Management of Biofilm Producing Methicillin-Resistant Staphylococcus aureus Infections: History
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Contributor:
Ashlesha Kaushik
,
Helen Kest
,
Mangla Sood
,
Bryan W. Steussy
,
Corey Thieman
,
Sandeep Gupta

Since its initial description in the 1960s, methicillin-resistant Staphylococcus aureus (MRSA) has developed multiple mechanisms for antimicrobial resistance and evading the immune system, including biofilm production. MRSA is now a widespread pathogen, causing a spectrum of infections ranging from superficial skin issues to severe conditions like osteoarticular infections and endocarditis, leading to high morbidity and mortality. Biofilm production is a key aspect of MRSA’s ability to invade, spread, and resist antimicrobial treatments. Environmental factors, such as suboptimal antibiotics, pH, temperature, and tissue oxygen levels, enhance biofilm formation. Biofilms are intricate bacterial structures with dense organisms embedded in polysaccharides, promoting their resilience. The process involves stages of attachment, expansion, maturation, and eventually disassembly or dispersion. MRSA’s biofilm formation has a complex molecular foundation, involving genes like icaADBC, fnbA, fnbB, clfA, clfB, atl, agr, sarA, sarZ, sigB, sarX, psm, icaR, and srtA. Recognizing pivotal genes for biofilm formation has led to potential therapeutic strategies targeting elemental and enzymatic properties to combat MRSA biofilms. 

  • methicillin-resistant Staphylococcus aureus
  • MRSA
  • biofilm
  • infection
  • treatment
  • antibiotics

1. Introduction

Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a highly formidable pathogen in contemporary times, causing significant levels of illness and death due to its ability to counteract immune defenses through various mechanisms. First identified in the 1960s, MRSA has evolved to develop numerous mechanisms of antimicrobial resistance and evasion of the host’s immune system [1][2]. This enables MRSA to cause invasive diseases, including those involving biofilm formation. With its diverse arsenal of evasion strategies against the host’s defenses, MRSA has become a pervasive pathogen responsible for a range of infections. These infections span from chronic and recurring skin and soft tissue infections (SSTIs) to more deeply-seated conditions such as infections of the bones and joints (osteoarticular infections) and endocarditis, leading to substantial morbidity and mortality [3][4][5][6]. 

Suggested approaches for management of S. aureus biofilm infections include treatment by antimicrobials alone/in combination along with surgical debridement or device removal, inhibiting biofilm formation by limiting bacterial attachment to medical devices with surface modification, application of newer anti-biofilm agents, or novel technologies like laser Shock waves (LSW).
While several novel strategies for treatment/inhibition of biofilms are being investigated, the most commonly used approaches for management of biofilm producing MRSA infections currently center around prolonged use of appropriate antibiotics and removal of sources/foci of infection/foreign bodies like catheters [7][8].

2. Current Guidelines for Treatment of MRSA Infections

Antibiotics represent the cornerstone of therapy for infections caused by MRSA strains known for their biofilm-forming capabilities. The Infectious Disease Society of America (IDSA) guidelines address management of MRSA infections including skin and soft tissue infections, bacteremia, infective endocarditis, pneumonia, osteomyelitis, joint infections, and central nervous system infections, all of which are facilitated by biofilm production [7]. When managing MRSA infections, the IDSA strongly recommends debriding and draining any soft tissue abscesses associated with the infection whenever possible, in addition to initiation of antimicrobials.

Recommended antibiotics for the treatment of MRSA osteomyelitis include vancomycin, daptomycin, or linezolid, with some experts recommending additional rifampin therapy. Duration of therapy is also important and an individual with osteomyelitis should receive at least 8 weeks at minimum and possibly 3 months or longer of therapy [7][9]. After an initial intravenous therapy course, patients with MRSA osteomyelitis should be transitioned to oral therapy and some experts suggest rifampin with any of the following based on susceptibilities: trimethoprim–sulfamethoxazole (TMP-SMX), a tetracycline derivative, or clindamycin [7].

Similar to the treatment of osteomyelitis without device involvement, managing patients with osteoarticular infections related to medical devices follows similar antimicrobial therapy guidelines, with the inclusion of combination therapy involving rifampin [7]. Patients who develop an infection within 2 months after surgery or those with a stable implant and hematogenous infection should receive the aforementioned parenteral therapy in combination with rifampin for a duration of 2 weeks.

