Diagnosis and treatment of Aspergillus terreus and Klebsiella pneumoniae coinfection following myocardial infarction: A case report and literature review

Abstract

Background

Aspergillus terreus (A. terreus) is an opportunistic fungal pathogen increasingly reported among immunocompromised individuals, particularly those admitted to intensive care units (ICUs). Due to its intrinsic resistance to amphotericin B and partial resistance to azoles, treatment remains challenging. Coinfection with bacterial (Klebsiella pneumoniae [K. pneumoniae]) and viral pathogens (herpes simplex virus type 1 [HSV-1], cytomegalovirus [CMV]) further complicates the clinical course.

Case report

We describe a 53-year-old male who developed A. terreus and K. pneumoniae bloodstream infections following acute myocardial infarction (MI). Diagnosis was primarily achieved via next-generation sequencing (NGS) of blood samples, supplemented by clinical and imaging findings. Despite aggressive antimicrobial therapy—including isavuconazole, liposomal amphotericin B, piperacillin-tazobactam, and mechanical support strategies (e.g., extracorporeal membrane oxygenation [ECMO], continuous renal replacement therapy [CRRT])—infection control was difficult. The patient eventually recovered partial consciousness and was discharged for rehabilitation.

Discussion

Invasive fungal infections, particularly those caused by A. terreus, present diagnostic and therapeutic challenges in critically ill patients. Early molecular identification and tailored antifungal therapy based on pathogen resistance profiles are essential. Moreover, recognizing and managing bacterial and viral coinfections are vital for optimizing patient outcomes.

Conclusion

This case highlights the necessity of prompt, multimodal diagnostic approaches and individualized antifungal and antibacterial therapy in the management of ICU-acquired infections post-myocardial infarction.

Introduction

Invasive fungal infections (IFIs) represent a significant cause of morbidity and mortality in critically ill patients, particularly those experiencing immune dysfunction following major events such as myocardial infarction (MI) [1]. A. terreus is a soil-borne, opportunistic mold distinguished by its high virulence and natural resistance to several standard antifungal agents, including amphotericin B [2].

In recent years, A. terreus has emerged as a notable cause of invasive aspergillosis, accounting for an increasing proportion of Aspergillus-related infections worldwide [3]. Unlike Aspergillus fumigatus, A. terreus exhibits not only intrinsic resistance to amphotericin B but also a higher propensity for hematogenous dissemination, particularly involving the central nervous system [4]. Clinical outcomes associated with A. terreus infections are often poorer compared to other Aspergillus species, necessitating early and aggressive antifungal therapy, typically with voriconazole or isavuconazole [5].

Patients in the ICU often require broad-spectrum antibiotics, corticosteroids, and mechanical ventilation, all of which can predispose them to fungal infections [6]. Klebsiella pneumoniae is a common cause of nosocomial bloodstream infections, often exhibiting multidrug resistance [7]. Additionally, viral reactivations such as HSV-1 and CMV are increasingly recognized as significant contributors to disease severity and mortality [8].

While culture and microscopy remain the gold standard methods for fungal identification, rapid and accurate diagnosis of invasive fungal infections is crucial for improving survival.Traditional culture methods are often insensitive or too slow for timely clinical decision-making. NGS offers a promising adjunct by enabling early pathogen identification directly from blood samples [9]. However, reliance on NGS alone without culture or histopathology confirmation carries limitations, including false positives, detection of colonization rather than true infection, and lack of susceptibility data.

Herein, we report a rare case of bloodstream coinfection with A. terreus and K. pneumoniae in a post-MI patient requiring VA-ECMO (veno-arterial extracorporeal membrane oxygenation) and CRRT (continuous renal replacement therapy). We emphasize the importance of early molecular diagnostics, appropriate antifungal selection, and the need for integrated management of fungal, bacterial, and viral infections in critically ill patients.

Case report

A 53-year-old previously healthy male presented with 8.5 h of chest tightness and 6.5 h of altered consciousness after engaging in intensive post-typhoon electrical repair work. He was urgently transferred via the green channel for percutaneous coronary intervention (PCI), coronary angiography (CAG), and intra-aortic balloon pump (IABP) due to extensive acute anterior and inferior myocardial infarction.

