A Case of New Delhi Metallo-ß-Lactamase-Producing Enterobacter and a Review of Cases in the United States From January 2009 to September 2022

Antimicrobial resistance is a growing problem. Novel resistance mechanisms continue to emerge, and the pipeline of antimicrobial development struggles to keep up. Antimicrobial stewardship and proper infection control are key in preventing the spread of these infections. A case of a carbapenem-resistant Enterobacter cloacae complex urinary isolate was identified in an 81-year-old male patient at the San Antonio Veterans Affairs hospital, Texas, USA. The patient was placed on isolation, and further testing of the isolate to other antibiotics requested. The purpose of this study is to analyze the details of reports of such cases and to review at-risk populations and appropriate treatment for resistant organisms.


Introduction
New Delhi Metallo-ß-lactamase (NDM) producers are known to be resistant to multiple antimicrobial drug classes, thus making treatment difficult [1].Infection control measures and antimicrobial stewardship (ASP) interventions have important roles to prevent spread in NDM [1].Detection of these organisms initially occurred in individuals with travel to endemic locations where carbapenemases with the blaNDM gene were prevalent [2].Plasmid-mediated transfer of these genes eventually resulted in spread across Enterobacterales, and the returning traveler is known to carry these isolates, resulting in imported infections in various parts of the world [2].We report a case of the NDM isolate in an individual with no prior travel outside of San Antonio, Texas, USA, without any identifiable risk factors.We also perform a review of all cases reported in the USA from January 2009 to September 2022 to determine baseline characteristics, risks, and treatment.

Case Presentation
A 81-year-old male, with no relevant travel history, not of Southeast Asian origin, and with multiple comorbidities, including coronary artery disease, pulmonary fibrosis, prior stroke, obstructive sleep apnea, type 2 diabetes, and dyslipidemia, was hospitalized at the Veterans Affairs at San Antonio, Texas, USA, in 2021.Prior to this hospitalization, he was not on any antibiotics in the past year, nor did he have a history of multi-drug resistant organisms.He had a 5 mm left distal ureteral calculus and was not a candidate for general anesthesia given his cardiac risk.Therefore, he previously had a percutaneous nephrostomy tube placed two months prior to admission.After cardiac clearance for surgery, he had a pre-operative urine culture performed prior to planned cystoscopy, ureteroscopy, laser lithotripsy, and ureteral stent placement.The urine culture grew carbapenem-resistant Enterobacter cloacae complex and Enterococcus faecalis.The E. cloacae complex was a carbapenemase producer, detected by the Cepheid Carba-R, carbapenem resistance molecular test, and the antibiogram indicated resistance to all beta-lactams and carbapenems, sensitivity to tigecycline, and intermediate sensitivity to tobramycin.Cefiderocol susceptibilities were requested thereafter, and the isolate noted to be susceptible.Of the genotypes tested, blaNDM was detected.blaIMP, blaVIM, blaOXA-48, and blaKPC were not detected in this isolate.The patient was admitted five days later for the urologic procedure and was not initially placed on contact precautions.Contact precautions were initiated within 24 hours of his admission.The in-patient unit and the operating room (OR) staff were notified, and the case reported to Texas Department of State Health Services.The OR was terminally cleaned, and the patient was educated on precautions by the Infection Prevention and Control team.There were no secondary cases infected from this patient.In terms of treatment, the patient was empirically treated for his urine cultures prior to susceptibilities, with levofloxacin.Since the urologic procedure had already been performed when susceptibilities (Table 1) were reviewed, and this case was asymptomatic bacteriuria rather than a symptomatic urinary tract infection, treatment with other broader antibiotics was not pursued.He returned to urology follow-up a month later with no complaints.We conducted a review of NDM cases in the literature from January 2009 to September 2022, and we have summarized individual characteristics of cases identified in the United States.Google Scholar and PubMed were search engines used to search for articles, and the keywords, "New-Delhi Metallo-ß-Lactamase", "NDM", "United States", "USA", "carbapenem resistant", "multi-drug resistant", and "CRE" were used to locate articles pertaining to this review.Duplicates of cases summarized in other articles as part of another author's literature review process were encountered.These were carefully identified and eliminated.To our knowledge, this is a complete review of all cases reported in the United States within this timeframe.