The treatment of osteomyelitis in pediatric populations diverges from adult recommendations [10]. In children aged 4 months to 18 years, vancomycin monotherapy is the indicated treatment. However, for isolates that are sensitive, second-line options such as linezolid, daptomycin, TMP-SMX, or clindamycin may be considered [10]. Newborns under 4 months of age should be treated with either vancomycin or linezolid. The recommended treatment duration for pediatric osteomyelitis is four to six weeks.

S. aureus is one of the more common bacteria associated with vertebral osteomyelitis and empiric therapy for this condition should include MRSA coverage. IDSA MRSA treatment guidelines recommend treatment regimens that include vancomycin and either ceftriaxone, cefepime, or levofloxacin for additional Gram-negative coverage [7]. Alternative recommended MRSA antimicrobial agents include daptomycin or linezolid. Treatment of vertebral osteomyelitis is usually prolonged with patients needing antibiotics for a total duration of 8 weeks or more [7]. For patients with spinal implant infections occurring less than or equal to 30 days after an implant procedure, a similar initial dosing strategy is recommended. Parenteral therapy including rifampin is recommended with a transition to oral coverage including dual oral therapy with rifampin. It is recommended to continue oral therapy until spinal fusion has occurred. For patients experiencing an infection greater than 30 days after implant procedure, device removal is recommended with a similar antimicrobial treatment strategy.

MRSA endocarditis treatment recommendations depend on the presence of a native or mechanical cardiac valve. In patients with infective endocarditis without a prosthetic valve, vancomycin or daptomycin, both as monotherapy, are recommended for an extended course of 4–6 weeks [7]. In pediatric patients, vancomycin is the drug of choice for infective endocarditis, and daptomycin may be considered as an alternative [7]. When a prosthetic cardiac valve is present, a combination therapy regimen approach is recommended, with vancomycin and rifampin administered for a total of 6 weeks with the addition of low dose gentamicin for the first 2 weeks of treatment.

IDSA guidelines recommend managing MRSA meningitis with intravenous vancomycin for a total of 2 weeks [7]. Some experts recommend adding rifampin to this regimen. Other treatment options include linezolid or TMP-SMX. If a CNS shunt is present, removal of the device is strongly recommended. Guidelines recommend leaving the shunt out until cerebrospinal fluid cultures are repeatedly negative. Pediatric patients diagnosed with MRSA meningitis should receive vancomycin alone.

Due to the complex nature of these infections and the principles of pharmacokinetics, such as drug distribution and concentration levels in various tissues, dosing strategies for vancomycin and daptomycin in these patients are more aggressive. Vancomycin has traditionally been dosed based on actual body weight, with a range of 15–20 mg/kg per dose administered every 8–12 h, not exceeding 2 g per dose [7]. Although traditionally vancomycin trough concentrations have been used for vancomycin monitoring with target trough concentrations for serious infections between 15–20 μg/mL, the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists revised their vancomycin dosing guidelines in 2020, recommending using the Bayesian-derived AUC (area under the curve)/MIC (minimal inhibitory concentration) ratio for vancomycin monitoring instead of trough concentrations in order to achieve optimal drug efficacy and reduce the risk of acute kidney injury [11]. In general, according to these guidelines, vancomycin target AUC goals of 400 and 600 mg × h/L are desired in patients with a confirmed MRSA diagnosis and MRSA isolates with MIC value of ≤1 mg/L [12]. For critically ill adult patients, the guidelines recommend a vancomycin dosing approach that includes a 20–35 mg/kg loading dose with a maximum not to exceed 3 g before initiating a pharmacokinetic-based calculated regimen. The guidelines recommend monitoring of AUC levels early in the course of treatment (24–48 h) [11].

In patients with MIC values greater than 1 mg/L, alternatives to vancomycin therapy should be considered, as treating MRSA isolates with an MIC > 1 mg/L requires higher doses of vancomycin to achieve desired AUC goals and increases the risk of toxicities. Daptomycin doses are also generally higher for these indications (8–10 mg/kg and occasionally 12 mg/kg every 24 h).