ICU admission and initial management

On admission to the intensive care unit (ICU), the patient was comatose (Glasgow Coma Scale score: 3), with cardiac and respiratory arrest requiring endotracheal intubation, mechanical ventilation, and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) (initial parameters: speed 3600 rpm, flow 3.11 L/min, oxygen concentration 100 %).

Initial diagnoses included

• •Acute extensive anterior and inferior myocardial infarction
• •Cardiogenic shock
• •Ischemic-hypoxic encephalopathy
• •Metabolic acidosis
• •Electrolyte disturbances (hypokalemia, hypocalcemia)

Laboratory and imaging findings

Laboratory tests showed

• •WBC: 30.7 × 10⁹/L
• •CRP: 110 mg/L
• •PCT: 5.2 ng/ml
• •NT-proBNP: 25,659 pg/ml
• •Coagulation dysfunction: APTT 170 s, PT 18.1 s, PTA 43.1 %, fibrinogen initially low (0.52 g/L), later rose to 6.77 g/L

Initial chest X-ray (Fig. 1), revealed a large patchy consolidation in the right middle and lower lung zones, blurring of the right diaphragmatic contour, and slight tracheal deviation to the left. These findings were consistent with bilateral pulmonary infiltrates and early pulmonary edema, suggesting systemic inflammation and pulmonary infection. Blood and sputum cultures were repeatedly negative.

Fig. 1.

Chest X-ray on the day of admission.

Antimicrobial and antiviral therapy

Empirical therapy with piperacillin-tazobactam and linezolid was initiated on Day 1. Following the detection of Klebsiella pneumoniae by mNGS on Day 7, piperacillin-tazobactam was continued based on genotypic susceptibility, as no β-lactamase resistance genes were identified. K. pneumoniae was no longer detectable by Day 11.

Aspergillus terreus was also detected on Day 7 with a low read count (9), prompting initiation of voriconazole. Antifungal therapy was intensified in response to progressive fungal burden (29 reads on Day 9; 19,928 on Day 21), with isavuconazole initiated on Day 9 and liposomal amphotericin B added on Day 20 as part of combination antifungal therapy. This escalation was initially guided by the 2016 IDSA guidelines for invasive aspergillosis. Although A. terreus is intrinsically resistant to amphotericin B and the 2016 IDSA guidelines advise against its use in confirmed cases, its administration was deemed appropriate in this instance due to the lack of culture-based identification, rising fungal load, and progressive clinical deterioration. The combination of isavuconazole and liposomal amphotericin B was employed as salvage therapy, consistent with the 2021 ECIL-6 guidelines, which recognize liposomal amphotericin B as an alternative treatment in patients who fail or cannot tolerate mould-active azoles (moderate recommendation, level II evidence) [10].

Detection of HSV-1 and CMV (Days 7 and 11) suggested viral reactivation in the setting of immune suppression.Intravenous ganciclovir was initiated at a loading dose of 0.4 g, followed by a maintenance dose of 0.2 g once daily for antiviral coverage.

Organ support and clinical course

On Day 11, the patient received artificial liver support (DPMAS + plasma exchange) due to liver dysfunction and persistent inflammatory state.

By Day 23:

• •Inflammatory markers showed partial improvement
• •Neurological status: shallow coma with spontaneous eye opening and light reflex
• •Respiratory status: still on mechanical ventilation
• •Renal status: dependent on continuous renal replacement therapy (CRRT)
• •Hemodynamic status: stabilized, with ECMO weaning underway

The patient was transferred to a secondary care facility for continued supportive care and rehabilitation.

NGS methods and interpretation

NGS was performed on peripheral blood samples collected on Days 7, 9, 11, and 21 of hospitalization. Metagenomic sequencing and analysis were conducted by Hugobiotech Co., Ltd. (Beijing, China) using a validated clinical mNGS platform. DNA was extracted using the QIAamp® UCP Pathogen DNA Kit (Qiagen, Germany), followed by library construction with the MGIEasy DNA Library Prep Kit (MGI Tech, China) and sequencing on the BGISEQ-50 platform (BGI, China).