Discussion
The study of carbapenemase-producing strains and knowledge of their epidemiological distribution has tremendous clinical significance.As we combat various bacterial strains with antibiotics, there is a slow growth in innumerous resistance mechanisms that bacteria exhibit to circumvent the deleterious effects of antibiotics [1].Identification of these resistant isolates early is crucial to institute contact precautions and prevent further spread [2].We present one of the few cases of NDM in E. cloacae complex.
A review of NDM cases in the literature from January 2009 to September 2022 showed that exposure risks included travel to endemic places, as well as acquisition through inadequately sterilized equipments.Individuals with prior travel to these countries, should prompt early consideration of NDM presence, in the setting of clinical non-improvement while on standard broad-spectrum therapy.As of January 2013, the Center for Disease Control and Prevention (CDC) reported 69 patients in the United States with NDM strains, out of which 44 were from Northeastern Illinois.Twenty-three of these cases were noted to be acquired through an exposure involving culture-positive endoscope during endoscopic retrograde cholangiopancreatography (ERCP).Subsequent to this outbreak, successful gas sterilization with ethylene oxide was achieved [3].A retrospective cohort details a total of eight patients identified on review of cases from January 2012 to October 2012 in Colorado [4].Following these CDC reports, there have been additional cases, with one such report arising from University of Texas MD Anderson Cancer Center at Houston in 2015.
All the Enterobacterales isolates that were resistant to meropenem in this hospital were tested for susceptibility to CAZ-AVI via the E test technique, or disk diffusion, confirmed by the broth microdilution method.PCR testing of various genetic sequences expressed in CREs was undertaken.Surprisingly high rates of six out of the 11 isolates with CREs were identified as NDM, out of which four had a history of foreign travel within the previous year [5].
Of the 85 patients reviewed in Tables 2-3, E. coli predominated as the cause, with 53 cases, or 62.4% of total infections due to this organism.With the available data, it can be ascertained that upwards of 14 cases (16.5%) were secondary to Klebsiella, and nine cases (10.6%) secondary to blaNDM-1 carrying Enterobacter.Enterobacter spp., as is seen in our patient, is rarely seen as a causative organism, of which E. cloacae complex was implicated in eight total infections in the Unites States, nine including our case patient.Infections have occurred in all (reported) age groups, varying from 13 months to 81 years, with 14 out of 23 (60.8%) cases known to occur in older individuals over 50 years of age, likely since there is a correlation between long exposure to antibiotics, resulting in increasing resistant mutations.Our patient who carried an autochthonous isolate is stipulated to have developed genetic mutations, resulting in NDM resistance due to prior exposure, since he did not have any prior travel history.Cluster of cases are known to occur with secondary infection from an index case, the largest of which is the Illinois outbreak with infection from duodenoscopes [3].Of the dozen cases that reported all resistant genes identified, six of the isolates possessed blaCTX-M and blaTEM-1; five isolates possessed blaOXA [5][6][7][8][9][10].Infections are identified in the USA starting from January 2011 [11].Of the E. coli isolates with reported sensitivities, six out of seven (85.7%) was sensitive to tigecycline, followed by three out of seven (42.9%) sensitive to colisin, one each sensitive to trimethoprimsulfamethoxazole (TMP-SMX), tetracyclines, polymyxin B, and fosfomycin.Of the K. pneumoniae isolates with reported sensitivities, five out of 10 (50%) showed sensitivity each to tigecycline and colistin; two isolates (20%) showed sensitivity to fosfomycin, minocycline, and polymyxin B; and one isolate was sensitive to tetracycline.Of the E. cloacae complex reported, all isolates, including our patient, were sensitive to tigecycline; five out of eight isolates (62.5%) were sensitive to gentamicin; four isolates (50%) to colistin; and one isolate to tetracycline and tobramycin.Our case patient had a sensitive isolate to cefiderocol, although it is uncertain whether the other