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1 JMM CASE REPORTS 2 Case report template 4 Achromobacter Xylosoxidans Endocarditis and Septic Arthritis in an Infant Affected by Generalized Arterial Calcification of Infancy 5 Craig S. Levoy1, MD, David J. Hall2, MD, and David Berman3, DO, MS 3 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Address: 1 Department of Family Medicine, Bayfront Health, 700 Sixth Street South, St. Petersburg, FL, USA, 33701 2 Division of General Pediatrics and Adolescent Medicine, Johns Hopkins University School of Medicine and All Children's Hospital Johns Hopkins Medicine, 601 Fifth Street South, St. Petersburg, FL, USA 33701 3 Division of Pediatric Infectious Diseases, All Children's Hospital Johns Hopkins Medicine, 601 Fifth Street South, St. Petersburg, FL, USA 33701 Corresponding author: Craig S. Levoy, MD Corresponding author email address: [email protected] 21 22 23 In order to assist us in choosing the correct editor to handle your paper, please choose one box in each of the following categories: 24 Field: 25 Subject: X Human ☐Dental ☐Veterinary/Fisheries X Bacteriology ☐Virology ☐ Mycology ☐ Parasitology 26 27 Keywords: Please provide at least one keyword for each of the following categories: 28 Disease/Indication: Achromobacter xylosoxidans, Generalized Arterial Calcification of Infancy 29 Pathology/Symptoms: endocarditis, septic arthritis 30 Treatment: Colistin 31 1 32 ABSTRACT 33 34 35 Introduction: Achromobacter xylosoxidans is a non-fermentative aerobic Gram-negative bacillus, which most frequently causes nosocomial infections. Endocarditis from the pathogen has only rarely been reported, and has a near-fatal outcome without surgical intervention. 36 37 38 39 Case Presentation: We present a case of Achromobacter xylosoxidans endocarditis and septic arthritis in an infant affected by Generalized Arterial Calcification of Infancy (GACI). The patient was successfully treated with six weeks of intravenous colistin, meropenem, and trimethoprimsulfamethoxazole. 40 41 42 Conclusion: This is the first reported case of colistin used to treat A. xylosoxidans endocarditis. We discuss the antibiotic challenges of treating multi-drug resistant (MDR) A. xylosoxidans endocarditis in a patient who is not a surgical candidate. 43 INTRODUCTION 44 45 46 47 48 49 50 51 52 Achromobacter xylosoxidans is a non-fermentative aerobic Gram-negative bacillus, which most frequently causes nosocomial infections. Taxonomy has changed several times since its original description in 1971, including the nomenclature Alcaligenes xylosoxidans, but most recent studies have classified the bacterium as Achromobacter xylosoxidans (Yabuuchi & Oyama, 1971; Yabuuchi et al., 1998). Infections with the pathogen vary and are traditionally noted in immunocompromised patients. A. xylosoxidans is well-described among cystic fibrosis patients, presenting as an opportunistic lung infection that readily acquires drug resistance (Jeukens et al., 2015; Tokuyasu et al., 2012). A. xylosoxidans endocarditis has only rarely been described in the literature, and has a near fatal outcome without surgical intervention (Derber et al., 2011). 53 54 55 56 57 58 59 60 61 62 63 Generalized Arterial Calcification of Infancy (GACI, OMIM 208000) is a rare autosomal recessive disorder, most attributed to mutations of the ENPP1 gene, characterized by calcification of the internal elastic lamina of muscular arteries (Chong & Hutchins, 2008; Edouard et al., 2011; Farquhar et al., 2005; Kalal et al., 2012; Ramjan et al., 2009; Rutsch et al., 2008; Rutsch et al., 2003; Shaireen et al., 2013; van der Sluis et al., 2006). GACI is often fatal within the first 6 months of life, usually secondary to myocardial ischemia resulting in refractory heart failure (Chong & Hutchins, 2008; Rutsch et al., 2008; Rutsch et al., 2003). Recent studies, however, have demonstrated survival of patient’s with GACI beyond the infancy period when treated with bisphosphonate therapy (Edouard et al., 2011; Ramjan et al., 2009; Rutsch et al., 2008; van der Sluis et al., 2006). No formalized treatment plan exists in the literature for patients affected by GACI. Drug choice, dosing, duration, and route remain controversial (Ramjan et al., 2009). 64 65 66 67 68 Colistin, also known as polymyxin E, is an antibiotic that has been used in the Cystic Fibrosis population as a drug of “last resort” for multi-drug resistant (MDR) gram-negative bacterial pneumonia (Biswas et al., 2013). A recent study demonstrated that intravenous colistin was safe and effective in the treatment of severe nosocomial infections caused by MDR gram-negative bacteria in the pediatric population (Karl et al., 2013). 69 70 71 Our case describes a six-month-old Hispanic male with GACI, found to have MDR A. xylosoxidans endocarditis and septic arthritis/myositis, who was successfully treated with six weeks of intravenous colistin, meropenem, and trimethoprim-sulfamethoxazole. 