Multidrug-Resistant and Infection in an Oncohematologic Patient

Introduction

Elizabethkingia meningoseptica (E. meningoseptica), previously known as Chryseobacterium meningosepticum, is a gram-negative, aerobic, biofilm-forming, non-motile bacterium. It is considered an opportunistic pathogen with the potential to cause nosocomial infections and is often associated with a high mortality rate [1,2].

E. meningoseptica is responsible for various hospital-acquired infections, including sepsis, meningitis, pneumonia, bacteremia, and endocarditis [3–5]. It can form biofilms and can survive for extended periods in moist environments, such as water sources, tap water, hospital sinks, faucets, and humidifiers [6]. This bacterium commonly contaminates medical equipment and flushing solutions [1].

Immunocompromised individuals or neonates and those diagnosed with hematological disease such as leukemia, aplastic anemia, cancer, tuberculosis, neutropenia, diabetes, and other type of cancer [2,6–8], are particularly susceptible to infections caused by this pathogen due to their compromised immune status. These patients often require invasive procedures, such as mechanical ventilation and central venous access, which further increase their risk of infection [1,4,6,9].

E. meningoseptica is often described as intrinsically resistant (both chromosomal- and plasmid-mediated) to most antibiotics, including broad-spectrum β-lactams and aminoglycosides [1,2]. It exhibits particular sensitivity to minocycline, trimethoprimsulfamethoxazole, fluoroquinolones, and piperacillin-tazobactam. However, no definitive drug of choice has been established, and infections are clinically challenging to treat due to the lack of established minimum inhibitory concentration (MIC) breakpoints for antibiotics against this pathogen [2,10].

Infections caused by this type of bacteria can be fatal for immunocompromised individuals, particularly those with hematological diseases. Due to the risk of dissemination in a hospital environment, these infections have become a significant challenge for both effective antibacterial therapy and the control of infectious processes [8,11].

Regarding Enterococcus faecium (E. faecium), the global emergence of a subtype with increased virulence and resistance to multiple antimicrobial classes is currently linked to the majority of healthcare-associated infections (HAIs). E. faecium is a gram-positive bacterium that can acquire resistance to glycopeptides, particularly vancomycin, a crucial antibiotic for treating infections involving gram-positive bacteria [5]. Therapeutic options for serious infections caused by E. faecium are primarily limited to glycopeptides or oxazolidinones [5,12,13].

Both isolates, as MDR pathogens, possess characteristics that make them highly adaptable to the hospital environment. This adaptability is driven by gene acquisition and loss, facilitated by plasmid transfer and homologous recombination, and mediated by insertion sequence (IS) elements that promote the spread of high-risk clones (STs) associated with infections carrying high mortality rates [7,8,11]. This type of resistance is conferred by a set of regulatory, functional, and accessory genes forming the van operon [5].

Vancomycin-susceptible Enterococci (VSE) can evolve into vancomycin-resistant Enterococci (VRE) through the horizontal transfer of mobile genetic elements (MGEs) containing van gene cluster, such as van A, B, D, E, G, M, N, and P [13,14].

High-level resistance to both vancomycin and teicoplanin characterizes VanA-type VRE, while VanB-type VRE shows resistance to vancomycin only, with a minimum inhibitory concentration (MIC) range of 1 to >256 mg/L in clinical isolates [13,14]. It is also noteworthy that vancomycin-susceptible E. faecium that acquires the vanA or vanB gene is often implicated in hospital outbreaks [12].

Hospitals care for an increasing number of elderly and immunocompromised patients who are susceptible to various infectious processes and are often treated with a wide range of antimicrobials. The use of multiple antibiotics creates selective pressure on antibiotic resistance genes [13,15]. Early diagnosis of infections, combined with laboratory identification of the causative species, can help minimize invasive procedures such as mechanical ventilation and central venous catheterization, while also improving hand hygiene management and aseptic practices. Additionally, timely treatment of infections can help reduce the morbidity and mortality associated with E. meningoseptica and E. faecium, as well as prevent hospital outbreaks [9].

Therefore, we report the clinical case of a 25 year-old patient who underwent a surgical procedure and was subsequently diagnosed with acute myeloid leukemia (AML). Following his immediate admission to a specialized hospital unit for hematology and hemotherapy to undergo chemotherapy, a concurrent infection with multidrug-resistant E. meningoseptica and E. faecium was identified. Although all available resources were used to treat these infections, the patient died due to multidrug resistance of the diagnosed pathogens, which highlights the need for serious attention to the risks of hospital infections and care.