Data analysis involved host sequence removal (human genome hg38), alignment against a curated microbial database (PMDB, BGI-Shenzhen, China), and quantification based on unique, non-overlapping reads. A microbe was considered positive if it had:

• •Significantly higher reads than in negative controls (defined as >10 × the read count in negative controls)
• •Known pathogenicity in the clinical context
• •Consistent temporal trends (increasing reads or persistent detection)

Detected pathogens included:

• •Aspergillus terreus
• •Klebsiella pneumoniae
• •Herpes Simplex Virus-1
• •Cytomegalovirus

The dynamic change in pathogen reads is summarized in Table 1. Notably, A. terreus reads increased progressively, while K. pneumoniae became undetectable by Day 11. Blood cultures remained negative throughout, highlighting the added value of mNGS for early pathogen detection in immunocompromised or critically ill patients.

Table 1.

Summary of medication, laboratory indices, and imaging examinations.

Date	Medications/Procedures	Laboratory Indices	CT/Imaging Examination
Admission	Aspirin enteric-coated 300 mg, Clopidogrel bisulfate 300 mg, Atorvastatin calcium 40 mg, Tenecteplase 16 mg, Norepinephrine 9.6 mg, RBC 8 U, Plasma 1200 ml, Cryoprecipitate 24 U	Hb: 55 g/L, APTT: 170.00 s, TT: 84.20 s, PTA: 35.80 %, WBC: 10.22 × 10^9/L, K: 3.20 mmol/L, Na: 157.2 mmol/L, PCT: 33.91 ng/ml, Troponin I: 40,000.0 pg/ml, IF-4: 8.92 pg/ml, IF-6: 12,519.29 pg/ml, IF-10: 138.83 pg/ml	1. Echocardiogram: Right atrium/ventricle normal size, left atrium/ventricle normal diameter, reduced wall motion, hyperactive motion at left ventricle anterior and apex walls, basal segments only.
Day 1	Indobufen 0.1 g, Clopidogrel 75 mg, Piperacillin-tazobactam 3 mg, Pantoprazole 80 mg, Somatostatin 3 mg, RBC 7 U, Platelets 1 therapeutic dose, Cryoprecipitate 24 U, Plasma 800 ml, Albumin 80 g	NGS: Human Papillomavirus 2 (Seq: 10), CMV (Seq: 7) Hb: 85 g/L, APTT: 26.90 s, TT: 18.60 s, FIB: 2.97 g/L, PTA: 76.20 %, WBC: 11.01 × 10^9/L, CRP: 35.24 μg/ml, PCT: 81.45 ng/ml, Na: 149.9 mmol/L, IF-6: 3412.00 pg/ml	1. Echocardiogram: Segmental wall motion abnormalities due to ECMO + IABP; Reduced heart function. 2. Gastroscopy: Acute gastric and duodenal mucosal lesions. 3. Chest ultrasound: Right massive pleural effusion.
Day 7	Levosimendan 12.5 mg, Vancomycin 750 mg, Piperacillin-tazobactam 4.5 mg, RBC 2 U, Platelets 1 therapeutic dose, Cryoprecipitate 400 ml, Human Immunoglobulin 100 ml, Artificial Liver	NGS: Aspergillus terreus (Seq: 9), Klebsiella pneumoniae (Seq: 75), HSV-1 (Seq: 120), CMV (Seq: 106) Hb: 95 g/L, PT: 14.40 s, FIB: 5.65 g/L, PTA: 58.80 %, IF-6: 609.00 pg/ml, Bilirubin: 383.1μmol/L	1. Echocardiogram: Left ventricular end-diastolic diameter: 44 mm, Inferior vena cava: 22 mm, TAPSE: 19 mm, Right atrium/ventricle: 27 × 44 mm/31 × 36 mm, VTI: 10.4 cm, EF: 36 %.
Day 9	Meropenem 1 g, Vancomycin 750 mg, Isavuconazole 200 mg, Plasma 400 ml, Human Immunoglobulin 100 ml	NGS:Aspergillus terreus (Seq: 29), Klebsiella pneumoniae (Seq: 230), HSV-1 (Seq: 39), CMV (Seq: 421) Hb: 89 g/L, Total Bilirubin: 346.3μmol/L, APTT: 48.60 s, TT: 33.50 s, FIB: 4.20 g/L	Echocardiogram: Left ventricular end-diastolic diameter: 44 mm, Inferior vena cava: 18 mm, TAPSE: 23 mm, Right atrium/ventricle: 33 × 47 mm/38 × 42 mm, VTI: 11 cm, EF: 38 %.
Day 11	Meropenem 1 g, Vancomycin 750 mg, Isavuconazole 200 mg, Hydrocortisone 50 mg, Vitamin C 1.5 g, Noradrenaline 30 mg, Human Albumin 60 g, Human Immunoglobulin 100 ml	NGS: Aspergillus terreus(Seq: 55), Klebsiella pneumoniae (Seq: 18), HSV-1 (Seq: 273), CMV (Seq: 890) Hb: 92 g/L, Total Bilirubin: 262.9μmol/L, CRP: 10.00 μg/ml, PCT: 8.83 ng/ml	Echocardiogram: Left ventricular end-diastolic diameter: 46 mm, Inferior vena cava: 21 mm, TAPSE: 16 mm, Right atrium/ventricle: 34 × 43 mm/31 × 52 mm, VTI: 11.1 cm, Mitral valve mild to moderate regurgitation, EF: 45 %.
Day 21	Cefoperazone-avibactam 1.25 g, Tigecycline 100 mg, Isavuconazole 200 mg, Amphotericin B 480 mg, Ganciclovir 0.4 g, Immunoglobulin 100 ml, Human Albumin 300 ml	NGS: Aspergillus terreus (Seq: 19928), HSV-1 (Seq: 18116), CMV (Seq: 53490), EBV (Seq: 204), HHV−6B (Seq: 132) Hb: 81 g/L, WBC: 19.44 × 10^9/L, Total Bilirubin: 82.3μmol/L, CRP: 119.47 μg/ml, PCT: 20.02 ng/ml, IF-6: 2109.8 pg/ml Serum galactomannan assay:negative