72 73 2 74 CASE REPORT 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 A six-month-old Hispanic male with a medical history of GACI presented with fever and a two-day history of right hip pain with decreased range of motion. The patient was receiving long-term weekly intravenous bisphosphonate therapy via a tunnelled central venous catheter for treatment of his GACI. The patient had a rectal temperature of 38.6° C on presentation. There was no cardiac murmur on the initial physical examination. His right hip was held in a flexed position and he cried with passive hip movement. Magnetic Resonance Imaging of the right hip demonstrated a small right joint effusion with synovial and adjacent muscle enhancement. The patient subsequently underwent incision and drainage of the right hip. Culture of the hip joint aspirate, as well as blood cultures from peripheral and central venous line sites ultimately grew Achromobacter xylosoxidans. Identification of the organism was accomplished using Microscan Walk-Away combo ID and MIC panel (Beckman Coulter, Brea, CA) The initial isolate was susceptible to ceftazidime, levofloxacin, meropenem, piperacillin/tazobactam, imipenem-cilastatin, trimethoprim-sulfamethoxazole, and ticarcillin/clavulanate; intermediate to ceftriaxone; and resistant to amikacin, aztreonam, cefepime, ciprofloxacin, gentamicin, and tobramycin. Antimicrobial susceptibility testing to these antibiotics was performed using both MicroScan Walk-Away and Etest (bioMérieux, Durham, NC) with CLSI (Clinical and Laboratory Standards Institute) interpretation. The patient’s tunnelled central line was removed and he was started on intravenous piperacillin/tazobactam (300 mg kg–1 day–1). 92 93 94 95 96 Despite central line removal, the patient remained persistently bacteremic and ultimately a systolic murmur was auscultated on physical exam. A transthoracic echocardiogram revealed a hyperechoic lesion on the anterior mitral leaflet measuring 5 mm x 6 mm, increased in size from a calcification previously noted as a sequela of the patient’s underlying GACI in the same position several months prior during routine outpatient care. 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 After three days of antimicrobial therapy, the patient persisted with fever and bacteremia. At the recommendation of specialist consultation, piperacillin/tazobactam was discontinued and triple antibiotic therapy was instituted with intravenous meropenem (60 mg kg–1 day–1), levofloxacin (20 mg kg–1 day–1), and trimethoprim-sulfamethoxazole (18 mg kg–1 day–1). Following fourteen days of this antibiotic regimen, daily blood cultures continued to grow A. xylosoxidans. Additional susceptibility testing demonstrated the development of resistance to levofloxacin, identified using the described antimicrobial susceptibility testing. Using the disk-diffusion method for colistin susceptibility, the disk diffusion zone was measured at 11 mm, considered susceptible by most standards (Biswas et al., 2013). Levofloxacin was therefore discontinued and substituted with intravenous colistin (7 mg kg– 1 day–1). Repeat susceptibility testing obtained one day following colistin administration demonstrated resistance to all antibiotics tested (ceftazidime, levofloxacin, meropenem, piperacillin/tazobactam, imipenem-cilastatin, trimethoprim-sulfamethoxazole, ticarcillin/clavulanate, ceftriaxone, amikacin, aztreonam, cefepime, ciprofloxacin, gentamicin, and tobramycin). However, as the patient had been afebrile after starting colistin, the regimen was continued. Blood cultures obtained three days after the initiation of colistin demonstrated no bacterial growth. 112 113 114 115 116 Repeat transthoracic echocardiogram, however, demonstrated progression of the hyperechoic lesion on the anterior mitral valve leaflet with a hypermobile vegetation measuring 7 mm x 8 mm prolapsing into the left atrium during ventricular systole. Surgical intervention was considered. Specialist consultation and pediatric team meetings, however, determined that cardiothoracic surgery posed too high of a risk of mortality given the patient’s underlying GACI. 117 118 119 120 121 122 The patient was therefore continued on intravenous meropenem, trimethoprim-sulfamethoxazole, and colistin for a total of six weeks after the first set of negative blood cultures were obtained. Subsequent blood cultures over the six weeks showed no bacterial growth. Towards the latter part of the hospital course, one blood culture from a peripherally inserted central catheter (PICC) grew Candida parapsilosis. The PICC line was immediately removed and the patient was treated with intravenous fluconazole (12 mg kg–1 day–1), with repeat peripheral blood cultures demonstrating no growth. 3 123 124 125 126 127 To avoid the need for placement of a new central venous line, the patient was transitioned to oral bisphosphonate therapy (risedronate 5 mg once per week) for treatment of his GACI. Six months following hospital discharge, the patient remained afebrile with negative blood cultures. Outpatient follow-up transthoracic echocardiogram showed no significant change. The patient did not develop any neurotoxic or nephrotoxic side effects as a result of colistin therapy. 