MRSA bacteremia remains an ongoing treatment challenge for practitioners with treatment failure associated with poor patient outcomes. Further investigation of the impact of both monotherapy and dual-therapy treatment regimens on clinical success rates is warranted [13]. For MRSA bacteremia, combination therapies have been utilized, especially in case of resistance to daptomycin and vancomycin. A literature review by Lewis et al. evaluated case-study reviews of antimicrobial regimens in patients with MRSA bacteremia [13]. Findings included daptomycin in combination with anti-Staphylococcal beta-lactam antibiotics such as nafcillin, oxacillin, and ceftaroline showing improved clinical success rates in persistent MRSA bacteremia. Based on recent studies, it has been recommended that if repeat blood cultures fail to become negative at 3–5-days despite appropriate antibiotic therapy, the patient should be considered to have monotherapy failure, prompting the addition of ceftaroline to vancomycin or switching to daptomycin with a second antimicrobial agent [14][15]. Daptomycin has been successfully used in combination with rifampin or trimethoprim–sulfamethoxazole to treat MRSA bacteremia [16][17]. Similarly, combination therapy including vancomycin-based regimens with anti-Staphylococcal beta-lactams has shown to be potentially useful [18][19].

According to IDSA guidelines, vancomycin, gentamicin, and rifampin remain the standard of care for staphylococcal prosthetic valve endocarditis [7]. Rifampin in particular shows a strong ability to permeate biofilms and hence bactericidal activity against biofilm-producing microbes that are susceptible. In a study, rifampin in combination with daptomycin was demonstrated to be a successful regimen in treating persistent MRSA infections commonly involving biofilm formation in 10 of 12 patients [16]. In fact, IDSA guidelines recommend using rifampin in conjunction with other antibiotics for MRSA infections in prosthetic joints, infective endocarditis on prosthetic valves, and ventriculitis and meningitis with hardware [7][20][21][22][23][24]. Dosing for rifampin for biofilm-associated S aureus infections in a pediatric population range from 10 mg/kg/d to 20 mg/kg/d, given in 1 to 3 doses, with a maximum of 600 mg per dose and 900 mg/d [7]. Other combinations that have shown promise include ceftaroline alone or combined with trimethoprim–sulfamethoxazole or vancomycin [25][26], combinations of linezolid with a carbapenem, or telavancin with ceftaroline or rifampin [27][28]. Quinupristin–dalfopristin can also be used as a salvage therapy agent; however, it is not preferred given the adverse effect profile.

Thus, to summarize, dual antimicrobial therapy must be considered, especially while treating critical MRSA infections with hardware such as endocarditis, central nervous system infections, or osteomyelitis. Most of these combinations include rifampin with its property of biofilm penetration.

3. Ethanol Locks, Antibiotic Lock Therapy, and Coated Implants to Inhibit Biofilms

In addition to antibiotics with infection-source control as the first line therapy, other strategies to prevent biofilm mediated device infections have been suggested. Alcohol lock therapy may be of some benefit as shown by some studies [29][30]. Ethanol has been demonstrated to have high anti-biofilm activity, is easy to use, and is inexpensive, without reports of resistance with successful catheter salvage rates of >70% [29][30]. In one study, heparinized 40% ethanol lock solution significantly reduced bacterial metabolic activity; however, it was not able to eradicate the biofilm completely [29]. Despite these advantages, some disadvantages include lack of consensus guidance around exact dosing, timing/combinations with anticoagulants, several notable adverse effects including, catheter occlusion, plasma protein precipitation, and risk of thrombosis [30][31], and concerns about abnormalities in catheter integrity, including one case leading to catheter embolization [30].
Antibiotic lock therapy with daptomycin, minocycline alone, and minocycline in combination with rifampin have been studied; however, these therapies are not preferred given the concern for rapid emergence of antimicrobial resistance. In a study, authors showed that antibiotics, especially daptomycin and minocycline, were effective in MRSA eradication when employed as lock therapy [32]. The study showed that after 3 days of 4-h every-day exposure, daptomycin, minocycline, and tigecycline had a significantly faster effect in eradicating biofilms than linezolid, rifampin, and vancomycin. Rifampin in combination with any of these antibiotics was significantly more effective in biofilm eradication than any antibiotic used alone; however, when used alone, rifampin led to rapid emergence of rifampin-resistant MRSA [32]. Antibiotic locks are not recommended as the preferred strategy given the high risk of resistance.
Implants and catheters coated with antiseptics (chlorhexidine and silver sulfadiazine) have been shown to inhibit S. aureus-associated biofilm formation. In a study, Sampath et al. used a murine model to compare the inhibitory properties of various catheters impregnated with minocycline on their luminal surfaces and rifampin on their exterior surfaces, catheters coated with silver sulfadiazine, chlorhexidine, and both on the external surface and in the lumens [33]. Both catheters inhibited the growth of S. aureus biofilms. However, the major concern of the antibiotic coated implants and catheters is the rapid emergence of resistant strains that can result from their use. Hence, the use of coated catheters is not encouraged.

