Antimicrobial Resistance in Immunocompromised Outpatients: A Narrative Review of Current Evidence and Challenges

Abstract

Immunocompromised outpatients, including people living with HIV/AIDS (PLWH), diabetes, cancer, and organ transplant recipients, are at high risk of antimicrobial resistance (AMR) due to their weakened immune systems and use of immunosuppressive therapies. The high prevalence of prophylactic and therapeutic antibiotic use in this vulnerable population, coupled with frequent contact with healthcare facilities and limited outpatient antimicrobial resistance surveillance systems, contributes to the increase in antimicrobial resistance. The majority of available data pertains to inpatients, and there is a lack of comprehensive outpatient information on pathogen distribution, resistance patterns, and diagnostic challenges. Moreover, nonspecific clinical presentations, diminished inflammatory responses, and limitations of traditional diagnostic methods complicate infection diagnosis in this population. Increasing resistance surveillance, developing rapid diagnostic tools, and implementing accurate and personalized approaches are key strategies to reduce the burden of disease, mortality, and healthcare costs in the immunocompromised outpatient population. This study was designed as a narrative review based on a comprehensive search of major databases and guidelines. It aims to examine the available evidence and address the challenges associated with AMR in immunocompromised outpatients.

1. Introduction

Immunocompromised status, defined by a weakened immune system, severely impairs the ability to combat infections, posing significant risks to people living with HIV/AIDS (PLWH) [1], diabetes [2], febrile neutropenia [3,4], solid organ transplantation (SOT) [5], or hematopoietic stem cell transplantation (HSCT) [6]. Treatments such as chemotherapy, immunosuppressive medications, and organ transplantation exacerbate this vulnerability [7,8]. Diagnosing and treating infections in these patients is significantly more challenging than in individuals with healthy immune systems. In outpatient settings, inadequate medical oversight heightens the risk of serious infections, making treatment even more difficult [9].

Antimicrobial resistance (AMR) is a major global health threat, with the World Health Organization (WHO) prioritizing pathogens based on mortality, transmissibility, treatability, and preventability [10]. The 2021 global burden of disease (GBD) study reports 4.71 million AMR-associated deaths, including 1.14 million directly caused by resistant infections. Low- and middle-income countries bear the most significant burden due to antimicrobial overuse, limited outpatient antimicrobial resistance surveillance systems, and limited diagnostic capabilities. From 1990 to 2021, AMR deaths in children under five declined by over 50% but increased by over 80% in adults over 70. Projections estimate 8.22 million associated deaths by 2050, especially in South Asia and Latin America [11]. Immunocompromised outpatients face an increased risk of AMR due to their frequent use of antimicrobials, which promotes resistance, and their greater exposure to resistant pathogens in community settings. The prevalence rates of resistant pathogens among cancer patients range from 1.5% for carbapenem-resistant pathogens to 53% for methicillin-resistant Staphylococcus aureus. Additionally, the nasal carriage rate of Staphylococcus aureus is 25% in PLWH, with 60% of these cases being multidrug-resistant (MDR) [12,13].

Although AMR has declined in the general pediatric population, some subgroups remain at high risk. Immunocompromised children—especially those with hematologic malignancies or undergoing stem cell or organ transplantation—are highly vulnerable due to prolonged antibiotic exposure, neutropenia, and repeated hospital contact. In onco-hematology settings, resistant Gram-negative infections such as carbapenem-resistant Klebsiella pneumoniae are associated with high mortality. Targeted antimicrobial stewardship programs have demonstrated clear benefits in these patients, underscoring the need for stronger AMR monitoring and control strategies in pediatric oncology and hematology [14,15,16].

AMR in immunocompromised outpatients is clinically significant; however, it has been insufficiently investigated in the literature. Most existing research focuses on inpatient environments because outpatient settings often lack the systematic monitoring infrastructure found in hospitals. This leads to inconsistent or incomplete microbiological testing and reporting. Additionally, these patients may experience irregular follow-ups and inconsistent healthcare access, with diagnostic sampling often being infrequent and primarily limited to clinical episodes rather than routine screening, which complicates monitoring efforts [17,18,19]. Moreover, differences in immunocompromising diseases and antibiotic exposure patterns complicate data collection and interpretation, leading to a considerable deficiency in comprehending the dynamics of resistance, infection outcomes, and appropriate stewardship interventions for community-managed immunocompromised patients [18].

The present study was structured as a narrative review, based on a comprehensive search of principal databases (PubMed, Scopus, Web of Science) and authoritative guidelines. All relevant study types related to AMR in immunocompromised outpatients were considered up to 2025 to provide a comprehensive and interpretative summary. This review aims to synthesize existing evidence about AMR in immunocompromised outpatients and identify priorities for research and treatments, focusing on epidemiology, key pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), extended-spectrum β-lactamase (ESBL), carbapenem-resistant Enterobacteriaceae (CRE), and vancomycin-resistant Enterococci (VRE), as well as surveillance trends since 2019, including the impact of COVID-19, diagnostic and therapeutic challenges, evaluates infection prevention and antibiotic stewardship strategies, and identifies gaps, including insufficient outpatient data and the need for point-of-care diagnostics.

2. Immunocompromised Outpatients—A High-Risk Population

The immune system is divided into two categories: (1) the innate immune system, which includes the skin, mucosal barriers, the complement system, and cellular components that can heighten the risk of bacterial infection if weakened; and (2) the adaptive immune system, which encompasses humoral immunity (primarily driven by B-cells) and cell-mediated immunity (T-cells), increasing the risk of infections from viral, fungal, and intracellular bacterial pathogens when suppressed [20]. Immunocompromised individuals comprise a diverse group of patients with increased vulnerability to prolonged infectious episode periods due to medications and treatments (e.g., chemotherapy agents, radiation, organ or stem cell transplantations, corticosteroids, and immunosuppressants), human immunodeficiency virus (HIV) infection, malignancies, and malnutrition. The impaired immune system function results in alterations in the duration, frequency, presentation, and severity of infections, with atypical and opportunistic manifestations noted. Although most pathogens in this group are community-acquired, their frequent exposure to various pathogens and the delay in infection detection and treatment initiation due to less monitoring compared to inpatient individuals complicate the infection’s course in this population [21].

