvage therapy for require surgery.18 It is difficult to aneurysm with a prior history refractory MRSA bacteremia with of ventricular septal defect. Case determine treatment options high vancomycin MIC. Long-term and because MPAA in children is rare. report with review of literature. multidrug conservative treatment Pneumonol Alergol Pol. 2016;84(3): We continued conservative therapy should be selectively considered as 178–180 because the patient did not have any a treatment option for clinically stable 9. Gupta S, Sakhuja A, McGrath E, Asmar B. symptoms of rupture or imaging and patients with MPAA instead of fi Trends, microbiology, and outcomes echocardiography ndings indicating surgical and endovascular treatment. surgery at the time when the MPAAs of infective endocarditis in children during 2000-2010 in the United were found, and the MPAAs tended to States. Congenit Heart Dis. 2017;12(2): shrink over time. Authors of a recent ABBREVIATIONS 196–201 report described the selection of conservative treatment for patients in CT: computed tomography 10. Bor DH, Woolhandler S, Nardin R, Brusch J, Himmelstein DU. 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Downloaded from www.aappublications.org/news by guest on September 28, 2021 Successful Conservative Treatment of Mycotic Pulmonary Artery Aneurysms Caused by MRSA Bacteremia Yoichi Iki, Atsuko Hata, Midori Fukuyama, Takakazu Yoshioka, Ken Watanabe, Seishi Asari and Daisuke Hata Pediatrics 2019;144; DOI: 10.1542/peds.2019-0672 originally published online October 17, 2019;

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