Hb:Hemoglobin.

RBC:Red Blood Cell.

APTT:Activated Partial Thromboplastin Time.

PT: Prothrombin Time.

TT: Thrombin Time.

FIB: Fibrinogen.

WBC: White Blood Cell.

PCT: Procalcitonin.

NGS: Next-Generation Sequencing.

CMV: Cytomegalovirus.

HSV-1: Herpes Simplex Virus Type 1.

CRP: C-Reactive Protein.

IF-6: Interleukin-6 (commonly abbreviated as IL-6).

PTA: Plasma Thromboplastin Antecedent.

Discussion

Aspergillus terreus is an opportunistic fungal pathogen that has garnered increasing attention due to its highly invasive behavior in immunocompromised individuals. This species is widely distributed, particularly in humid and tropical regions such as India, Southeast Asia, and South America [11]. Notably, A. terreus has emerged as a significant cause of opportunistic infections (OIs), characterized by lower treatment response rates and higher mortality compared to infections caused by non-terreus Aspergillus species, largely attributable to its intrinsic resistance to amphotericin B [12].

In this case, the patient presented with acute myocardial infarction complicated by multi-organ dysfunction, and started on corticosteroid therapy, likely creating an immunosuppressive milieu conducive to opportunistic infections such as that caused by A. terreus. Although the initial NGS of blood samples revealed a low read count for A. terreus, the progressive increase in its detection over time may reflect both the deteriorating immune status and the advancing infectious process. Corticosteroids, while essential for managing inflammatory and organ dysfunction syndromes, may inadvertently facilitate fungal proliferation by dampening host immune responses.