2.1. Types of Immunodeficiency and Representative Outpatient Groups

Inborn errors of immunity, also referred to as primary immunodeficiency disorders (PID), are a heterogeneous group of disorders that exceed 450 due to genetic mutations and account for approximately six million cases globally [22]. These disorders are classified into eight distinct categories, including syndromic combined immunodeficiencies, cellular and humoral immunodeficiencies, antibody deficiencies, immune deregulatory diseases, phagocytic diseases, innate immunodeficiencies, autoinflammatory diseases, complement deficiencies, bone marrow failure-related disorders, and phenocopies of PIDs [22].

Contrary to PIDs, secondary immunodeficiency disorders (SIDs) refer to acquired immune system impairments due to malignancies, infections, and specific treatments, including medications and surgical treatments (splenectomy and thymectomy) [20,23]. Oral corticosteroids, indicated in various disorders, inhibit the synthesis of nuclear factor kappa B (NF-κβ) and activator protein-1 and decrease the expression of inflammatory mediators, resulting in reduced pro-inflammatory cytokines. Additionally, they reduce the peripheral function of leukocytes and decrease neutrophil adherence to the vascular endothelium, resulting in dose-dependent immunosuppression [24]. Antimetabolites, which are used to treat various cancers and certain autoimmune disorders, exert their immunosuppressive properties by interfering with nucleic acid synthesis. This chemical interference results in impaired DNA replication and subsequently suppresses the proliferation of immune cells [24]. Another group of immunosuppressive agents consists of calcineurin inhibitors, which bind to immunophilin and inhibit calcineurin, an enzyme essential for T-cell activation. This inhibition results in reduced production of cytokines necessary for T-cell replication, making these inhibitors suitable for treating T-cell-mediated autoimmune disorders and preventing solid organ transplant (SOT) rejection [24]. Similarly, mammalian target of rapamycin (mTOR) inhibitors is used as antirejection treatment options in those undergoing SOTs due to their negative impact on T-cell proliferation and dendritic cell function [24]. Antithymocyte globulins (ATG) are another immunosuppressant agent that induces a profound cluster of differentiation 4 (CD4+) T-cell depletion by increasing T-cell apoptosis and impairing T-cell function [24]. Additionally, anti-CD20 monoclonal antibody agents, including rituximab, induce cytotoxicity, resulting in peripheral B-cell depletion [24].

Malnutrition suppresses the immune system through similar mechanisms, including a decrease in the CD4+ T-cell population, shrinkage of primary lymphoid organs, an increased pro-inflammatory state, disruption of gut microbiota, and increased oxidative stress [25]. Infections, such as sepsis, also contribute to immunosuppression by increasing the production of anti-inflammatory cytokines like interleukin-4 (IL-4), IL-10, and IL-37; causing immunocyte apoptosis and pyroptosis; reducing HLA-DR expression, which decreases the activation of adaptive immune system components; and increasing the expression of immune checkpoints that lead to T-cell exhaustion, ultimately resulting in immunosuppression [26].

Acquired immunodeficiency syndrome (AIDS) is a significant global public health issue that accounted for 39 million cases in 2022 and is caused by human immunodeficiency virus-1 (HIV-1) and HIV-2. The primary viral targets for these pathogens are CD4+ T-cells and macrophages; upon entry into the host cells, viral replication occurs along with the destruction of CD4+ T-cells. If left untreated, this infection can progress to AIDS, which is the advanced form of HIV infection [23]. In addition to all the above, malignancies or their therapeutic interventions can result in reduced immunity, possibly due to immunosuppressive molecule secretion by the tumoral tissue, including IL-10 and transforming growth factor-β, direct suppression of natural killer cells and cytotoxic T-cells, and involvement of chemotherapy, radiation, and other treatment options [20,23].

2.2. Antimicrobial Use Patterns in Immunocompromised Outpatients

Most recently, one study conducted on oncologic outpatients in the USA reported higher prevalence of resistant Pseudomonas aeruginosa (two times higher compared to controls), fluoroquinolone- and carbapenem-resistant Enterobacteriaceae, vancomycin-resistant enterococci (VRE) (three times higher than healthy controls), methicillin-resistant Staphylococcus aureus (MRSA), fluoroquinolone- and carbapenem-resistant Acinetobacter baumannii species and in total, higher occurrence of AMR pathogens in cancer outpatients compared to controls, similar to another study’s findings, where 54% of cancer outpatients with urinary tract infections were infected with at least one MDR species, possibly due to high rates of prophylactic antimicrobial administration in this population [12,27]. Similarly to cancer patients, opportunistic infections (OIs) in PLWH outpatient impose significant morbidity, as one study noted the OI prevalence rates of 39.5%, including tuberculosis (TB), oral candidiasis, herpes zoster, and bacterial pneumonia, with heightened risk in those with lower CD4+ counts [28]. Furthermore, studies have reported high rates of antimicrobial agent prescription (60%), including sulfonamides and co-trimoxazole, in this population [29].

