Running out of options: Extensively drug-resistant urinary tract infection in an infant

A 1-month-old term male infant was recently evaluated at our centre for bladder exstrophy repair. He spent the first month of life in a neonatal intensive care unit in India where he was in a shared room and received 1 week of intravenous (IV) antibiotics for presumed sepsis according to parents. Microbiological investigations and specific antibiotics used abroad were not available. Swabs for antibiotic-resistant organisms (AROs) were completed as per our institution’s risk-based screening policy, and he was found to be colonized with multidrug resistant strains of Escherichia coli and Klebsiella pneumoniae carrying the New Delhi metallo-β-lactamase (NDM) gene (Figure 1). Antibiotic-resistant organisms (ARO) rectal swab screen results. Confirmatory polymerase chain reaction (PCR) testing done at BC Centre for Disease Control (BCCDC) Public Health Laboratory. Amp C Chromosomal bla (AmpC) β lactamase; ESBL Extended-spectrum β lactamase; NDM New Delhi metallo-β-lactamase. Antibiotic-resistant organisms (ARO) rectal swab screen results. Confirmatory polymerase chain reaction (PCR) testing done at BC Centre for Disease Control (BCCDC) Public Health Laboratory. Amp C Chromosomal bla (AmpC) β lactamase; ESBL Extended-spectrum β lactamase; NDM New Delhi metallo-β-lactamase. He was readmitted at 4 months for delayed bladder and abdominal wall closure. Bilateral ureteral stents were placed. Suprapubic catheter and urethral catheter were sutured in place to prevent bladder distension and reflux during the healing process. Repeat ARO screen showed persistent colonization with NDM-positive E coli and newly found NDM-positive Citrobacter freundii (Figure 1). He remained in a single room on contact precautions. In addition to nitrofurantoin, he received routine preoperative prophylactic cefazolin that was stopped 48 hours after the procedure. Five days after surgery he developed fever and tachycardia and received empiric IV meropenem, ciprofloxacin and vancomycin. Fever and tachycardia resolved and urine sterilized within 24 hours. Blood cultures were negative. Urine cultures from both catheters grew > 100 × 106 colony-forming units/liter of Pseudomonas aeruginosa. Susceptibility testing demonstrated extensive drug resistance including resistance to carbapenems. Further molecular testing at the reference laboratory confirmed presence of imipenemase metallo-β-lactamase (IMP) gene (Figure 2). Once susceptibilities were known, his treatment was changed to IV ciprofloxacin and colistin for a total of 7 days. Ongoing treatment with these two agents was chosen due to the risk of developing resistance to colistin and in-vivo response to ciprofloxacin. Stents were removed. Catheters could not be immediately replaced or removed as this would compromise postoperative healing. One week after completing treatment he had a second febrile catheter-associated urinary tract infection (CA-UTI), with urine cultures positive for the same organism as previous UTI (Figure 2). He was treated empirically with meropenem and ciprofloxacin. Both catheters were removed and once susceptibilities were available he completed 10 days of IV ciprofloxacin (10 mg/kg/dose every 8 hours) and colistin (1 mg/kg/dose colistimethate every 8 hours). No nephrotoxicity, neurotoxicity, or other side effects were observed. He was discharged without further complications. Urine culture isolate antibiotic sensitivity profile. Amp C Chromosomal bla (AmpC) β lactamase gene; ESBL Extended-spectrum β lactamase; IMP Imipenemase metallo-β-lactamase; MCR Mobile colistin resistance; PCR Polymerase chain reaction; I Intermediate; R Resistant; S Susceptible. Susceptibility testing performed by BD Phoenix automated identification. Ceftazidime, ciprofloxacin, piperacillin, and carbapenems results confirmed by ETEST bioMérieux strips. Colistin confirmed by broth microdilution performed at the Microbiology, Health Sciences Center, courtesy Dr. George Zhanel. Minimum inhibitory concentration breakpoints as per the Clinical & Laboratory Standards Institute (CLSI) guidelines, except for ciprofloxacin and piperacillin-tazobactam which were interpreted by European Committee on Antimicrobial Susceptibility Testing (UCAST) guidelines. Urine culture isolate antibiotic sensitivity profile. Amp C Chromosomal bla (AmpC) β lactamase gene; ESBL Extended-spectrum β lactamase; IMP Imipenemase metallo-β-lactamase; MCR Mobile colistin resistance; PCR Polymerase chain reaction; I Intermediate; R Resistant; S Susceptible. Susceptibility testing performed by BD Phoenix automated identification. Ceftazidime, ciprofloxacin, piperacillin, and carbapenems results confirmed by ETEST bioMérieux strips. Colistin confirmed by broth microdilution performed at the