128 DISCUSSION 129 130 131 132 To our knowledge, this is the only pediatric case report of a patient with GACI diagnosed with leftsided native valve A. xylosoxidans endocarditis and right hip septic arthritis/myositis. This is also the only report of a patient with A. xylosoxidans endocarditis treated, successfully or otherwise, with colistin as part of the antibiotic regimen. 133 134 135 136 137 138 139 140 No formalized therapeutic plan exists in the literature for patients affected by GACI. In our case, the patient presented with a treatment regimen consisting of long-term weekly low-dose (0.1 mg kg–1) intravenous pamidronate. The probable source of infection in our patient was the indwelling tunnelled central venous line. The patient’s pre-existing mitral valve calcification secondary to his underlying GACI likely acted as a nidus for the opportunistic A. xylosoxidans bacterium. Using the Modified Duke criteria for infective endocarditis, the patient met two major (positive blood culture and evidence of endocardial involvement) and two minor criteria (predisposing heart condition and fever >38 C) (Li et al., 2000). 141 142 143 144 145 A MEDLINE search of the English language literature resulted in only two case reports of A. xylosoxidans septic arthritis (San Miguel et al., 1991; Suryavanshi & Lalwani 2015). Broadening the search to include cases of osteomyelitis resulted in a total of seven reported cases (Dubey et al., 1988; Fort et al. 2014; Hoddy & Barton, 1991; Pamuk et al. 2015; Ozer et al., 2012; Stark, 2007; Walsh et al., 1993). 146 147 148 149 150 151 152 153 A MEDLINE search of the English language literature for infective endocarditis secondary to A. xylosoxidans resulted in only fourteen reported cases (Ahn et al., 2004; Davis et al., 1982; Derber et al., 2011; Lofgren et al., 1981; Malek-Marin et al., 2009; Martino et al., 1990; McKinley et al., 1990; Nanuashvili et al., 2007; Olson & Hoeprich, 1982; Rafael et al. 2014; Sasaki et al., 1993; Storey et al., 2010; Tokuyasu et al., 2012; van Hal et al., 2008). A review of those cases demonstrated a greater than fifty-percent mortality rate (Derber et al., 2011; Tokuyasu et al., 2012). Of the surviving patients, only one case series reported survival in a patient who did not undergo surgical intervention (McKinley et al., 1990). 154 155 156 Based on expert medical opinion, our patient was not a surgical candidate. Additionally, resistance to antibiotic therapy developed during treatment. Given the near certain risk of fatality without surgical intervention, we explored additional antibiotic options. 157 158 159 160 161 162 163 164 165 166 Little is known about optimal antibiotic therapy for A. xylosoxidans infections. Neither the CLSI nor the EUCAST (The European Committee on Antimicrobial Susceptibility Testing) provide specific guidance beyond nonspecies-related breakpoints. Intrinsic antibiotic resistance patterns and acquired resistance has been widely reported (Abbott & Peleg 2015). It has been suggested that the most active antibiotic agents against A. xylosoxidans are piperacillin-tazobactam, meropenem, and trimethoprimsulfamethoxazole, with tetracyclines having variable activity (Abbott & Peleg 2015). In the CF patient population, the use of concurrent inhaled colistin has been reported as effective (Abbott & Peleg 2015; Jacquier et al. 2012; Biswas et al. 2013; Karl et al. 2013). The use of intravenous colistin, in conjunction with meropenem and trimethoprim-sulfamethoxazole, led to resolution of bacteremia in our patient. 167 168 169 This case demonstrates two important, but separate, findings: the first specifically for patients affected by GACI, and the second for patients with difficult to clear A. xylosoxidans infections. First, while inherently limited, the current literature on GACI treatment has demonstrated similar efficacy of 4 170 171 172 173 174 175 176 177 178 short-term intravenous bisphosphonate therapy followed by transition to oral bisphosphonate therapy when compared to long-term intravenous bisphosphonate therapy alone (Ramjan et al., 2009). Our case highlights the importance of the former approach over the latter, secondary to the risk of line infection associated with long-term intravenous therapy. Second, this is the first known case report of A. xylosoxidans infective endocarditis treated with intravenous colistin. Clearance of the bacteria was noted within three days of starting colistin therapy. Our case is one of only two known reports of survival in a patient with A. xylosoxidans endocarditis who did not undergo surgical intervention. 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Microbiology and immunology 42, 429-438. 7 299 Figure/Table Captions 300 N/A 301 302 Abbreviations 303 N/A 304 305 Ethical Statement 306 N/A 307 308 Acknowledgements/Declaration of Interest 309 N/A 310 311 Signature: 312 313 314 315 Date: 13 September 2015 8