Infections following SOTs, commonly caused by MRSA, VRE, ESBL Enterobacteriaceae, and MDR and XDR Gram-negative pathogens, impose significant mortality and morbidity, with death rates ranging from 21% to 63.1% [20]. Additionally, different periods post-transplant led to different infection types, with bacterial pathogens causing the majority of infections in the first month following transplantation [30]. During the 1–6 months post-transplantation, which is considered the peak immunosuppression period, both bacterial and viral pathogens are responsible, including Mycobacteria, Nocardia spp., Listeria monocytogenes, Salmonella spp., Campylobacter spp., atypical respiratory pathogens, cytomegalovirus, Epstein–Barr virus (EBV), human herpesvirus (HHV) 6, 7, and 8, herpes simplex virus (HSV), varicella-zoster virus (VZV), hepatitis viruses, respiratory viruses (respiratory syncytial virus (RSV), influenza, parainfluenza, etc.), polyomavirus, and papillomavirus [30]. During the late period (6–12 months post-transplantation), bacterial pathogens remain the most common microorganisms responsible for infections. However, viral and fungal pathogens are less commonly isolated than in previous periods [30]. Commonly administered antibiotics in SOT recipients vary between different individuals. Cefazolin is most widely prescribed for prophylactic purposes. Additionally, vancomycin is preferred for those colonized with MRSA, and broad-spectrum antibiotics are used in liver and lung transplant recipients in cases of MDR colonization [31].

Drug-induced immunosuppression puts individuals at higher risk of viral, bacterial, and fungal pathogens, differing between different immunosuppressive agents [20]. Glucocorticoids act in a dose-dependent manner, and a higher prevalence of opportunistic infections, including TB, Pneumocystis jirovecii, and strongyloides hyperinfection syndrome (SHS), has been recorded in these patients, similar to antimetabolites, which increase the risk of TB and P. jirovecii [32]. Moreover, a higher frequency of TB, herpes zoster, and hepatitis B virus (HBV) is reported in calcineurin inhibitor and mTOR recipients [32]. Although prophylactic administration of antimicrobials is often recommended, a significant literature gap lies in the antimicrobial’s prescription pattern in therapeutic agents-induced immunosuppressed individuals. Moreover, one recent study proposed nirmatrelvir/ritonavir as a promising treatment option for COVID-19 in these individuals [32,33].

3. Antimicrobial-Resistant Pathogens in Immunocompromised Outpatients

The global burden of diseases revealed that Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Streptococcus pneumoniae, Staphylococcus aureus, and Escherichia coli account for 73% of deaths associated with AMR [34].

Antimicrobial resistance can be categorized into three priority classes based on clinical importance and level of resistance [35]:

• Critical priority: Includes third-generation cephalosporin-resistant Enterobacterales, carbapenem-resistant Acinetobacter baumannii, and carbapenem-resistant Enterobacterales (CRE).
• High priority: Includes Shigella spp., non-typhoidal Salmonella and fluoroquinolone-resistant Salmonella Typhi, methicillin-resistant Staphylococcus aureus (MRSA), carbapenem-resistant Pseudomonas aeruginosa, and vancomycin-resistant Enterococcus faecium (VRE).
• Medium priority: Comprises ampicillin-resistant Haemophilus influenzae and macrolide-resistant Streptococcus pneumoniae.

Here, we review the most common bacterial pathogens associated with antimicrobial resistance, which include the following:

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Methicillin-resistant Staphylococcus aureus (MRSA): MRSA has resistance to one or more of the antibiotics, including cefoxitin, methicillin, and oxacillin. There can be asymptomatic proliferation of MRSA in the nose or skin or low-level infection of soft tissues. However, an intensive and sudden infection of the endocardium, blood, and surgical wound is possible. There is an assessment of 323,700 cases of infection and 10,600 cases of death attributable to MRSA among inpatients in the U.S. annually [36].

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Drug-resistant, non-typhoidal Salmonella (NTS): Consuming polluted food or coming into contact with contaminated feces can transmit non-typhoidal Salmonella, leading to diarrhea, often accompanied by dysentery, fever, and abdominal cramps, with a significant risk of developing septic shock. Estimates suggest that non-typhoidal Salmonella causes 1.35 million cases and 420 related deaths annually in the U.S. Antimicrobial agents are responsible for 212,500 infection cases and 70 deaths [37].

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Drug-resistant Salmonella typhi: Annually, there are an estimated eleven to twenty-one million cases of Salmonella typhi globally; approximately 5700 cases occur in the U.S., with 4100 exhibiting AMR, resulting in five or fewer fatalities each year. Salmonella typhi causes typhoid fever, which becomes more severe in the presence of headache, abdominal pain, and elevated fever. Severe infections sometimes lead to intestinal perforation, resulting in shock and mortality [38].

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Multidrug-resistant Pseudomonas aeruginosa: Multidrug-resistant Pseudomonas aeruginosa, characterized by resistance to at least three classes of antimicrobial agents such as tazobactam/penicillin, carbapenems, aminoglycosides, fluoroquinolones, and extended-spectrum cephalosporins, is linked to infections arising from medical treatment, including pneumonia, surgical site infections (SSIs), urinary tract infections (UTIs), and bloodstream infections (BSIs). This pathogen predominantly affects immunocompromised or hospitalized patients and individuals with chronic lung disease, resulting in an estimated 32,600 infections and 2700 deaths among inpatients in the U.S. annually [36].

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Vancomycin-resistant Enterococci (VRE): Severe infections in the UTIs, SSIs, BSIs, and so on arise from Gram-positive bacteria named enterococci. VRE causes nearly a third of these healthcare-related infections [39]. It is estimated that 54 thousand infections and 5400 deaths are associated with VRE acquisition in patients hospitalized in the U.S. annually. Enterococcus faecium and Enterococcus faecalis are the two most prevalent types of Enterococci; the former is more likely to be resistant to vancomycin. Prolonged residence in health centers, receiving care for cancer, having gained an organ graft, and being accepted to an Intensive Care Unit (ICU) are among the risk factors for contracting VRE-related infections [40].

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Carbapenem-resistant Enterobacteriaceae (CRE): The CRE is considered a significant global concern as a cause of infections in about 13,100 patients and nearly 1100 cases of death in U.S. hospitals annually [36].