The diagnosis of invasive aspergillosis remains inherently challenging. Conventional fungal blood cultures are hampered by low sensitivity—reported at only 10–30 %—and prolonged turnaround times [13]. In this case, the initial failure to isolate Aspergillus terreus may be attributable to a low fungal load and the inherent difficulty of culturing atypical fungi using conventional methods. Additionally, early blood draws may not have contained adequate fungal DNA, increasing the likelihood of false-negative results. The application of NGS proved instrumental in the early detection of multiple pathogens, including A. terreus, Klebsiella pneumoniae, HSV-1, and CMV from peripheral blood. Nonetheless, NGS carries important limitations:

• •It may detect nucleic acids from non-viable organisms or environmental contaminants.
• •It does not reliably distinguish between colonization and true invasive infection.
• •It does not provide antifungal susceptibility profiles, necessitating integration with clinical, radiological, and histopathological findings for accurate interpretation [14].

Therefore, while NGS significantly contributed to early pathogen identification in this immunocompromised host, the absence of confirmatory histopathology and culture-based diagnostics for Aspergillus remains a significant limitation. A multidisciplinary diagnostic approach—including tissue sampling when feasible—remains essential to confirm invasive fungal disease and guide appropriate antifungal therapy.

According to the 2016 Infectious Diseases Society of America (IDSA) Guidelines for the Treatment of Invasive Aspergillosis, voriconazole is the recommended first-line agent due to its established efficacy in treating Aspergillus species infections [15]. In alignment with this guidance, voriconazole was promptly initiated upon clinical suspicion of invasive aspergillosis.

However, despite early empirical therapy, fungal DNA was detected via next-generation sequencing (NGS) on Day 7 (Table 1). The delay in transitioning to isavuconazole until Day 9 reflected a cautious interpretation of early molecular data: the fungal sequence reads were initially low, and conventional mycological diagnostics (e.g., blood cultures, serum galactomannan) remained negative at that time. Given the current limitations in quantitative NGS interpretation and absence of consensus thresholds for initiating treatment based solely on sequencing results, antifungal escalation was deferred pending further clinical corroboration.

Isavuconazole was selected on Day 9 following a pattern of worsening hepatic transaminases, as it offers a more favorable hepatic safety profile than voriconazole [16]. This decision followed IDSA-recommended principles for antifungal stewardship, which emphasize individualized adjustment based on drug toxicity and treatment tolerance.

Further escalation to liposomal amphotericin B on Day 21 was prompted by progressive clinical deterioration and radiographic worsening despite triazole therapy. While A. terreus is intrinsically resistant to amphotericin B, its introduction reflected a salvage therapeutic approach in a setting of refractory infection and rising fungal burden, compounded by limited remaining options. Such use is acknowledged in expert consensus guidelines as a potential recourse in life-threatening, treatment-refractory cases, especially when susceptibility testing is not rapidly available [10].

The stepwise escalation strategy—initial voriconazole, followed by isavuconazole and ultimately amphotericin B—was thus guided by a combination of IDSA recommendations, evolving clinical parameters, toxicity profiles, and diagnostic limitations of early NGS-based fungal detection.

Additionally, while NGS enabled early detection, the absence of supportive culture or biomarker evidence led to initial underestimation of clinical significance. This highlights a key challenge in fungal diagnostics: distinguishing true invasive infection from colonization or transient DNAemia in immunocompromised hosts. Therefore, treatment decisions remained conservative until corroborated by clinical and radiographic progression.

A bacterial–fungal coinfection was identified on Day 7, with K. pneumoniae and A. terreus isolated concurrently. The strain of K. pneumoniae was considered susceptible to piperacillin–tazobactam based on genotypic analysis of mNGS data, which revealed no detectable β-lactamase resistance genes. Prompt administration of the antibiotic led to microbiological clearance by Day 11.Despite this, inflammatory markers (CRP, PCT) remained elevated, likely indicating ongoing fungal infection. The presence of bacterial coinfection likely contributed to the patient’s initial clinical deterioration and underscores the importance of early recognition and targeted management of mixed infections in critically ill individuals.

Reactivation of HSV-1 and CMV during the ICU course reflected underlying immune suppression and physiological stress, both frequently observed in critically ill patients. These viral reactivations may contribute to systemic inflammation and complicate clinical assessment, thereby necessitating the initiation of antiviral therapy [17]. The rebound in CRP and PCT levels by Day 21, following initial improvement, raised concerns for treatment failure or a new infectious process. However, in light of the persistent detection of A. terreus and the patient’s overall clinical context, this was interpreted as ongoing invasive fungal infection despite partial bacterial resolution, justifying the continuation of antifungal therapy.

