Epidemiology and Pathogenesis of Staphylococcus Bloodstream Infections in Humans: a Review

Introduction

Staphylococcus aureus is one of the most frequently isolated pathogens from the hospital or community-acquired infections. Staphylococci are a large group of bacteria in every environment; however, these bacteria can proliferate only in humans or animals. Many staphylococcal species colonize the skin and mucosal membranes, especially the perineum and pharynx. The other sites that harbor these bacteria are the gastrointestinal tract, vagina, and axilla, but carriage in those areas is less frequent (Kosecka-Strojek et al. 2018). Traditionally, staphylococci have been divided into two groups based on the production of extracellular enzyme coagulase: coagulase-positive staphylococci (CoPS) and coagulase-negative staphylococci (CoNS). The first group is represented by well-known opportunistic pathogens such as Staphylococcus aureus, Staphylococcus schleiferi, Staphylococcus intermedius, and Staphylococcus pseudintermedius, and the second group traditionally includes nonpathogenic or opportunistic pathogens; however, recently, several clinical reports have presented CoNS as dangerous pathogens, particularly for newborns or immunocompromised patients (Heilmann et al. 2019). A few species, namely Staphylococcus hyicus, Staphylococcus agnetis, and Staphylococcus felis, belong to the third group – coagulase-variable staphylococci. These species are usually grouped with CoPS but cannot produce clumping factors, and coagulase production tests give variable results (Becker et al. 2014). As opportunistic pathogens, staphylococci exhibit saprophytic characteristics under physiological conditions, but the bacteria become severe pathogens under additional infection-facilitating conditions.

Staphylococci are etiological agents of diseases with various localizations, manifestations and/or courses of infection. The most frequent infections are local infections, and the bacteria can cause lesions in various anatomical tissues. Overall, the infections are grouped into skin and soft tissue infections (SSTIs) with manifestations such as dermatitis, abscesses, furunculosis, boils, folliculitis, impetigo, or mastitis, and also includes other severe diseases such as staphylococcal foodborne disease, toxic shock syndrome, and staphylococcal scalded skin syndrome (SSSS) (Foster 2012; Tong et al. 2015). Staphylococci are also common pathogens of deep tissue infections, including foreign bodies infection. Most studies focused on S. aureus infections, but there is strong evidence of the CoNS involvement in severe diseases. Osteomyelitis, otitis, wound infection, endophthalmitis, urinary tract infection, meningitis, or even pneumonia may be caused by S. epidermidis, Staphylococcus saprophyticus, Staphylococcus lugdunensis, and S. schleiferi (von Eiff et al. 2002; Becker et al. 2014; Argemi et al. 2019). When staphylococci gain entry into the bloodstream, colonization becomes systemic as bacteremia and then advances to infection.

The literature was screened based on a PubMed search using the terms „staphylococci”, „Staphylococcus” and „bloodstream infections” and/or „sepsis”. The publications were then evaluated based on a citation index. Specific criteria were used to describe the worldwide occurrence of S. aureus, and CoNS bloodstream infections and/or sepsis, such as: only original articles were included; the data from different geographical regions/countries were analyzed; the articles with the highest number of participants and bacterial strains isolated, and those containing long-term studies or the recent data, were selected to the analysis.

Bacteremia, bloodstream infection, and sepsis

Bacteremia. Bacteremia is characterized by the presence of pathogens in the blood (Pai et al. 2015). Transient bacteremia is limited to one or two days, without any manifestations, and may be caused by some staphylococcal species. Furthermore, the phenomenon does not indicate any further manifestation in healthy hosts (Samet et al. 2006). The presence of bacteria in the blood is eliminated by immunological defense systems and is known in the literature as „natural bacteremia” or „physiological bacteremia”.

Bloodstream infection. However, in predisposed hosts, bacteremia advances to bloodstream infection (BSI), manifesting as an inflammatory response against microorganisms or/and against their metabolites present in the body (Dayan et al. 2016). The BSI can be successfully treated or advances to sepsis (Thomer et al. 2016; Michalik et al. 2020). Sepsis is related to organ dysfunction, perfusion disturbances, or hypotension with accompanying lacticaemia, oliguria, and/or psychological disorders (Samet et al. 2006; Hotchkiss et al. 2016).

Therefore, some S. aureus bacteremia complications, such as endocarditis, attributable mortality, embolic stroke, or recurrent infection during the 12-week follow-up period, are circumstances associated with the increased sepsis frequency from 11% to 43%. When the inflammatory response is triggered by the massive release of pro-inflammatory Th1 cytokines, such as TNF-α, IL-1β, IL-6, and IFN-γ, a septic shock may occur (Dayan et al. 2016).