Microbiology, Health Sciences Center, courtesy Dr. George Zhanel. Minimum inhibitory concentration breakpoints as per the Clinical & Laboratory Standards Institute (CLSI) guidelines, except for ciprofloxacin and piperacillin-tazobactam which were interpreted by European Committee on Antimicrobial Susceptibility Testing (UCAST) guidelines. This patient had an extensively drug-resistant infection with a carbapenemase producing organism (CPO). To our knowledge, this is the first case reported in Canada of a paediatric patient infected with a CPO only susceptible to one antibiotic. In addition, he was colonized with three other CPOs. Carbapenemases are beta-lactamase enzymes capable of breaking down carbapenem antibiotics such as meropenem and imipenem. Carbapenemases are often encoded on mobile genetic elements, facilitating horizontal spread of resistance among many Gram-negative bacteria (GNB) (1). Carbapenemase-mediated resistance is usually accompanied by resistance genes for multiple other antibiotics (2). Similar to adults, the risks for CPO infection in children include prolonged or frequent hospitalizations, use of invasive medical devices, and exposure to antibiotics (2–5). Suboptimal infection control facilitates transmission of CPOs among hospitalized patients. While not all CPO infections are foreign-acquired, they are frequently associated with travel and hospitalization in endemic regions (1,5,6). We hypothesized that our patient became colonized with CPOs during prolonged neonatal intensive care unit stay in India where NDM and IMP carbapenemases are endemic. IMP colonization was likely present from the outset but went undetected on the ARO screens. Prolonged postoperative catheterization at our centre led to a CA-UTI with P aeruginosa that probably acquired its carbapenemase resistance via horizontal transfer from other colonizing bacteria. Unfortunately, source control was not immediately achieved as indwelling catheters could not be safely removed or replaced during the initial CA-UTI episode (7). This likely contributed to the patient’s second CA-UTI. Prescribing and overprescribing of antibiotics in humans and animals has led to selective pressure and emergence of multidrug resistant organisms (8,9). Rampant use of third-generation cephalosporins lead to the emergence of extended-spectrum beta-lactamase (ESBL) producing GNB and frequent carbapenem use lead to CPOs to give but a few examples. CPO colonization alone does not require treatment (10). CPO infections are associated with higher morbidity and mortality (1,2). Since carbapenems are often one of the final treatment options for GNB infections, the antibiotic options for CPOs are extremely limited and can be associated with significant side effects. CPO colonization or infection is currently a reportable condition in British Columbia and Alberta (11). The P aeruginosa isolate in our patient was only fully susceptible to colistin. Colistin (polymyxin E) was retired in the 1970s due to reports of high rates of neurotoxicity and nephrotoxicity. Colistin has been reintroduced as an antibiotic of ‘last resort’ against common GNB infections resistant to carbapebems. Resistance to colistin via mobilized colistin resistance (MCR) 1 gene that can be horizontally transferred between various GNB has been recently reported in animal and human isolates, underscoring the need for judicious use (8). Resistance to ciprofloxacin in our patient was likely overcome due to concentration of the drug in the bladder, and resulted in clinical improvement. Ciprofloxacin has been associated with increased risk of arthropathies and other adverse events in children and should be avoided when alternative agents can be safely used (12,13). Infections caused by CPOs in Canada have been increasing in recent years and have been associated with hospital outbreaks in adult and paediatric settings (1,11). Treatment options for CPO infections are limited and associated with significant adverse effects making these infections challenging to manage. CPOs have the capacity to rapidly spread and acquire various resistance mechanisms, underscoring the need for local, national and global antimicrobial resistance surveillance systems, careful antibiotic stewardship and effective infection prevention and control measures. Clinicians should remain judicious with their antimicrobial use in an effort to prevent rampant spread of multidrug resistant organisms already observed in other parts of the world from occurring in Canada. Informed consent: Informed consent was obtained from patient’s parents for this publication. Funding Information: There are no funders to report for this submission. Potential Conflicts of Interest: All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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