Case Report

LABORATORY FINDINGS:

Following the positive blood culture BACT/ALERT FA PLUS (Biomérieux, Brazil), and positive urine culture using URILAB-CLED/Mac Conkey (laminoculture-Laborclin Biokar Diagnostics France) with a bacterial growth of 100 000 CFU/ mL, subcultures were performed on 5% sheep blood agar and MacConkey agar (Himedia-Hexasystems, Mumbai, India). These were then incubated for 24 h at 35.4°C. Single isolated colonies were selected and phenotypic identification and minimum inhibitory concentration (MIC) values for E. meningoseptica and E. faecium were determined using a rapid test system (VITEK-2, bioMérieux, France), following the guidelines of the Clinical and Laboratory Standards Institute (CLSI, 2022) and the Brazilian Committee on Antimicrobial Susceptibility Testing (BrCAST, 2022) [10,11].

E-Test strips were used to assess the susceptibility of E. faecium to vancomycin and teicoplanin. The glycopeptide susceptibility test was conducted using Mueller-Hinton agar with E-test strips for vancomycin and teicoplanin at concentrations ranging from 0.016 to 256 μg/mL. The diameters of the inhibition zones were measured, and MIC interpretations for sensitivity, intermediate sensitivity, or resistance to antibiotics were made according to BrCAST guidelines. Staphylococcus aureus (S. aureus) ATCC 25923 was used as a control for the susceptibility tests.

Microbiological laboratory tests identified 2 species: E. meningoseptica and E. faecium. The susceptibility test results for E. meningoseptica, performed using VITEK-2, showed a multidrug-resistance profile with sensitivity only to the quinolone antibiotics ciprofloxacin and norfloxacin. For E. faecium, resistance was detected to ampicillin, levofloxacin, vancomycin, and teicoplanin. E-test for glycopeptides indicated a high level of resistance, with MIC exceeding 256 µg/mL (Table 1).

KEY TURNING POINTS LEADING TO THE PATIENT’S DETERIORATION:

The patient’s clinical condition deteriorated significantly due to a series of complications. After the detection of thrombocytopenia and an acute hemorrhagic abdomen, he underwent exploratory laparotomy and was subsequently diagnosed with acute myeloid leukemia (AML). Although initially stable and on antibiotic therapy, he developed pleural effusions, hepatomegaly, and renal issues. Suspected infection and bleeding at the catheter insertion site led to changes in antibiotic therapy and venous access, which did not prevent the emergence of new signs of infection. The infiltration of AML into the central nervous system and bone marrow aplasia, combined with successive infections by E. meningoseptica and E. faecium, contributed to persistent febrile episodes and ultimately septic shock, resulting in the patient’s death.

CLINICAL DECISIONS:

Due to the new concomitant infection, meropenem was discontinued, and polymyxin and linezolid were introduced. Subsequently, meropenem, polymyxin, and amphotericin B were replaced with amikacin while maintaining linezolid. As there was no clinical improvement, meropenem was reintroduced in combination with amikacin and linezolid. The patient’s hemodynamic instability worsened due to septicemia, necessitating his transfer to the Intensive Care Unit (ICU). Despite intensive treatment, he died due to septic shock later in December 2022.

Discussion

Throughout the diagnosis and treatment of his malignant hematological disease – AML – the patient underwent several invasive procedures and chemotherapy sessions. These factors contributed to the development of severe infectious processes with rapid progression and an unfavorable outcome, caused by multidrug-resistant pathogens. Studies have reported infections with E. meningoseptica in patients with comorbidities undergoing surgical or dialysis procedures, but there are few documented cases in hematological patients [16].

Onco-hematological patients are highly susceptible to multi-drug-resistant bacterial infections due to their compromised immunity. In this case, in addition to having this comorbidity, the patient underwent 2 consecutive surgical procedures shortly before starting oncological treatment, which involved multiple invasive procedures such as venous access and bone marrow punctures. Several studies have reported that E. meningoseptica is a newer and rarer cause of infection in hospitalized patients, increasingly emerging as a significant pathogen in immunocompromised populations or those undergoing immunosuppressive treatment [2,3,6].

Phenotypic susceptibility testing for E. meningoseptica showed an extensive drug resistance profile, with sensitivity only to norfloxacin and ciprofloxacin, partially differing from the findings of Das (2022) [12] and Lima (2014) [4], who reported a susceptibility profile of E. meningoseptica isolates to cefoxitin, piperacillin/tazobactam, tigecycline, and ciprofloxacin. It is important to note that E. meningoseptica has an intrinsic multi-drug-resistant profile to most β-lactams, such as aztreonam, carbapenems, aminoglycosides, and chloramphenicol, as mentioned in other studies [4,17], furthering highlighting the clinical challenges in selecting an effective therapeutic option and that contributes to the increased mortality rate.