Sepsis. Sepsis is the incorrect, inflammatory response of the host organism to infection, and often, it is a result of systemic bloodstream infections. Recently, sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection (Singer et al. 2016). Untreated sepsis can lead to severe sepsis or septic shock and, consequently, multiple organ failure (Sequential Organ Failure Assessment, SOFA) and death (Stevenson et al. 2016). Sepsis is a critical clinical stage of general toxemia and organ dysfunction, and a patient’s inflammatory response interferes with the functioning of vital organs, such as the heart, kidneys, lungs, or liver. Sepsis-3 recommends a new sepsis scoring system, rapid sequential assessment of organ failure (qSOFA), consisting of 3 elements: an altered mental state, respiratory rate, and systolic blood pressure (Minejima et al. 2019). Patients with suspected infection expected to have a prolonged ICU stay can be identified at the bedside with quick SOFA, i.e., alteration in mental status, systolic blood pressure ≤ 100 mmHg, or respiratory rate ≥ 22/min. Moreover, patients with septic shock can be identified with a clinical construct of sepsis with persisting hypotension requiring vasopressors to maintain MAP ≥ 65 mmHg and having a serum lactate level > 2 mmol/l (18 mg/dl) despite adequate volume resuscitation (Singer et al. 2016).

Pathogenicity of staphylococcal bloodstream infections

Antibiotic resistance. Staphylococci exhibit a wide resistance to antibiotics. One of the most dangerous features of staphylococci is their multi-resistance. Research indicates that both the CoPS and CoNS species have staphylococcal chromosome cassettes mec (SCCmec) that determine resistance to methicillin in both groups. Furthermore, the SCCmec elements of CoNS present extreme diversity, which causes many diagnostic problems (Hosseinkhani et al. 2018). The increase of methicillin-resistant S. aureus (MRSA) isolates in hospital and the community due to horizontal gene transfer across bacterial species occurred. The environmental and animal-associated CoNS may be underestimated factor for the spread of the resistance genes into more pathogenic species like S. aureus (Kosecka-Strojek et al. 2016; Lisowska-Łysiak et al. 2019). Methicillin and vancomycin resistance remain the major antimicrobial resistance phenotype of concern. Although still relatively infrequent, multi-resistant CoNS with reduced susceptibility to glycopeptides are emerging pathogens of clinical concern and should be kept in mind in empirical and rational therapy of BSI (Veach et al. 1990; Natoli et al. 2009). In recent years an emerging spread of linezolid-resistant Staphylococcus capitis and S. epidermidis strains in Europe was shown (Tevell et al. 2017; Kosecka-Strojek et al. 2020). An increased resistance is the result of antibiotic pressure, which could select resistant clones among staphylococci.

Virulence determinants and other invasion/evasion determinants. Staphylococci exhibit a strong capacity to infect human hosts by using specific strategies to enable the adherence, invasion, persistence, and evasion of the host’s immunity mechanisms. However, the infection ability is not similar for all species within the Staphylococcus genus. In general, CoNS isolates present lower levels of virulence determinants than CoPS, but the factors involved in colonization support invasion in the host (Becker et al. 2014). It is especially true in extremely immature infants, in whom more than 80% of late-onset sepsis (diagnosed after 72 hours of life) is caused by CoNS (Lauterbach et al. 2016; Wójkowska-Mach et al. 2019). However, despite the relatively low level of virulence, immature infants with sepsis caused by these pathogens present a wide range of clinical symptoms (Lauterbach et al. 2016). It was shown that S. lugdunensis was responsible for sepsis and endocarditis on the 1st day of life in a term newborn, which underwent lotus birth (Ittleman and Szabo 2018). In contrast, S. aureus strains often exhibit a vast arsenal of toxins and enzymes involved in staphylococcal pathogenesis. Toxins can lead to a weak response of the human organism because they can degrade certain host cells, manipulate the innate and adaptive immune response, and degrade intercellular junctions, contributing to the S. aureus proliferation (Oliveira et al. 2018).