4. Other Potential Approaches for Management of Biofilm Producing MRSA Infections

Several bio-molecules are being investigated as adjunctive therapies and as novel anti-biofilm agents, including bacteriophages, metal chelators, phytochemicals, nanoparticles, repurposed drugs, antimicrobial peptides (AMPs), enzymes, and antibodies to inhibit or treat biofilms. These treatment modalities are briefly discussed as follows.

4.1. Chelators and Sulfhydryl Compounds

Cations (e.g., Mg2+, Fe2+, Ca2+) play a crucial role in bacterial growth by promoting inter-bacterial interactions and aggregation and are thought to be important for microbial adherence and biofilm formation. By sequestering these ions, high-affinity metal ion chelators such as ethylenediamine tetra acetic acid (EDTA), ethylene glycol tetra acetic acid (EGTA), and tri-sodium citrate (TSC) inhibit biofilm formation as well as bacterial adhesion to surfaces, thus showing useful antibacterial properties in vitro [34].

4.2. Nanoparticles

The application of nanotechnology to the field of biofilm inhibition is a novel area of scientific exploration. Nanoparticles (e.g., gold, silver, iron, copper and selenium), and nanomaterials have shown enhanced biofilm matrix penetration compared to free drug molecules [35], as such interfering with biofilm formation and bacterial adhesion. The field of nanotechnology provides novel approaches to tackle S. aureus biofilm-associated infections. Several nanomaterials, nanoparticles (NP), and drug encapsulated nanoparticles have been shown to possess better antibacterial and anti-biofilm activities. Because nanoparticles can interact with and penetrate the biofilm matrix more effectively than free drug molecules [17], they interfere with S. aureus adhesion and thus prevent its biofilm formation. Utilizing nanoparticles like silver and zinc oxide as an adjunctive therapy, given their enhanced biofilm penetrative properties to antibiotics, has been proposed [36].
A study showed Gold nanocage (AuNC@NO) to display potential application as a beneficial antibiofilm agent for treating biofilm-associated infections [37].
Gold nanocage (AuNC@NO) releases nitric oxide (NO), which is activated by near-infrared (NIR) irradiation to provide NO and produce hyperthermia for biofilm removal [37].
AuNC@NO has the qualities of delayed NO release at physiological temperature and on-demand fast NO release under NIR irradiation, as well as steady and good photothermal conversion efficiency [37].
Based on these characteristics, AuNC@NO displays in vitro bactericidal and antibiofilm performance and could eliminate 85.4% of biofilms and reduce bacteria by four orders of magnitude under NIR irradiation [37]. According to the in vivo results, NO release from AuNC@NO was significantly accelerated after 5 min of 0.5 W cm2 NIR irradiation, which led to the dispersal of MRSA biofilms and worked in conjunction with photothermal therapy (PTT) to kill planktonic MRSA that had lost its biofilm protection [37]. Due to the controlled photothermal temperature and toxicity, the surrounding tissues suffered little harm. This novel nanocomposite technology offers a promising therapeutic approach and needs further evaluation in clinical settings.

