Multidrug-Resistant Sepsis: A Critical Healthcare Challenge

Abstract

Sepsis globally accounts for an alarming annual toll of 48.9 million cases, resulting in 11 million deaths, and inflicts an economic burden of approximately USD 38 billion on the United States healthcare system. The rise of multidrug-resistant organisms (MDROs) has elevated the urgency surrounding the management of multidrug-resistant (MDR) sepsis, evolving into a critical global health concern. This review aims to provide a comprehensive overview of the current epidemiology of (MDR) sepsis and its associated healthcare challenges, particularly in critically ill hospitalized patients. Highlighted findings demonstrated the complex nature of (MDR) sepsis pathophysiology and the resulting immune responses, which significantly hinder sepsis treatment. Studies also revealed that aging, antibiotic overuse or abuse, inadequate empiric antibiotic therapy, and underlying comorbidities contribute significantly to recurrent sepsis, thereby leading to septic shock, multi-organ failure, and ultimately immune paralysis, which all contribute to high mortality rates among sepsis patients. Moreover, studies confirmed a correlation between elevated readmission rates and an increased risk of cognitive and organ dysfunction among sepsis patients, amplifying hospital-associated costs. To mitigate the impact of sepsis burden, researchers have directed their efforts towards innovative diagnostic methods like point-of-care testing (POCT) devices for rapid, accurate, and particularly bedside detection of sepsis; however, these methods are currently limited to detecting only a few resistance biomarkers, thus warranting further exploration. Numerous interventions have also been introduced to treat MDR sepsis, including combination therapy with antibiotics from two different classes and precision therapy, which involves personalized treatment strategies tailored to individual needs. Finally, addressing MDR-associated healthcare challenges at regional levels based on local pathogen resistance patterns emerges as a critical strategy for effective sepsis treatment and minimizing adverse effects.

Keywords: critical illness; drug resistance; healthcare costs; microbial; mortality; sepsis.

Figure 1

Overview of the pathogenesis of sepsis. (a) Immune Response: Sepsis occurs when the body responds to infection with an excessive immune system reaction, causing a disturbance in the usual equilibrium of the inflammatory response to maintain homeostasis. Activation of PRRs initiates both proinflammatory responses and immune suppression, ensuing hyperinflammation and immune suppression to the extent that is detrimental to the host. (b) Receptor Response: Once a pathogen successfully breaches the host’s mucosal barrier, it can induce sepsis, depending on its quantity and virulence. The host’s defense system identifies molecular components of invading pathogens (PAMPs) through specialized receptors called PRRs. This activation triggers the expression of target genes responsible for proinflammatory cytokines (resulting in leukocyte activation), inefficient utilization of the complement system, coagulation system activation, simultaneous downregulation of anticoagulant mechanisms, and necrotic cell death. This sets in motion a detrimental cycle, leading to the progression of sepsis, exacerbated by the release of endogenous molecules from injured cells (DAMPs or alarmins), further stimulating PRRs. Immune suppression manifests as extensive apoptosis, causing depletion of immune cells, reprogramming monocytes and macrophages into a state with reduced capacity to release proinflammatory cytokines, and an imbalance in cellular metabolic processes. (c) Organ Response: Organs respond to internal or external stimuli by initiating inflammation, undergoing changes in function, or activating compensatory mechanisms aimed at maintaining homeostasis and resolving disturbances. These responses are crucial for the body to cope with stress, injury, infection, or other challenges, ensuring proper functioning and survival. The main organs and their specific responses are described below. 1. Brain: (i) Delirium: Acute disturbance in attention and cognition, leading to confusion and altered perception. (ii) Encephalopathy: Brain dysfunction causing altered mental function, affecting cognition, consciousness, and behaviors. 2. Lungs: Acute Respiratory Distress Syndrome (ARDS) triggered by MDR bacteria is a severe and potentially life-threatening condition characterized by the rapid onset of widespread inflammation in the lungs. Infections, especially severe bacterial infections caused by multidrug-resistant bacteria, lead to direct lung injury, cytokine storms, secondary infections, and ventilator-associated pneumonia (VPA). 3. Heart: High distributive shock with MDR sepsis places immense strain on the heart due to systemic vasodilation and reduced blood flow, leading to compromised cardiac function and potential myocardial damage. The combination of multidrug-resistant sepsis and shock increases the risk of cardiac dysfunction, contributing to the severity of the condition and complicating treatment. 4. Liver: Cholestasis during MDR sepsis involves a disruption in bile flow due to both the effects of severe infection and potential liver dysfunction from multidrug-resistant bacteria. This combination worsens jaundice, impairs detoxification processes, and contributes to the systemic complications of sepsis. 5. Gastrointestinal tract: An inflamed intestine barrier exacerbated by multidrug-resistant bacterial infections leads to severe inflammation and compromised intestinal integrity, increasing the risk of bacterial translocation. This can result in the systemic dissemination of pathogens, exacerbating MDR sepsis. 6. Kidney: In MDR sepsis, acute kidney injury is a combination of sepsis-induced circulatory changes, and the potential nephrotoxicity of the pathogens contributes to kidney dysfunction, increasing the risk of severe complications and mortality. 7. Suppression cytopenia: During MDR sepsis, suppression cytopenia leads to a significant reduction in blood cell counts. The combination of multidrug-resistant pathogens and the immunosuppressive effect of sepsis increases the risk of complications, including compromised immunity and susceptibility to bleeding or infections. Abbreviation: ARDS, acute respiratory distress syndrome; AKI, acute kidney injury; DAMPs, danger-associated molecular patterns; DNA, deoxyribonucleic acid; HMGB1, high-mobility group box-1 protein; HSPs, heat shock proteins; LPS, lipopolysaccharide; LTA, lipoteichoic acid; PAMPs, pathogen-associated molecular patterns; PPRs, pattern recognition receptors; RNA, ribonucleic acid. The dashed lines depict the disrupted immune response triggered by infection, which makes the body unable to restore its equilibrium and causes harm to the organs. This culminates in a severe and life-threatening state known as sepsis.