Post-typhoon environmental conditions have been increasingly recognized as a contributing factor to the risk of invasive fungal infections. Several studies have reported that natural disasters such as hurricanes and floods can lead to significant elevations in environmental mold levels, thereby heightening the risk of both respiratory and cutaneous fungal infections among exposed populations. For example, following Hurricane Katrina, elevated indoor mold concentrations were associated with increased reports of fungal-related illnesses in New Orleans residents [18]. More recently, a study conducted in the aftermath of Hurricane Harvey (2017) identified a higher risk of invasive mold infections among immunocompromised individuals participating in post-flood cleanup activities due to exposure to mold-contaminated environments [19], [20]. In addition, occupational exposure—particularly in construction, agriculture, and disaster recovery work—has been independently associated with increased incidences of invasive fungal infections, including those caused by Aspergillus species [21].

In the present case, the patient’s involvement in post-typhoon electrical repair work likely increased his exposure to airborne fungal spores in a water-damaged environment, predisposing him to A. terreus infection. This observation is consistent with current evidence linking post-disaster environmental exposures to an elevated risk of opportunistic fungal infections, particularly in individuals engaged in high-risk occupational activities in affected areas.

Conclusion

This case highlights the diagnostic and therapeutic challenges posed by Aspergillus terreus infections in critically ill patients following myocardial infarction. Early application of molecular diagnostic tools, such as NGS, facilitated timely pathogen identification, though limitations in confirming true invasive disease persisted.

Coinfection with Klebsiella pneumoniae and viral reactivations (HSV-1, CMV) further complicated the clinical course, emphasizing the need for comprehensive infection surveillance and multidisciplinary management in the ICU setting.

Given the intrinsic resistance of Aspergillus terreus to amphotericin B, antifungal therapy was carefully individualized based on the evolving clinical course and the absence of culture-based susceptibility data. Although the 2016 IDSA guidelines advise against the use of amphotericin B in confirmed A. terreus infections, liposomal amphotericin B was introduced as salvage therapy in light of persistent fungal burden, radiographic progression, and clinical deterioration. Notably, the 2021 ECIL-6 guidelines state that liposomal amphotericin B may be considered as an alternative treatment in patients with invasive aspergillosis who fail or cannot tolerate mould-active azoles (moderate recommendation, level II evidence). Treatment escalation may have contributed to temporary stabilization, although definitive infection control could not be confirmed in the absence of microbiological or radiologic resolution.

Environmental factors, such as post-typhoon exposure, may contribute to fungal infection risk and should be considered when assessing patient histories. Further research is warranted to optimize diagnostic algorithms, antifungal stewardship, and integrated management protocols for invasive fungal and bacterial coinfections in critically ill populations.

CRediT authorship contribution statement

Hang Yu: Writing – original draft, Data analysis. Zhi-Kun Luo: Data curation, Resources. Ting-Ting Lu: Investigation, Data collection. Yue Deng: Methodology, Statistical analysis. Jia-Ni Xia: Conceptualization, Study design. Wan-Yue Li: Supervision, Project administration. Jing-Hao Li: Funding acquisition, Review & editing.

Ethical Statement

This case report was conducted in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Ethical approval was waived for this study, as it involved a single case report without experimental intervention. Written informed consent was obtained from the patient's legal guardian for the publication of this case report and any related images.

Funding

This work was supported by the National Natural Science Foundation of China [Grant No. 82360386]; the National Key Clinical Specialty Discipline Construction Program of China [Grant no. 46000022T000000640013]; and the Hainan Province Graduate Student Innovation Research Project [Grant Nos. Qhys2024-475 and Qhys2024-444]. The funding bodies had no role in the design of the study, data collection and analysis, interpretation of results, writing of the manuscript, or the decision to submit the article for publication.

Declaration of Competing Interest

The authors declare no competing financial or personal interests that could have influenced the content or outcomes of this work.