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Carbapenem-resistant Acinetobacter spp. (CRAB): Antimicrobial resistance-generating genes in many Acinetobacter strains produce carbapenemase enzymes, making them resistant to sulfamethoxazole/trimethoprim, ampicillin/sulbactam, ESBL, and fluoroquinolones. Nearly all CRAB-related infections (urinary tract, wound, bloodstream, and pneumonia) occur in hospitalized patients, especially in critical care [41].

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Multi-drug-resistant Neisseria gonorrhoeae: Approximately 550 thousand out of 1.14 million new Neisseria gonorrhoeae infections are AMR annually [36].

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Extended Spectrum β-lactamase producing Enterobacteriaceae (ESBL): ESBLs are defined as enzymes that break down β-lactams, comprising cephalosporin and penicillin. Each year, approximately 197,400 infections and 9100 deaths occur among patients hospitalized in the U.S. due to ESBL-producing bacteria [42], primarily leading to urinary tract infections as well as wound, bloodstream, and respiratory tract infections [43].

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Multi-drug-resistant Shigella: Shigellosis, characterized by abdominal pain, fever, and diarrhea, occurs due to Shigella, which predominantly spreads through orofecal contact with contaminated food or surfaces. Studies from the US estimate 450,000 Shigella infections, 77,000 of which are AMR, and fewer than five deaths each year. Immunocompromised individuals, travelers, children, and homosexual men are more susceptible to infection [44].

Resistance to antifungal agents—including caspofungin, amphotericin, and fluconazole—has been reported in Aspergillus, Cryptococcus, and Candida species [45], especially for patients with compromised immunity. Worldwide, about 500,000 people are afflicted by candidiasis with a rate of mortality of 45–75% per year [46]. Parasites, including helminths and protozoa, are showing increased resistance to antiparasitic agents due to several factors: prolonged treatment, noncompliance with the prescribed duration or dosage of medications, issues with antiparasitic agent absorption, antiparasitic agent interactions, poor antiparasitic agent quality, misdiagnosis, and mutations in parasite genes [47]. Regarding antiviral resistance, the WHO estimates approximately 1 billion human influenza cases annually, of which 3–5% are considered severe, particularly affecting immunocompromised individuals, the elderly, and children, resulting in 290,000 to 650,000 deaths each year. Immunocompromised patients face an increased risk of antiviral resistance, primarily associated with A (H1N1) pdm09 influenza and less commonly with A (H3N2) and B influenza [48].

3.1. Antimicrobial Resistance Surveillance and Emerging Trends Post-COVID-19

The COVID-19 pandemic has increased antimicrobial resistance due to the widespread use of antibacterial, antiparasitic, and antiviral agents, as well as anti-inflammatory treatments in coronavirus patients, aimed at preventing further infections [49]. During the COVID-19 period, there have been reports of outbreaks of MRSA in the bloodstream, Candida, Acinetobacter resistant to antibiotics, and aspergillosis [50]. Furthermore, due to increased AMR during the COVID-19 pandemic, New Delhi carbapenemase-resistant metallo-β-lactamase-producing Enterobacterales infection in patients with COVID-19 was complicated and more prolonged [51]. Additionally, mucor mycosis appears to be among the primary complications of the remedy for COVID-19 treatment, primarily due to the shift in steroid treatment, dysglycemic condition, and defect in the immune system [52]. Recent studies have shown that secondary bacterial co-infections and superinfections with multidrug-resistant organisms—such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Enterococcus species—can complicate the course of COVID-19 and contribute to severe outcomes [53,54,55]. Overall, AMR during the period of COVID-19 was high; the most prevalent antibiotic-resistant agent among Gram-negative and Gram-positive bacteria was Acinetobacter baumanii, with Escherichia coli and Staphylococcus aureus in second rank, respectively [56].

3.2. Factors Driving Antimicrobial Resistance in Immunocompromised Outpatients

Factors such as frequent interactions with healthcare facilities, long-term prophylactic use of antimicrobial agents, and invasive medical procedures contribute to the proliferation of AMR in immunocompromised individuals, including patients with diabetes, organ transplants, cancer, ICU admissions, and HIV/AIDS. MDR bacteria, particularly Gram-negative bacilli, are more prevalent in these patients and tend to be more virulent and treatment-resistant [57]. This process is mainly due to impaired innate immunity and disruption of the normal intestinal flora, which allows Gram-negative bacteria to dominate and invade the bloodstream, especially in cases of neutropenia or gastrointestinal tract injury [58]. Moreover, in patients with immunosuppression, a genetic mutation in VRE is associated with dietary sorbitol or laxatives used during chemotherapy [59]. In addition, intestinal microbiota can be a reservoir of resistance-inducing genes and promote antimicrobial resistance even without antibiotic use [60]. Metabolic factors further increase susceptibility to AMR in immunocompromised patients. For example, in type 2 diabetes mellitus, obesity may act as a risk factor due to adipose tissue–derived inflammatory and pro-inflammatory substances. Additionally, suboptimal antibiotic concentrations in these patients can hinder the eradication of harmful pathogens [61].

3.3. Antimicrobial Stewardship in Immunocompromised Outpatients

Antimicrobial resistance is a global issue influenced by various factors, including environmental, economic, clinical, sociopolitical, and biological influences. It affects human health, animal populations, and ecosystems (One-health). Key contributors include human vulnerability, microbial evolution, demographic shifts, inadequate environmental management, technological advancements, international movement, weakening public health infrastructure, social disparities, and political commitment. Antibiotic stewardship involves healthcare professionals prescribing antibiotics responsibly, choosing appropriate ones, administering them correctly, and maintaining treatment duration to minimize resistance risks [62,63].