Paradoxically, another study revealed that E. meningoseptica is sensitive to antibiotics typically effective against gram-positive bacteria, such as quinolones, vancomycin, tigecycline, trimethoprim-sulfamethoxazole, and rifampin [17]. This unusual sensitivity profile underscores the need for more in-depth studies on this pathogen.

Our results partially align with the data published by the SENTRY Antimicrobial Surveillance Program Report (1997–2001), which identified 3 isolates of E. meningoseptica from patients aged 66–90 years admitted to an ICU in São Paulo. These isolates showed sensitivity to ciprofloxacin, piperacillin/tazobactam, piperacillin, tigecycline, and fluoroquinolones [4,17]. Huang and collaborators (2019) [2] cautioned clinicians about hospital outbreaks caused by E. meningoseptica with carbapenem resistance, noting that its mortality rate can be as high as that of any other non-fermenting pathogen.

Additionally, the number of cases has significantly increased in recent years, and the challenges in selecting appropriate therapeutic options, as seen in this case report, may have contributed to this rise, highlighting the need for more in-depth studies on this species [18].

Another critical factor contributing to the increase in case numbers is the lack of standardized susceptibility breakpoints for this pathogen. Antibiotics such as trimethoprim-sulfamethoxazole, rifampicin, and vancomycin, reported as effective in clinical practice by Lima et al (2014) [4] and Pereira et al [17], are not standardized for use against this pathogen.

The other clinically significant bacterium identified was vancomycin-resistant E. faecium. Enterococci are considered among the most important hospital pathogens worldwide [19], with epidemiology varying by geographic region. In Europe, for example, the prevalence is 17.2% [20], with the CC17 clone most frequently associated with resistance to multiple classes of antimicrobials and carrying several virulence genes [5].

A particularly concerning characteristic of E. faecium is the ability to rapidly acquire resistance to vancomycin, a common antibiotic used to treat serious infections caused by gram-positive bacteria. Infections caused by this pathogen are generally difficult to treat and can easily spread within hospital environments [5,19]. Vancomycin resistance is primarily associated with the vanA, vanB, and vanM genotypes, located in the van operon, which confer high levels of resistance and are present in mobile genetic elements that can also transfer resistance to other species, such as staphylococci [3,14–16,19].

In this study, the E-test result indicated high-level resistance to vancomycin and teicoplanin, likely due to the presence of the vanA genotype, but with sensitivity to tigecycline and linezolid, which differs from findings reported in another study [19].

Given that initial antimicrobial therapy for infections is often empirical, the rational use of antibiotics is directly related to an understanding of antimicrobial resistance characteristics. Therefore, rapidly identifying the genotype and phenotype of the pathogen, along with its susceptibility profile, can be crucial for successful treatment of the infection and the patient’s recovery [21].

This is the first case report from this reference hospital unit for hematology and hemotherapy in Amazonas, where a patient with AML was identified with a urinary infection caused by E. meningoseptica and a hematogenous infection caused by E. faecium, both resistant to multiple antibiotics, resulting in death due to sepsis.

Future research could focus on several key areas to improve the understanding and management of infections caused by E. meningoseptica and E. faecium. There is an urgent need for the standardization of susceptibility breakpoints for E. meningoseptica, as the lack of consensus limits effective therapeutic options.

Additionally, more in-depth studies on the molecular mechanisms of resistance and virulence factors of these pathogens are needed to understand how they survive and spread in hospital settings. Research should also explore new therapeutic alternatives or combinations of antibiotics to treat infections caused by these multidrug-resistant bacteria. Finally, developing more effective infection control strategies and conducting detailed epidemiological studies to identify specific risk factors are essential to prevent outbreaks and improve clinical outcomes.

Conclusions

Aseptic techniques are crucial in healthcare, especially for immunocompromised patients undergoing invasive procedures, as strict isolation and hygiene practices can prevent life-threatening infections. This case highlights the need for robust infection control and early pathogen identification, particularly for multidrug-resistant bacteria like Elizabethkingia meningoseptica and Enterococcus faecium.

Rapid identification and knowledge of resistance profiles are key to guiding effective treatments. Due to the lack of standardized breakpoints and limited treatment options for these infections, updated guidelines and new research on resistance mechanisms and alternative therapies are needed. Although this is a single case report, it emphasizes the need for further studies to improve infection management and prevention strategies.