4.3. Repurposed Drugs

Utilizing repurposed drugs, i.e., Food and Drug Administration (FDA)-approved drugs indicated for non-MRSA infections/autoimmune diseases, has been proposed for the treatment of biofilm infections. Some examples of these include niclosamide, a drug commonly used for treating Taenia (tapeworm) infections, thioridazine, which is an anti-psychotic agent, and auranofin, which is an antirheumatic agent, given their anti-biofilm activity shown in vitro [38]. However, their applicability in clinical settings needs to be further studied.

4.4. Antimicrobial Peptides (AMPs)

These are peptides that are positively charged, amphipathic in nature; and composed of fewer than 50 amino acids in length. To date, more than 5000 AMPs have been described [39]. AMPs can bind to and disrupt bacterial membranes, and some of these AMPs possess anti-biofilm activity against S. aureus. Although larger than AMPs, human short-palate lung and nasal epithelial clone 1 (SPLUNC1) protein possess anti-biofilm activity against S. aureus. SPLUNC1 is a 256-amino acid multifunctional protein secreted by the human respiratory tract. SPLUNC1 helps in maintaining fluid homeostasis in airway epithelia and possesses antimicrobial activity [40]. Based on the sequences of naturally occurring antimicrobial peptides, synthetic peptides are thought to be a promising treatment option for bacterial infections that are resistant to standard antibiotics. Small, cationic peptides with a variety of antimicrobial and immunological activities are known as antimicrobial peptides or AMPs. One of the main human AMPs that is crucial to the body’s defense against both systemic and local infections is LL-37 [41]. A synthetic derivative of LL-37, designated OP-145 or P60.4Ac, which includes the core antimicrobial region of LL-37 has improved antimicrobial and similar endotoxin-neutralizing activities of LL-37. Recent studies have shown that OP-145, when incorporated in a biodegradable implant coating, can prevent S. aureus-induced biomaterial-associated infection in rabbits [42].
Another molecule SAAP-148 is able to prevent the formation of predominantly polysaccharide, as well as proteinaceous biofilms, and to promote their breakdown and eradicate established S. aureus biofilms. S. aureus persisters that survived an extremely high dose of rifampicin were completely eradicated within 2 h by SAAP-148 at low micromolar concentrations. This peptide rapidly interacts with and subsequently permeabilizes the cytoplasmic membrane of bacteria, leading to bacterial death. The powerful activity of SAAP-148 against dividing and nondividing, metabolically inactive bacteria living in a biofilm, as well as against persister cells, is consistent with the method of action comparable to that used by LL-37 and LL-37 derivatives. It has long been thought that because of this rapid, membrane-based mechanism of action, resistance development to AMPs is very unlikely [43]. Thus, AMPs might prove to be a promising adjunctive therapeutic option for treating biofilms, and research is actively ongoing in this area [44].

4.5. Enzymes as Biofilm Disrupting Agents

Various enzymes have been identified to be effective against S. aureus biofilms. These can weaken S. aureus biofilms by destroying their cell wall or extracellular matrix, and include different cell wall hydrolases that can degrade the pentaglycine bridges in the S. aureus cell wall (e.g., lysostaphin, α-amylase, hyaluronidase, cysteine/histidine-dependent amidohydrolase/peptidase, endolysins) [45], proteases (e.g., V8 protease and cysteine proteases), and DNases.
Lysostaphin, a glycyl glycine endopeptidase that cleaves the pentaglycine cross-bridge of staphylococcal cell walls, has been shown to be able to lyse and disrupt the intricate structure of staphylococcal biofilms [46] and bacteriophage endolysins including cysteine/histidine-dependent amidohydrolase/peptidase from phage K (CHAPK), LysH5 from phage vB-SauS-phiIPLA88, and endolysin from phi11 phage have been found to possess the ability to lyse and disrupt the complex structure of staphylococcal biofilms [47].
In the quest for methods that can disrupt the biofilms, attempts have also been made to use proteases and nucleases encoded by staphylococci. Among the proteases, V8 protease was noted to inhibit S. aureus biofilm development and encourage biofilm detachment by inactivating autolysin (AtlA), and nucleases such as staphylococcal nuclease (Nuc), have also demonstrated anti-biofilm efficacy [48][49].