Antimicrobial stewardship programs (ASPs) are essential for immunocompromised patients, particularly in outpatient settings, as this population is susceptible to severe and complex infections due to immunodeficiency. The inappropriate use of antibiotics in these groups might result in AMR, adverse effects, and heightened healthcare costs. Designing targeted stewardship measures for immunocompromised individuals enhances clinical outcomes and promotes responsible antibiotic use [64].

In outpatient settings, where many patients receive care after organ transplantation or chemotherapy, implementing these programs is crucial for reducing unnecessary antibiotic prescriptions [31]. Practical guidelines for healthcare providers suggest that educating physicians, monitoring prescribing behaviors, and adapting protocols to the special needs of immunocompromised patients may significantly impact the prevention of AMR. Consequently, antimicrobial stewardship in immunocompromised patients is a crucial strategy to ensure effective and sustainable therapy for this at-risk population [65].

4. Diagnostic Challenges of Infections in Immunocompromised Outpatients

Diagnosing infectious diseases in immunocompromised outpatients is particularly difficult. These patients often exhibit vague, atypical, or nonspecific symptoms that diverge from the classical inflammatory signs seen in immunocompetent individuals [66,67,68,69]. For example, fever may be the only manifestation, and in neutropenic patients, a blunted inflammatory response can obscure clinical indicators, as standard biomarkers such as C-reactive protein (CRP) and procalcitonin often lack sufficient sensitivity, particularly when their levels are affected by immunosuppressive therapies. This limitation reduces their reliability in distinguishing infections [70,71]. Moreover, common noninfectious conditions in this population, including tumor lysis syndrome, cytarabine toxicity, and hemophagocytic lymphohistiocytosis, can mimic infectious presentations, further complicating clinical assessment; in cases of pneumonia, radiographic evidence becomes indispensable in the absence of overt clinical signs, and differentiating Clostridioides difficile infection from chemotherapy-induced diarrhea remains problematic [72]. These challenges are further intensified by the wide range of pathogens encountered, from common to opportunistic microorganisms. The prevalence of MDR organisms—such as MRSA, VRE, ESBL-producing, and carbapenemase-producing Gram-negative bacteria—is increasing. Infections like carbapenem-resistant Klebsiella pneumoniae pose a significant risk, with mortality rates nearing 60% in high-risk groups [20,73,74,75].

Moreover, the rapid progression of infections, where patients who initially appear stable can precipitously deteriorate into severe conditions requiring intensive care, often due to acute hypoxemic respiratory failure, illustrates the importance of prompt and precise diagnostic interventions, as delays are directly correlated with increased mortality [76,77,78].

A range of limitations hinders the use of traditional diagnostic methods for infectious diseases in immunocompromised patients. Culture-based techniques, despite being a diagnostic cornerstone, exhibit long turnaround times—preliminary identification requires 12–24 h, with susceptibility testing demanding even greater delays—and consequently necessitate empiric antimicrobial therapy that may suppress pathogen growth, resulting in false-negative outcomes [79]. Moreover, these methods confront challenges such as slow organism growth, the inability to culture fastidious pathogens like Pneumocystis jirovecii, and the difficulty of detecting intracellular organisms such as Bartonella quintana, which requires specialized processing techniques yet yields remain low [80]; the sensitivity for common pathogens, as seen in bacterial pneumonia, is similarly variable, compounded by the challenge of differentiating small colonization from true infection [79]. Serological assays become unreliable in immunocompromised individuals due to weakened or delayed antibody responses, reducing their effectiveness, with immunosuppressive therapies contributing both to false negatives—as exemplified by indirect immunofluorescent assays for Bartonella quintana and toxoplasmosis tests indicating only past exposure—and to false positives via donor-derived antibody transfer, all complicated further by limited specificity and cross-reactivity [79,80]. Biomarkers such as CRP and procalcitonin, while indicative of systemic inflammation, are non-specific since their levels may rise in various shock states or be suppressed by immunosuppressants, and although novel host RNA biosignatures show promise in distinguishing bacterial from viral infections, their validity in immunocompromised populations remains uncertain [66,68,70]. Additionally, radiological modalities, including chest X-rays and computed tomography, present interpretation difficulties due to non-specific findings, atypical clinical presentations that often lack classic inflammatory signs, and a broad differential diagnosis encompassing both infectious and non-infectious etiologies—factors that have led to the adoption of diagnostic frameworks such as the “DIRECT” mnemonic to enhance interpretative accuracy [70,77]. Additionally, non-invasive sampling methods, despite offering advantages in patient comfort and safety, are limited by low pathogen yields, the potential for identifying nonviable organisms or commensals that obscure true infection status, risks of contamination (notably in urine cultures), and a frequent lack of antimicrobial susceptibility data from nucleic acid assays even as emerging panels attempt to incorporate resistance gene profiles [81,82]. Polymerase chain reaction (PCR)-based assays and multiplex panels enable rapid detection of microbial nucleic acids yet are limited in immunocompromised patients by insufficient sensitivity, incomplete pathogen coverage—omitting organisms such as Nocardia and Stenotrophomonas—and an inability to differentiate viable from nonviable organisms, complicating clinical interpretation [79]. Moreover, these tests may detect genetic material from benign colonizers, necessitating careful correlation between clinicians and laboratories to differentiate true infection from mere carriage, while their reliance on predefined targets, lack of comprehensive antimicrobial susceptibility data, escalating costs, and gaps in clinician knowledge further constrain their utility [81]. In contrast, metagenomic next-generation sequencing (mNGS) provides a pathogen-agnostic approach capable of identifying a wide range of bacteria, viruses, fungi, and protozoa—beneficial for diagnosing rare or co-occurring opportunistic infections—but its extended turnaround times (sometimes averaging up to 52 h), high operational expenses, intensive bioinformatics requirements, and challenges distinguishing clinically significant pathogens from contaminants restrict its routine application to specialized centers [80,83].

