Introduction
Candida auris (renamed to Candidozyma auris in 2024, however, will be referred to as Candida auris for the purpose of clarity in this paper) Reference Liu, Hu and Zhao1 is an emerging multidrug-resistant (MDR) fungal pathogen that poses a nosocomial threat to immunosuppressed and otherwise susceptible patients and potentially impacts health systems worldwide. Since first reported as a cause of human disease in Japan and South Korea in 2002, Reference Spivak and Hanson2 and subsequently in the United States in 2016, global cases have risen precipitously. Reference Spivak and Hanson2–Reference Cortegiani, Misseri, Fasciana, Giammanco, Giarratano and Chowdhary4 Bloodstream infections have been associated with an all-cause mortality of 30%–72%, Reference Spivak and Hanson2–Reference Cortegiani, Misseri, Fasciana, Giammanco, Giarratano and Chowdhary4 with 40%–86% Reference Spivak and Hanson2,Reference Cristina, Spagnolo and Sartini3 of isolates harboring azole resistance. Total number of cases in the United States rose from 53 to 4,514 between 2016 and 2023. 5 The Centers for Disease Control and Prevention (CDC) Antimicrobial Resistance Laboratory Network reported a 7% increase in azole resistance among C. auris isolates from 2019 to 2020, restricting treatment options. Reference Liu, Hu and Zhao1 C. auris has also been shown to contaminate the hospital environment even after room disinfection, heightening the risk of nosocomial outbreaks. Reference Sansom, Gussin and Schoeny6 As such, CDC classified C. auris as an “urgent threat” to public health in the 2019 and 2021–2022 Antibiotic Resistance Threats in the United States reports. 7
Reducing the risk of C. auris nosocomial transmission requires identifying and isolating colonized patients early. Hospital outbreaks have been reported internationally and are frequently attributed to deficient isolation and hygiene practices. Reference Cristina, Spagnolo and Sartini3 Although decolonization with antimicrobials is not currently recommended, CDC advocates for the implementation of isolation and infection control procedures in cases of C. auris colonization. The US Military Health System (MHS) cares for all active duty US service members, retirees, and their dependent family members. Given the global breadth of the US military, the MHS sees patients across the world and has a particular interest in preventing nosocomial transmission of emerging infectious diseases. Additionally, the military has a history of being particularly exposed and susceptible to MDR pathogens and could also be a vehicle to spread MDR organisms (MDROs) to the US population if precautions are not taken. Reference Granata and Petrosillo8 Here, we present 1 case of C. auris infection and 5 cases of C. auris colonization in MHS patients in 2024 identified by the Department of Defense Multidrug-Resistant Organism Repository and Surveillance Network (MRSN). Three hospitals in the MHS are included in this study, hereafter referred to as Hospital A, Hospital B, and Hospital C. Table 1 provides a summary of the cases. This is, to our knowledge, the first known case series of C. auris involving a healthcare network with presence in multiple nations that also investigates potential sources and screening protocols for the pathogen.
Summary of Candida auris cases in the Military Health System, 2024
Note. MHS, Military Health System; y.o., years old; MDRO, multidrug-resistant organism; ESBL, extended-spectrum beta-lactamase; CRAB, carbapenem-resistant Acinetobacter baumannii; N/A, not available.
Case 1: Hospital A
A 38-year-old male with a history of advanced multiple sclerosis with contractures complicated by paraplegia, neurogenic bowel and bladder with chronic suprapubic catheter, gastrostomy tube, colostomy, multiple ischial and sacral pressure ulcers stages 2–3, recurrent urinary tract infections (UTIs), nephrolithiasis, and bilateral nephrostomy tube placement was readmitted to Hospital A for planned lithotripsy. He notably had no recent international travel history but was frequently admitted to skilled nursing facilities in the local area.