Figure 2

Cell surface and intercellular receptors amend for the recognition of PAMPs and DAMPs. The onset of sepsis is heralded by the host’s detection, prompting the activation of inflammatory signaling pathways. An extensive array of cellular and intracellular receptors is used to identify PAMPs or DAMPs. Examples include microbial and host-originated glycoproteins, lipoproteins, and nucleic acids. The corresponding PRRs encompass Toll-like receptors, dectin 1 (a member of the C-type lectin domain family 7), and dectin 2 (a member of the C-type lectin domain family 6). At least ten distinct TLRs have been identified, usually forming homodimers or heterodimers. Upon activation, these signaling pathways typically integrate into interferon regulatory factor signaling and nuclear factor-κΒ. IRF is in charge of type I interferon production. NF-κΒ and activator protein 1 signaling predominantly oversee the early activation of genes involved in inflammation, such as TNF and IL1, as well as those encoding for endothelial cell surface molecules. Among the other notable components within this sepsis-related network are caspase recruitment domain-containing protein 9, lipopolysaccharide, myeloid differentiation primary response protein 88, and stimulator of interferon genes protein. Loss of lymphocytes is directly immunosuppressive, contributing to the lymphopenia observed in patients. The genetic mutation or pharmacological intervention that decreases sepsis-induced apoptosis improves survival in severe sepsis. The degree of lymphocyte apoptosis in animal models of sepsis correlates with the severity of sepsis, and persistent lymphopenia predicts sepsis mortality. The next generation of treatments evaluated for suppressing immune function through interaction with sepsis includes therapies targeting lymphocytes and leukocytes. Abbreviations: CARD9, caspase recruitment domain-containing protein 9; dsDNA, double-stranded DNA; dsRNA, double-stranded RNA; FcRγ, Fcγ receptor; HMGB1, high-mobility group box 1; iE-DAP, d-glutamyl-meso-diaminopimelic acid; LGP2, laboratory of genetics and physiology 2; LPL, lipoprotein lipase; LPS, lipopolysaccharide; LY96, lymphocyte antigen 96; MAPK, Mitogen-activated protein kinase; MCG, mannose-containing glycoprotein; MDA5, melanoma differentiation-associated protein 5; DAMPs, damage-associated molecular patterns; MDP, muramyl dipeptide; MYD88, myeloid differentiation primary response 88; TLRs, Toll-like receptors; C-type lectin domain family 7 member A (dectin 1) and C-type lectin domain family 6; NIK, NF-κB-inducing kinase; NOD, nucleotide-binding oligomerization domain; RAF1, RAF proto-oncogene member A (dectin 2); RIG-I, retinoic acid-inducible gene 1 protein; ssRNA, single-stranded RNA; STING, stimulator of interferon genes; NF-κB, nuclear factor-κB; SYK, spleen tyrosine kinase; NF-κB and activator protein 1 (AP-1).

Figure 3

Prevention and control of the rise in multidrug-resistant microorganisms. Everyday self-care routines that involve cleaning and sanitizing your body and hands are paramount to maintaining good health. Regular sterilization of surfaces prone to high contact is also significant in curbing the spread of harmful microorganisms. Face masks should be worn consistently, particularly when maintaining safe distances from others is difficult. Self-medication is a practice to avoid, especially in cases where the correct dosage and timing of intake are not known. Hospital waste should be correctly deposited into the designated trash receptacles to prevent contamination risks. Travel plans should be put on hold when one is unwell as a preventive measure against spreading the disease.