Toxins. One of S. aureus toxicity mechanisms is damage to host cell membranes caused by hemolysins, bicomponent leukocidins, or phenol-soluble modulins (Herrera et al. 2016). However, it has been proven that CoNS also secrete toxins and enzymes. Based on CoNS strains whole-genome sequencing (WGS) performed by Argemi et al. (2019), the presence of proteases, lipases, and hemolysins genes in S. epidermidis, S. capitis, and Staphylococcus caprae was shown. Moreover, enterotoxin genes in S. epidermidis and Staphylococcus haemolyticus genomes were shown (Nanoukon et al. 2018; Argemi et al. 2019). Other toxins produced by S. aureus are usually infection-specific, such as enterotoxins or toxic shock syndrome toxin. Furthermore, bacteria-host interactions depend on extracellular enzymes, and the largest group of enzymes includes proteases. This category consists of serine proteases, the metalloprotease aureolysin, and staphopains that are engaged in the evasion of complement-mediated killing, host tissue destruction, immunoglobulin degradation, and deregulation of fibrinolysis (Miedzobrodzki et al. 2002; Sabat et al. 2008; Kalińska et al. 2012; Martínez-Garcia et al. 2018).

Biofilm formation. Biofilm formation is an additional factor associated with CoPS and CoNS infections (Grzebyk et al. 2013; Argemi et al. 2019). Biofilm formation is one of the staphylococcal survival strategies within host organisms. The presence of staphylococcal biofilms is a key factor involved in bacterial resistance to various groups of antibiotics. Bacterial biofilms are defined as communities of bacterial colonies attached to the host surface and surrounded by exopolymeric matrix substances strictly regulated by numerous proteins engaged in the biofilm life cycle. It was shown that biofilms could evade the host immune response, which leads to the persistence of staphylococci. Bhattacharya et al. (2018) proved that S. aureus biofilms could release leukocidins, which affect extracellular trap formation and allow evasion of neutrophil-mediated killing. Biofilm production has also been proven for CoNS species, including S. lugdunensis that produces adhesins and other biofilm promoters (Argemi et al. 2017). Staphylococcal pathogenesis is a process that involves an array of extracellular proteins, biofilm, and cell wall components that are coordinately expressed in different phases of infection. The expression or suppression of two divergent loci, accessory gene regulator (agr) and staphylococcal accessory regulator (sar) are recognized as critical regulators of virulence in staphylococci (Arya and Princy 2013).

Risk factors present in humans: predisposed patients. Several studies have shown that host risk factors may significantly enhance the effects of BSIs, including mortality. The high-risk group of staphylococcal infections contains mostly patients with indwelling medical devices. The highly predisposed groups also contain premature newborns or elderly patients or multimorbid, chronically ill, or immunosuppressed patients. A large group of the patients infected is also those with inserted foreign plastic bodies, such as implants and venflons.

The essential patients’ factors that determine bloodstream infections and complications are age, presence of comorbidities, and appropriate initial antibiotic treatment (Ayau et al. 2017). Bloodstream infections occur in elderly patients over 75 years old, resulting in increased mortality (Gasch et al. 2013). A 9-year study performed by Ayau et al. (2017) underlined risk factors that increased the probability of mortality, such as age, cancer, heart disease, neurological disease, nursing home residence, and Charlson score greater than 3. In fact, cancer itself increases the 30-day mortality, but Bello-Chavolla et al. (2018) reported additional risk factors, including hematologic malignancy, hyperglycemia, abdominal source of infection, and endocarditis, based on studies conducted on patients with cancer. Malignancy was also confirmed to be a key factor associated with poor outcomes of infection in other studies (Papadimitriou-Olivgeris et al. 2019).

Epidemiology: Worldwide distribution of staphylococcal bloodstream infections

Staphylococcal bloodstream infections are currently a challenging issue for clinicians, diagnosticians, and microbiologists, primarily due to their high frequency worldwide. Studies on bloodstream infection episodes differ slightly from each other because of the high number of patients and the number of institutions involved in providing the data. Interestingly, all of these studies confirmed a high number of staphylococci isolated from blood samples, ranging from 23.9 to 79.2% (Table I). In many cases, S. aureus, usually MRSA isolates, and CoNS were the predominant species involved in BSI episodes. However, most importantly, staphylococcal bloodstream infections affect the whole world, not only developing countries. It is imperative to analyze the data to implement standard diagnostic methods, to compare the results among various countries, to evaluate existing preventive measures, and to plan effective infection prevention and control programs or establish new programs, including the use of advanced genetic methods (Dik et al. 2016; Sabat et al. 2017; Kosecka-Strojek et al. 2019). This study compares staphylococcal bloodstream infections in the world. The evaluation of S. aureus and CoNS as etiological agents of BSI of the cited publications was made under the following criteria: the studies included patients with symptoms of BSI/sepsis; pathogens grew on at least one percutaneous blood culture and a culture of the catheter tip; bacteria have been identified as S. aureus or CoNS species using commercial/automated identification tests; susceptibility testing was performed, and CoNS species from positive blood samples were included in comprehensive data for analysis except where specified in the laboratory records as contaminants.