Four months before this admission, the patient was diagnosed with sacral osteomyelitis and treated with doxycycline and levofloxacin. He also had a Candida albicans UTI treated with fluconazole followed by fluconazole suppressive therapy for 2 months. Two months prior to admission, he was seen at an outside hospital initially for bilateral lower extremity tenotomies and contracture releases. However, his course was complicated by vancomycin-resistant Enterococcus endocarditis and carbapenem-resistant Acinetobacter baumannii bacteremia, and he was started on appropriate antimicrobials. Prior to lithotripsy, a urine culture was obtained, and C. auris was isolated. Amphotericin B was started and then stopped after he developed a significant infusion reaction. Lithotripsy was rescheduled for after completion of the antibacterial course for his endocarditis.
Shortly after his planned lithotripsy, the patient became tachycardic, febrile, and hypotensive. At this time, C. auris was suspected as a potential causative organism for his decompensation given prior isolation in the urine, and the patient was started on micafungin in addition to daptomycin and ceftazidime/avibactam (amphotericin B was initially avoided given prior reaction). However, the patient continued to clinically worsen, and blood cultures collected 2 days later grew isolates of C. auris, prompting initiation of amphotericin B with aggressive pretreatment with steroids and antihistamines for 2 weeks. The patient completed this therapy and was discharged from the hospital.
Molecular analysis with next-generation genetic sequencing (NGS) was performed at MRSN in Silver Spring, Maryland, and compared with other C. auris isolates collected from the MHS (Figure 1). The isolate was identified as clade III (African). Antimicrobial susceptibility testing revealed a minimum inhibitory concentration (MIC) to fluconazole of >64 µg/mL (Table 2). Environmental investigation was performed at Hospital A through swabs of the sink and surfaces in the patient’s room after isocharge. No residual colonies of C. auris were isolated from those swabs.
Genetic relatedness of C. auris isolates from the Military Health System (MHS), 2024. Core genome phylogeny for 4 C. auris isolates from the MHS (Cases 1, 2, 3, and 6) and 6 reference isolates from GenBank. The phylogenetic tree was built using the GTR-GAMMA model in RAxML v8.2.11 and a core genome alignment from Panseq (fragmentation size of 500 base pairs to find sequences with ≥95% identity in ≥95% of the isolates, which resulted in a 13-Mb core genome and an alignment of 306,480 informative sites). All isolates except 1 isolate from Hospital A were found to be clade III (African); 1 isolate from Hospital A was found to be clade I (South Asian). Cases 4 and 5 were isolates that were unavailable for sequencing.
Susceptibility testing of Case 1 Candida auris isolate
Note. MIC, minimum inhibitory concentration; CDC, Centers for Disease Control and Prevention; N/A, not applicable.
a Per CDC 14 : “There are currently no established C. auris-specific susceptibility breakpoints. Therefore, breakpoints are defined based on those established for closely related Candida species and on expert opinion. Correlation between microbiologic breakpoints and clinical outcomes is not known at this time. Therefore, the information…should be considered as a general guide and not as definitive breakpoints for resistance.”
b Based on CDC-suggested breakpoints. 14
c CDC does not recommend breakpoint for 5-flucytosine.
Case 2: Hospital A
A 74-year-old female with a history of heart failure, diabetes mellitus, chronic obstructive pulmonary disease, and hypothyroidism was admitted to the intensive care unit of Hospital A for severe abdominal pain and distention, acute respiratory failure, and hypotension. She had no significant infectious history, and she lived in an apartment independently with no recent international travel history, but she had frequent admissions to outside hospitals and skilled nursing facilities for heart failure exacerbations. She was started on vancomycin and piperacillin/tazobactam for sepsis with a potential gastrointestinal, pulmonary, or urinary source. After initial improvement, she subsequently experienced symptomatic hypotension requiring vasopressors thought to be related to either an infectious or cardiogenic etiology. C. auris was isolated in 3 separate urine cultures that were obtained as part of a broad sepsis workup but ultimately was not treated given the lack of urinary-specific symptoms. Throughout her hospital course, she never developed symptoms of a UTI, and C. auris was not isolated elsewhere. She developed Ogilvie’s syndrome during her hospital course and ultimately died after spontaneous bowel perforation. Molecular analysis with NGS was performed at MRSN (Figure 1); the isolate was identified as clade III (African).