Table 1. Key diagnostic challenges in immunocompromised outpatients.

Category	Diagnostic Challenges	Examples/Details	Ref.
Specimen Handling and Transport	Risk of contamination and compromised integrity	Elevated urine culture contamination despite refrigeration and clear instructions.	[82]
Invasive Procedures	Risks in critically ill patients	Fiberoptic bronchoscopy with BAL → hypoxemia, bleeding; trend toward non-invasive alternatives.	[77,79]
Guidelines and Evidence Gaps	Lack of standardized protocols; exclusion from trials	Heterogeneous immunocompromised groups inconsistent stewardship, few accepted guidelines.	[64,84]
Advanced Molecular Assays	High cost, limited availability, over-detection	mNGS confined to resource-rich settings; risk of identifying colonizers/nonviable organisms; over-testing → inappropriate antibiotics.	[85,86]
HIV/AIDS	Immune defects predispose to common + opportunistic pathogens	CD4+ T-cell depletion, B-cell/neutrophil dysfunction; MDR bacteria rising.	[67,72]
Transplant Recipients	Atypical infection presentation	HSCT: multifactorial diarrhea (infection vs. mucositis vs. GVHD); risk of MDR Pseudomonas.	[86,87]
Cancer Patients (especially hematologic)	Neutropenia masks signs, ↑ MDR infections	Risk for MRSA, VRE, ESBL-producing and carbapenemase-producing Gram-negatives.	[88,89]
Autoimmune/Inflammatory Conditions	Expanded pathogen spectrum due to therapies	TNFα inhibitors → fungal, herpesvirus infections; anti-CD20 drugs → encapsulated bacteria.	[70]
Diabetes Mellitus (as comorbidity)	Higher MDR and fungal risks	MDR Pseudomonas; mucormycosis complicating diagnosis.	[87]

BAL: Bronchoalveolar lavage, HSCT: Hematopoietic stem-cell transplant, GVHD: Graft-versus-host disease, MDR: Multidrug-resistant, MDRB: Multidrug-resistant bacteria, TNFα: Tumor necrosis factor alpha, mNGS: Metagenomic next-generation sequencing.

summarizes key diagnostic challenges across outpatient immunocompromised populations, including issues related to specimen handling, invasive procedures, guideline gaps, and population-specific vulnerabilities.

Operational Barriers to Optimal Antibiotic Selection in Immunocompromised Outpatients

Diagnostic, guideline, expert consultation, and operational challenges constrain the selection of antibacterials for immunocompromised outpatients. Atypical presentations and subtle clinical signs delay diagnosis of pneumonia, sepsis, and urinary tract infections (UTIs), with routine urine culture results frequently unavailable at the point of care [90]. The lack of tailored outpatient guidelines and robust clinical data contributes to low adherence to international standards and inappropriate prescribing—such as unnecessary antimicrobial agent use, extended treatment durations, and misuse of broad-spectrum agents—while outpatient stewardship programs remain underdeveloped [81,82]. Limited access to infectious disease (ID) consultation further compromises treatment; although ID-led stewardship in collaboration with pharmacists has reduced mortality and rehospitalization in solid organ transplant recipients [91] and is recommended for complex infections like Bartonella quintana [80], insufficient evidence regarding its impact on clinical cure rates forces clinicians to rely on informal consensus [90], despite Centers for Disease Control and Prevention (CDC) guidance supporting enhanced stewardship [92].

Operational challenges in antibacterial selection significantly obstruct their successful clinical application, impacting treatment efficacy and patient outcomes. Diagnostic tests are often underutilized when they do not align with existing workflows or meet immediate needs, while microbiology laboratories, lacking extensive automation, require simplified specimen collection and processing. The limited robust outcome data proving benefits in patient morbidity, mortality, or cost savings compared to empiric treatment further constrains the use of new diagnostics, and the inherent complexity in interpreting molecular results demands specialized expertise and close laboratory-clinical collaboration [66]. Additionally, outpatient antibiotic stewardship programs remain underdeveloped, with insufficient infrastructure and sporadic payer support [81], and labor-intensive interventions such as post-prescription culture reviews are impractical due to delays in obtaining culture results, compounded by prevailing provider fears of under-treating infections—particularly UTIs—which promote excessive antibiotic use and necessitate intensive communication to encourage prudent prescribing [82].

Key challenges related to antimicrobial resistance and antibiotic stewardship programs implementation in immunocompromised outpatients are summarized in

Table 2. Challenges related to antimicrobial resistance and implementation of antibiotic stewardship in immunocompromised outpatients.