reported isolates were tested to this antibiotic.This highlights empiric use of tigecycline, colistin, and gentamicin for blaNDM carrying isolates, with additional sensitivities to be requested to cefiderocol.With higher minimum inhibitory concentration (MIC) to CAZ-AVI seen in isolates, and clinical decline in several cases, the fractional inhibitory concentration (FIC) index becomes necessary.Out of the cases reviewed, only three noted synergy by this testing method.Plasmid-transfer of the NDM gene from other Enterobacterales likely resulted in Enterobacter spp.acquiring this resistance pattern.The first ever case of Enterobacter with blaNDM was seen in 2015 [14].In our case, there was no secondary infection in the seven month follow-up period after terminal disinfection.CAZ-AVI and aztreonam, tigecycline, and gentamicin have been used successfully to eradicate the infection [8,12,17].More studies are required to assess difference in clinical outcome, eradication of the isolate via infection control practices, and different susceptibilities to antimicrobials in Enterobacter spp.compared to other Enterobacterales.Caution should be undertaken when reviewing clinical data from individuals with history of extensive antibiotic exposure, as well as resistance prevalent countries, with low threshold in suspecting NDM infections.To accurately identify every single case, it is also prudent for Infection control in a hospital to perform routine checks on all patients, as individuals like our patient could rarely present with no risk factors.System errors that occurred in our case can be curbed with alerts indicating buzzwords such as "highly resistant", "isolation mandated immediately", and "New-Delhi metallo-b-lactamase", with explanation requested in case the provider defers isolation.
In our review, we identified that K. pneumoniae and E. coli were predominantly implicated in carrying the NDM gene in the United States.Exposure risks to acquiring an NDM isolate are travel to endemic places and the use of inadequately sterilized equipments.Cluster of cases have been reported with secondary infection from an index case.Of the 85 patients we reviewed carrying an NDM isolate in the United States, E. coli predominated as the cause, with 53 cases, or 62.4% of total infections due to this organism.Meanwhile, 14 cases (16.5%) were secondary to Klebsiella, and nine cases (10.6%) secondary to blaNDM-1 carrying Enterobacter.Our case patient is the only individual case reported in the prior year in the Unites States with no relevant travel history and no immediately prior antibiotic exposure who was identified to carry a resistant isolate.Of the E. cloacae complex reported, all isolates, including our patient were sensitive to tigecycline; five out of eight isolates (62.5%) were sensitive to gentamicin; four isolates (50%) to colistin; and one isolate to tetracycline and tobramycin.Susceptibility testing in our case patient indicated sensitivity to cefiderocol, although this antibiotic was not tested against most of the isolates captured in this review.This highlights empiric use of tigecycline, colistin, and gentamicin for blaNDM carrying isolates, with additional sensitivities to be requested to cefiderocol.

Conclusions
NDM-producing Enterobacterales are a growing concern with pan-resistance being reported in the past and concerns of loss of synergy to CAZ-AVI and aztreonam in the future.Worldwide spread is known to occur with multiple areas of the United States affected to date as a result of travel from a prevalent location.The plasmid-mediated transfer results in fast transmission of resistance among Enterobacterales.NDMproducing strains are being isolated in individuals with no travel history as well, given community acquisition of resistance in the recent past.This requires increased awareness for adherence to applied infection prevention practices.Overall, the importance of appropriate contact precautions, hand hygiene, antimicrobial stewardship, and rapid laboratory detection has been crucial in the prevention of highly resistant organism transmission.We must all continue to be vigilant and cautious as these resistant organisms continue to be reported.Special importance to members from prevalent countries can help with early identification, and appropriate Infection control department routine screening is necessary to identify individuals with no risk factors.