Case 3: Hospital B
A 71-year-old male with a history of multiple transient ischemic attacks (2011, 2024), prostate cancer and prostatectomy in 2016, chronic obstructive pulmonary disease, urinary retention with chronic indwelling Foley catheter, and recent admission for pneumonia requiring intubation presented to the emergency department with nausea and vomiting. He lived in the community and did not report any recent international travel. He also complained of pain at the tip of his penis associated with his Foley catheter. Urinalysis revealed pyuria, leukocyte esterase, and budding yeast. Although fluconazole was started initially, the urine cultures ultimately grew C. auris. Infectious disease specialists were consulted, and they recommended exchanging the urinary catheter and stopping systemic antifungal therapy given there were no systemic signs of infection. He recovered from his episode of nausea and vomiting with supportive care and was eventually discharged without complications. Molecular analysis with NGS was performed at MRSN (Figure 1); the isolate was identified as clade I (South Asian).
Case 4: Hospital B
A 24-year-old active duty male without any significant past medical or international travel history (to include military deployments) was participating in military training exercises within the United States and was admitted from the field for shortness of breath, cough, fevers, chills, and night sweats for 2 weeks. After admission, he decompensated into septic shock from pneumonia. While receiving ventilatory and pressure support, he developed cardiac arrest from ventricular tachycardia. Lower respiratory PCR was positive for Streptococcus pneumoniae. He eventually recovered and completed a 7-day course of meropenem and linezolid. After discharge, urine cultures obtained during his hospitalization as part of a broad infectious workup for septic shock were positive for C. auris; however, this was not treated given the patient did not exhibit urinary symptoms and had fully recovered after receiving appropriate treatment for community-acquired pneumonia and sepsis. Due to a lack of access to this isolate, it was not sequenced, and the clade of the isolate was not found.
Case 5: Hospital B
A 74-year-old male with a history of heart failure, atrial fibrillation, type 2 diabetes, a fall (2023) resulting in central cord syndrome, and neurogenic bladder further complicated by C. albicans pyelonephritis and Clostridioides difficile infection presented to the emergency department with weakness and poor appetite. The patient was living in the community and had no recent international travel history. He was experiencing urinary leakage for several months and underwent urodynamic testing 1 week prior to admission which revealed poor bladder capacity and a contractility index consistent with urinary retention. Acute kidney injury was diagnosed, thought to be secondary to both poor oral intake and chronic urinary retention, and he was admitted to the hospital for intravenous (IV) fluid support and urology evaluation. Acute kidney injury improved after administration of IV fluids. A urine culture was performed and initially grew Candida not identified to the species level. The patient received fluconazole for 3 days, but it was discontinued given the absence of urinary symptoms. Infectious disease specialists were consulted and did not recommend further antimicrobial therapy given the absence of symptoms and presumed colonization. The patient was discharged after resolution of acute kidney injury, with outpatient urology follow-up for management of neurogenic bladder. Five days after discharge, C. auris was identified from the urine culture. Infectious disease specialists were re-consulted and recommended no treatment of C. auris, given the absence of symptoms. Due to lack of access to this isolate, it was not sequenced and the clade of the isolate was not found.
Case 6: Kenya, Germany, and Hospital C
A 31-year-old male MHS beneficiary with no significant past medical history suffered polytrauma during a skydiving accident outside of Mombasa, Kenya. The patient was admitted to the intensive care unit at Mombasa Hospital for initial stabilization and surgical management. During hospitalization, he received a blood transfusion, had suprapubic and subclavian central venous catheters placed, and underwent external fixation of right tibial/fibular and right hemipelvis fractures. After 2 days, he received additional blood transfusions in transit to a hospital in Germany, where he had orthopedic fixation adjusted. After 2 days in Germany, he was transferred to Hospital C in the United States for definitive management/rehabilitation. Prior to this injury, he had minimal exposure to healthcare settings.