Domain	Key Challenges	Examples/Evidence	Ref.
Antimicrobial resistance	High rate of inappropriate empirical antibiotic treatment (IEAT) due to urgent empiric use before pathogen ID	Pathogen identified in only ~50% of bacterial pneumonia cases; high IEAT in febrile neutropenia even under IDSA guidance.	[77,79]
	Limited effectiveness of empiric therapy in MDR infections	Only 23% of KPC + K. pneumoniae cases received adequate therapy vs. 74% in non-ESBL/KPC strains; <one third of MDR P. aeruginosa adequately treated; reluctance to use cefiderocol.	[87]
	Rising prevalence of MDROs among immunocompromised	CRE in 1–18% of transplant recipients; CRE bacteremia in 16–24% hematologic malignancies; 64% rise in community ESBL infections (2012–2017).	[64,82,87]
	Complex resistance mechanisms complicating therapy	P. aeruginosa OprD loss → carbapenem resistance; A. baumannii acquiring OXA carbapenemases + serine β-lactamases; widespread fosA gene in non-E. coli GNB.	[92]
	Diagnostic delays prolong broad-spectrum use	Cultures/AST 24–72 h; prescribers struggle to adjust despite rapid tests (MALDI-TOF, molecular).	[91]
	Limited new treatment options	A. baumannii carbapenem-resistant → pan-resistance risk; cautious use of cefiderocol; renewed interest in polymyxins, Fosfomycin.	[93]
	Difficulty differentiating colonization vs. infection	e.g., Stenotrophomonas maltophilia frequently colonizer but also risk factor for systemic infection.	[88]
	Antibiotics themselves drive resistance	Broad-spectrum exposure (vancomycin, carbapenems), prolonged hospitalization → selection pressure, relapse, GVHD.	[93,94]
Implementation of antibiotic stewardship	Clinicians’ reluctance to narrow the spectrum or shorten treatment	Driven by fear of undertreatment in high-risk patients despite toxicity/MDRO risk.	[64]
	Lack of customized, consistent guidelines	CAP guidelines vary—some same as immunocompetent, others recommend broader coverage and longer durations.	[64]
	Diagnostic limitations in outpatients	Minimal/atypical signs; invasive tests often not feasible (e.g., coagulopathy, severe illness); MDRO colonization vs. infection difficult.	[83]
	Therapeutic complexities	Drug–drug interactions with immunosuppressants; prophylactic antibiotics select resistance; cefiderocol linked to relapse/resistance.	[90]
	Operational/economic barriers	OPAT shaped by cost and insurance constraints; adherence issues; PWID complications (catheter misuse, vascular access infections).	[92]
	Patient adherence and psychosocial factors	Non-compliance, patient satisfaction pressures, and psychosocial stress undermine stewardship outcomes.	[92]

AMR: Antimicrobial resistance, IEAT: Inappropriate empirical antibiotic treatment, MDR: Multidrug-resistant, MDROs: Multidrug-resistant organisms, KPC: Klebsiella pneumoniae carbapenemase, ESBL: Extended-spectrum β-lactamase, CRE: Carbapenem-resistant Enterobacteriaceae, AST: Antimicrobial susceptibility testing, MALDI-TOF MS: Matrix-assisted laser desorption ionization time-of-flight mass spectrometry, CAP: Community-acquired pneumonia, OPAT: Outpatient parenteral antimicrobial therapy, PWID: Persons who inject drugs, GVHD: Graft-versus-host disease.

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5. Infection Control and Antimicrobial Resistance Management in Immunocompromised Outpatient

The outpatient setting poses unique challenges for infection prevention and control (IPC), as these patients frequently interact with healthcare centers while also spending significant time in the community, where monitoring and intervention are more difficult. Recent clinical guidelines, such as those from the Infectious Diseases Society of America (IDSA), address the management of AMR in this population and emphasize the importance of tailored antimicrobial therapy and robust infection control measures. The IDSA has released updated guidance (2023–2024) on the treatment of infections caused by major AMR pathogens, including extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E), AmpC β-lactamase-producing Enterobacterales (AmpC-E), carbapenem-resistant Enterobacterales (CRE), difficult-to-treat Pseudomonas aeruginosa, carbapenem-resistant Acinetobacter baumannii (CRAB), and Stenotrophomonas maltophilia. These guidelines are particularly relevant for immunocompromised patients, who may experience more severe outcomes from these infections. The IDSA guidelines for the immunocompromised outpatient setting include the following key points: Empirical therapy selection must consider disease severity, resistance risk factors, patient characteristics, and local resistance patterns (antibiogram), with a prompt transition to targeted therapy upon receipt of culture and sensitivity results. Infections caused by resistant bacteria are initially treated with antibiotics like carbapenems (meropenem, imipenem-cilastatin). If required, combinations with β-lactamase inhibitors, such as ceftazidime-avibactam or meropenem-vaborbactam, may be utilized. Outpatient management with intravenous antibiotics (OPAT) is an appropriate approach for immunocompromised patients, necessitating meticulous monitoring, patient education, and collaboration among medical and pharmaceutical teams. Given the complexities associated with treating antimicrobial resistant infections in these patients, it is advisable to consult infectious disease specialists to determine suitable treatment options and manage potential antimicrobial agent side effects [88].

6. Advancing Antimicrobial Resistance Management in Immunocompromised Outpatients

Antimicrobial resistance surveillance has historically under-sampled high-risk outpatients. For instance, a recent extensive U.S. study found only 3.2% of clinical isolates from cancer outpatients, highlighting a critical sampling gap [12]. A WHO-led scoping analysis reveals that antifungal resistance trends in immunosuppressed populations are largely unreported. Global assessments also highlight the lack of data in immunocompromised cohorts [95]. Therefore, the lack of outpatient-specific AMR (bacterial, fungal, and viral) data limits the precision of burden estimates and evidence-based recommendations. Thus, there is an urgent need to enhance infection surveillance and antibiotic use in outpatient immunocompromised individuals [12,95].

One important unfulfilled clinical need is an immediate diagnosis of pathogens and resistance. To reduce unnecessary antibiotic use, effective antimicrobial stewardship programs rely on rapid and accurate diagnostics, as highlighted in a recent review [96]. Clinicians mainly depend on the microbiology laboratory’s assessment of antimicrobial susceptibility or resistance when deciding on antibiotic treatment, but traditional techniques frequently take days to detect AMR; thus, they are forced to prescribe broad-spectrum empirical therapy [97]. Although they have not yet been approved for routine use in immunocompromised hosts, emerging point-of-care (POC) techniques like multiplex PCR panels, isothermal amplification assays (like CRISPR-based testing), and fast antigen or biomarker screenings may potentially offer same-day guidance [98]. Since they would allow for focused therapy and reduce the unnecessary use of broad-spectrum antimicrobial agents, the development and implementation of simple point-of-care tests to detect resistant bacteria and fungi (such as quick antimicrobial susceptibility testing (AST) cartridges or lateral-flow resistance markers) are a top research goal [12,96].

