Achromobacter xylosoxidans endocarditis and septic arthritis in an infant affected by generalized arterial calcification of infancy

Correspondence Craig S. Levoy cslevoy@gmail.com Department of Family Medicine, Bayfront Health, 700 Sixth Street South, St Petersburg, FL 33701, USA 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 33701, USA Division of Pediatric Infectious Diseases, All Children’s Hospital Johns Hopkins Medicine, 601 Fifth Street South, St Petersburg, FL 33701, USA


Introduction
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 & Ohyama, 1971;Yabuuchi et al., 1998).Infections with the pathogen vary and are traditionally noted in immunocompromised patients.A. xylosoxidans is well-described amongst 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).
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 multidrug-resistant (MDR) Gram-negative bacterial pneumonia (Biswas et al., 2013) MDR Gram-negative bacteria in the paediatric population (Karli et al., 2013).
Our case describes a 6-month-old Hispanic male with GACI, found to have MDR A. xylosoxidans endocarditis and septic arthritis/myositis, who was successfully treated with 6 weeks of intravenous colistin, meropenem, and trimethoprim/sulfamethoxazole.

Case report
A 6-month-old Hispanic male with a medical history of GACI presented with fever and a 2-day history of right hip pain with decreased range of motion.Despite central line removal, the patient remained persistently bacteraemic 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|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.
After 3 days of antimicrobial therapy, the patient persisted with fever and bacteraemia.At the recommendation of specialist consultation, piperacillin/tazobactam was discontinued and triple antibiotic therapy was instituted with intravenous meropenem (60 mg kg 21 day 21 ), levofloxacin (20 mg kg 21 day 21 ) and trimethoprim/sulfamethoxazole (18 mg kg 21 day 21 ).Following 14 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 disc diffusion method for colistin susceptibility, the disc 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 21 day 21 ).Repeat susceptibility testing obtained 1 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 3 days after the initiation of colistin demonstrated no bacterial growth.
Repeat transthoracic echocardiogram, however, demonstrated progression of the hyperechoic lesion on the anterior mitral valve leaflet with a hypermobile vegetation measuring 7 mm|8 mm prolapsing into the left atrium during ventricular systole.Surgical intervention was considered.Specialist consultation and paediatric team meetings, however, determined that cardiothoracic surgery posed too high of a risk of mortality given the patient's underlying GACI.
The patient was therefore continued on intravenous meropenem, trimethoprim/sulfamethoxazole and colistin for a total of 6 weeks after the first set of negative blood cultures were obtained.Subsequent blood cultures over the 6 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 21 day 21 ), with repeat peripheral blood cultures demonstrating no growth.
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.

Discussion
To the best of our knowledge, this is the only paediatric 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.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 21 ) 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 w38 uC) (Li et al., 2000).
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).
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.
Little is known about optimal antibiotic therapy for A. xylosoxidans infections.Neither the Clinical and Laboratory Standards Institute nor the European Committee on Antimicrobial Susceptibility Testing provide specific guidance beyond non-species-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 trimethoprim/sulfamethoxazole, with tetracyclines having variable activity (Abbott & Peleg, 2015).In the cystic fibrosis patient population, the use of concurrent inhaled colistin has been reported as effective (Abbott & Peleg, 2015;Jacquier et al., 2012;Biswas et al., 2013;Karli et al., 2013).The use of intravenous colistin, in conjunction with meropenem and trimethoprim/ sulfamethoxazole, led to resolution of bacteraemia in our patient.
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 short-term intravenous bisphosphonate therapy followed by transition to oral bisphosphonate therapy when compared with 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 3 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.In cases of non-operable MDR A. xylosoxidans endocarditis, we propose the consideration of colistin as part of an extended intravenous antibiotic regimen.
. A recent study demonstrated that intravenous colistin was safe and effective in the treatmexnt of severe nosocomial infections caused by 2015 The Authors.Published by Microbiology Society This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/). G 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 tempera- ture of 38.6 uC 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 A. xylosoxidans.Identification of the organism was accomplished using a MicroScan Walk-Away combo identification and MIC panel (Beckman).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 (bioMe ´rieux) with 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 21 day 21 ).