Per MEDEVAC isolation protocol, the patient was placed in contact isolation upon arrival to Germany, which was continued upon transfer to Hospital C. Perirectal surveillance swabs for MDROs were performed per protocol, identifying extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and ESBL-producing Klebsiella pneumonia. Per protocol, upon arrival at Hospital C, groin/axillary swabs for C. auris were collected and found to be positive for C. auris colonization.
The patient displayed no clinical evidence of fungal infection (systemic or localized); therefore, no antifungal treatment was initiated. Isolation precautions, instituted on admission to the MHS, were continued throughout his admission, the course of which was unremarkable from an infectious disease standpoint. No nosocomial transmission of C. auris was detected. Through molecular analysis at MRSN, the isolate was identified as clade III (African) and found to carry the VF125AL mutation in ERG11, indicating resistance to fluconazole. Antifungal susceptibility testing was performed at MRSN, resulting in a MIC of 256 µg/mL to fluconazole (Table 3).
Susceptibility testing of Case 6 Candida auris isolate
Note. MIC, minimum inhibitory concentration; CDC, Centers for Disease Control and Prevention; N/A, not applicable.
a Per CDC 14 : “There are currently no established C. auris-specific susceptibility breakpoints. Therefore, breakpoints are defined based on those established for closely related Candida species and on expert opinion. Correlation between microbiologic breakpoints and clinical outcomes is not known at this time. Therefore, the information…should be considered as a general guide and not as definitive breakpoints for resistance.”
b Based on CDC-suggested breakpoints. 14
c CDC does not recommend breakpoint for 5-flucytosine.
Discussion
CDC currently recommends screening for C. auris in patients with known exposure to the pathogen, patients with exposure to high-acuity postacute care facilities, including long-term acute care hospitals and ventilator-capable skilled nursing facilities, and patients who have had an overnight stay in a healthcare facility outside the continental United States (OCONUS). CDC also recommends considering screening individuals at higher risk for infection, including individuals on ventilatory support, infection with other MDROs, or with multiple IV lines or medical devices. 9 Our case series highlights the need for screening patients with exposure to OCONUS healthcare facilities (Case 6), as well as individuals with recurrent hospital stays, a history of infections or colonization with MDROs (Cases 1, 2, 3, and 5), or ventilatory support (Case 4).
Molecular analysis also provides some insight into the origin of the C. auris isolates. As illustrated in Figure 1, 3 of the 4 genotyped isolates were classified as clade III (African), with Case 4 classified as clade I (South Asian). Clade I isolates have been identified predominantly in the northeast United States, while clade III isolates have been identified in Indiana, Texas, Florida, and California. A 2019 study revealed a predominantly clade III outbreak in Los Angeles, California. Reference Price, Mirasol and Ward10 Although the exact location of transmission cannot be determined through genetic analysis, the genetic isolates from this series support the domestic presence of C. auris with multiple geographic and genotypic origins and are consistent with the genetic makeup of C. auris that has been transmitted domestically in the past. Reference Lyman, Forsberg and Sexton11 The identification of a Clade III isolate in Case 6 supports that transmission likely occurred in Africa as opposed to Germany, as Clade III has historically been more frequently isolated in Africa than Europe. Reference Chow, Muñoz and Gade12
The MHS routinely manages cases of illness and injury sustained outside the continental United States (OCONUS) from the point of injury to definitive care in the United States. In both peacetime and wartime, patient evacuations are received in military treatment facilities (MTFs) spanning the spectrum of care, from field-based or local national facilities OCONUS to more definitive care hospitals. Large-scale combat operations such as the conflicts in the Middle East saw extensive patient evacuation of military service members with MDRO colonization and infection, complicating treatment and posing a nosocomial threat. Reference Hospenthal, Crouch and English13 In 2009, MRSN was established at the Walter Reed Army Institute of Research in response to this threat and currently performs active surveillance, antimicrobial testing, and archival analysis of MDR isolates from across the MHS and partner healthcare systems. Although not observed in our series, the potential for nosocomial spread and emerging international incidence of C. auris in regions where the US military is actively engaged, and the potential to cause treatment-resistant disease among MHS patients, has prompted increased interest in surveillance for this pathogen. This is especially relevant as conflicts transition to new geographic areas and medical evacuation transfer routes change.