It is becoming increasingly acknowledged that the patient’s microbiome, particularly the gut ecosystems, is a reservoir of resistance genes that may affect the risk of infection. A portion of this resistome is captured by routine surveillance (such as rectal swab culture). Microbiome profiling may influence AMR risk in immunocompromised patients, according to studies using metagenomic sequencing. For instance, changes in the resistome composition and gut microbial diversity one week post a stem cell transplantation were predictive of the development of febrile neutropenia in pediatric cancer patients. More than 50% of patients in that study had resistance genes to the antibiotics they were given, and a small number of multidrug-resistant organisms (ESKAPE pathogens) contained significant subsets of the patient-specific resistome. Although these results suggest that gut resistome analysis may be used to stratify patient risk, these methods are still in the experimental stage. Personalized AMR surveillance may ultimately be made possible by combining clinical and antibiotic exposure data with microbiome data (such as shotgun stool sequencing). However, since conventional diagnostics overlook much of the microbiome’s resistance potential, achieving this goal requires further studies, from understanding microbiome-pathogen interactions to creating clinically feasible assays [99].

Personalized AMR risk models that guide treatment decisions would be beneficial for immunocompromised outpatients. This involves transitioning from generic antibiograms to decision-making tools that consider individual patient factors (such as immune status, comorbidities, previous colonization, antibiotic usage history, travel history, local epidemiology, etc.). Early examples of this precision stewardship approach include the application of machine learning models to develop personalized antibiograms derived from electronic health records. A multicenter study demonstrated that a personalized antibiogram provided coverage for bloodstream infections comparable to that of clinicians, while significantly reducing the use of broad-spectrum therapy [100]. Models based on machine learning have been created to estimate the likelihood of individual patients being resistant to broad-spectrum antibiotics in hospitalized patients with suspected healthcare-associated urinary tract infections (HA-UTIs). Simplified prediction models were also developed to facilitate clinical implementation and serve as a decision-support tool for selecting personalized empiric antibiotic treatment [101]. In conclusion, creating and verifying predictive models for assessing AMR risk in individual patients—and customizing empiric antibiotic choices based on that assessment—is a key focus for research in this field.

Table 3. Technologies, pilot programs, and real-world examples in antimicrobial resistance management for immunocompromised outpatients.

Technology/Program	Application in Immunocompromised Outpatients	Ref.
Rapid molecular diagnostics (FilmArray blood culture identification panel)	Identifies bloodstream pathogens (Gram-positive, Gram-negative, yeasts) within 1–2 h; reduces time to targeted therapy in CRE/VRE infections; ongoing trials show higher sensitivity and specificity vs. conventional blood cultures.	[102,103]
CRISPR-Cas Phage Systems PRESA (phage-delivered resistance eradication with subsequent antibiotic)	Phage-induced CRISPR-Cas9 eliminates resistance genes; recovers antibiotic susceptibility; durable effect (>240 h) without the emergence of mutational resistance; promising for high-risk immunocompromised patients.	[104,105]
AI-driven approaches and personalized medicine	Machine learning (ML) generates patient-specific treatment recommendations; reduces unnecessary broad-spectrum use; and enables targeted therapy; Rapid resistance prediction using Whole-Genome Sequencing.	[106]
Digital health applications for antimicrobial stewardship	Smartphone-based guideline integration (e.g., Firstline); improved outpatient prescribing aligned with WHO AWaRe; demonstrated large-scale impact in Abu Dhabi clinics.	[107]
Metagenomic surveillance systems	Shotgun metagenomics of gut microbiome predicts febrile neutropenia in pediatric cancer patients; tracks AMR genes in hospital wastewater; links patient microbiota with AMR dissemination in both hospital and urban settings.	[108]
Wearables for early infection detection	AI-powered smart wearables identify systemic inflammation and viral infections pre-symptomatically with 90% accuracy, which is vital for individuals with diminished immune responses.	[108]
Telemedicine-enhanced stewardship programs	Remote stewardship programs decrease antibiotic usage, guarantee adherence, and minimize costs; they are customized to the CDC’s Core Elements for outpatient settings.	[109]
Real-world implementation of novel antimicrobials (Cefiderocol programs)	Real-world use shows 53.3% clinical success in immunocompromised patients; these highlight the necessity of reserving novel antimicrobials for suitable clinical contexts while enforcing stringent stewardship management.	[74]
Educational and hospital-based stewardship bundles	Early screening and rigorous guidelines reduce AMR and enhance outcomes in organ transplant recipients; educational bundles decrease broad-spectrum antibiotic use in oncology outpatients.	[19]

AMR: Antimicrobial resistance, CRE: Carbapenem-resistant Enterobacterales, VRE: Vancomycin-resistant Enterococci, AI: Artificial intelligence, ML: Machine learning, WHO: World Health Organization, AWaRe: Access, Watch, Reserve (WHO antibiotic categorization), CDC: Centers for Disease Control and Prevention.

lists several technologies, pilot programs, and real-world examples to underscore promising strategies for addressing antimicrobial resistance in immunocompromised outpatients.

7. Conclusions

Immunocompromised outpatients, especially individuals with cancer, HIV/AIDS, or those who have undergone transplants, are at the highest risk of acquiring antimicrobial-resistant infections. Addressing these challenges requires a multidisciplinary approach. The limited outpatient-specific surveillance data and delays in swift pathogen identification complicate targeted antibiotic therapy. Utilizing point-of-care diagnostics, microbiome analysis, and customized antimicrobial resistance risk models may facilitate targeted therapy and reduce the need for broad-spectrum antibiotics. Future advancements necessitate enhanced monitoring of AMR, the creation of expedited diagnostic instruments, and integrated clinical–microbiome studies. These approaches could potentially lower disease burden, mortality, and healthcare costs in this vulnerable population.