The few MTFs that routinely receive OCONUS patient transfers for definitive or en route care institute some form of MDRO surveillance of OCONUS patient transfers, typically with skin and rectal bacterial swabs for MDR bacteria, and since 2021, some of these protocols have included C. auris fungal swabs.
Since 2021, Hospital A has expanded screening for MDRO and C. auris, per CDC recommendations, to all patients transferred to their hospital from any outside hospital, long-term care facility, or OCONUS. Lacking a robust clinical decision support system (CDSS) in the MHS electronic medical record (EMR), identification of these cases requires vigilance on the part of Infection Prevention and Control (IPAC) teams and clinical providers. In 2022, Hospital C expanded surveillance for C. auris in their facility by screening all patients admitted to the medical intensive care unit (MICU), regardless of admission pathway (including intra-hospital transfers) due to a lack of certain infection-control-related assets. Although still reliant upon clinical providers to ensure screening is performed, unit-based screening was trialed as an approach to optimize adherence to surveillance protocols. Hospital C collects C. auris axillary and groin swab specimens and utilizes ChromAgar techniques for screening. The specimen typically has a finalized result within 7 days.
At Hospital C, in the first 12 months of MICU-based surveillance, 215 groin and axillary samples were collected and processed with 1 positive sample (Case 6). Criteria-based surveillance based on CDC-recommended criteria for screening at Hospital A yielded 205 swabs in the first 8 months of 2024, none of which were positive. However, Hospital A reported the 2 cases of C. auris previously noted, found in urine and blood cultures drawn for diagnostic purposes. Currently, Hospital B is not performing surveillance for C. auris, and the cases described herein from that facility were found through routine urine cultures drawn for diagnostic purposes. Although the potential for a hospital outbreak is apparent, Reference Cristina, Spagnolo and Sartini3 nosocomial transmission was not associated with any of the cases reported in this series.
Challenges of performing surveillance for this emerging pathogen include the inability of surveillance to distinguish between colonization and infection and the difficulty of adherence to surveillance protocols. First, the value of surveillance may be unclear as C. auris is often deemed to colonize rather than cause disease among patients from whom it is isolated. Second, in reviewing surveillance protocols across the MHS, challenges of adherence to IPAC testing protocols and collection of accurate data are apparent, especially without a CDSS. These gaps prompted the expansion of surveillance at Hospitals A and C. Despite these challenges, and although C. auris nosocomial transmission has not yet been reported in the MHS, our description of C. auris associated with critically ill patients in the MHS regardless of travel or exposure history suggests the potential for nosocomial spread. Because of this, it is imperative to implement sustained and intentional surveillance at most, if not all, MTFs that may receive high-risk patients if we are to avoid outbreaks seen in other healthcare systems.
In this article, we presented 1 case of C. auris clinical infection and 5 cases of colonization. One case, likely acquired in a Kenyan hospital, was identified on protocolized surveillance in an MTF upon transfer to the United States. The 5 other cases were likely attributable to domestic spread of C. auris in regional healthcare systems and a history of MDRO colonization; however, 3 cases were not associated with significant risk factors, and none of these cases were associated with evidence of nosocomial transmission that has been observed elsewhere. Clinical risk factor and unit-based surveillance continue across the MHS but are hindered by a lack of a CDSS integrated into the EMR. Highly effective and consistent local surveillance will be critical in identifying C. auris and mitigating outbreaks of MDROs more broadly within the MHS should an influx of OCONUS medical evacuations occur.
Acknowledgments
The authors would like to acknowledge the MRSN, a division of the Walter Reed Army Institute of Research.
Financial support
None reported.
Competing interests
The authors declare none.
Disclaimer
I am a military service member or employee of the US Government. This work was prepared as part of my official duties. Title 17, U.S.C. §105 provides that copyright protection under this title is not available for any work of the US Government. Title 17, U.S.C. §101 defines a US Government work as work prepared by a military service member or employee of the US Government as part of that person’s official duties. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the US Government.
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