4.6. Phytochemicals

Plant derived compounds, including different phytochemicals (e.g., tannic acid, ellagic acid, xanthohumol, etc.), several polyphenolic compounds, and flavonoids, exhibit a wide range of anti-inflammatory, anti-allergic, hepatoprotective, antithrombotic, anti-carcinogenic, and vasodilatory actions. Phytochemicals are thought to act by affecting bacterial quorum-sensing activity, thus interfering in the cell–cell interactions and in biofilm formation [50]. Phytochemicals including 7-hydroxycoumarin (7-HC), indole-3-carbinol (I3C), salicylic acid, and saponin were analyzed, and 7-HC and I3C were shown to be the most effective against biofilm-producing S. aureus [50]. Research has also looked at using antibiotics and phytochemicals together to combat S. aureus biofilms, and some examples that have showed synergism include combinations of oxacillin and xanthohumol; 13C and tetracycline, erythromycin and ciprofloxacin [50][51].
Most of the plant derivatives hold great promise to tackle S. aureus biofilm infections; however, they require further in vivo experimental validations as all the data obtained from plant-derived compounds are based on in vitro results.

4.7. Staphylococcal Phages

Phages are naturally occurring viruses that infect bacteria. Bacteriophages are capable of killing antibiotic-resistant bacteria without harming commensals [52]. The mechanism of action of phage therapy involves penetration and degradation of extracellular biofilm by bacteriophages [53]. A phage can infect MRSA strains in both biofilm and planktonic phases, suggesting PAC regimens as effective adjuncts to antibiotics. It was shown that a triple combination of bacteriophage (Sb-1 phage), ceftaroline, and daptomycin effectively reduced S. aureus populations below detection limits, even in biofilm conditions, for several of the studied strains, irrespective of strain-specific MIC or growth stage [53]. Adjunctive intravenous phage therapy was studied in 13 patients with severe S. aureus infections and was noted to be well-tolerated [54] and the diSArm trial, which is a phase 1b/2a randomized trial studying the safety/efficacy of bacteriophage adjunctive therapy, is ongoing [14][55].
Phage cocktails have also been studied to target staphylococcal biofilms. For instance, Alves et al. demonstrated that a combination of BacteriophageK and DRA88 (a broad host range phage) can effectively reduce S. aureus biofilm biomass within 48 h [56].
Thus, phage and antibiotic combinations (PAC) may prove to be more effective for treating biofilms than either type of agent alone and their potential use as concomitant therapies seems promising; however, widespread use warrants continued investigation in clinical scenarios.

4.8. Surface Modifications of Medical Devices

As biofilm formation is influenced by the physical properties of the biomaterials, cell surface dynamics (including the hydrophobicity, topology, and electrostatic interactions) are an important determining factor in the attachment of staphylococci to biomaterial surfaces.
Increased surface smoothness enhanced S. aureus attachment, while increased surface roughness of the implant materials reduced S. aureus attachment [57], and S. aureus binding to implants was shown to be considerably decreased by nanopatterning titanium oxide to create rough implant surfaces [58].

4.9. Laser Shock Waves (LSW), Ultra Sound (US), and Photodynamic Therapy (PDT)

Ultra sound is an oscillating sound that is above the range of human hearing, and laser shock waves are high energy waves moving at supersonic speed. Both of these methods were shown to be effective at breaking up biofilms, enhancing antibiotic therapy [59]. Using a specific wavelength of light, photodynamic therapy activates photosensitizing agents and produces reactive oxygen species that are harmful to bacteria and Staphylococcal biofilms. These photosensitizers include malachite green, methylene blue, sinoporphyrin sodium, toluidine blue O, chlorin e6, and 5-aminolevulinic acid [60][61][62].

4.10. Antibodies/Vaccine Candidates

Vaccine/antibody development for S. aureus has been challenging, given the complex nature of staphylococcal infections and the production of a multitude of virulence factors [63]. Although attempts are being made to use capsular polysaccharide (type 5 and 8), clumping factors A and B, fibronectin binding protein, adenosine triphosphate binding cassette transporter, and amidase as potential vaccine candidates, and clumping factor A, adenosine triphosphate binding cassette transporter, and teichoic acids as therapeutic antibodies [64] to prevent and treat S. aureus infections, these are largely experimental. Several vaccine candidates have been proposed and most of the ones being investigated are antigen-based [63]. One of the vaccine candidates (rFSAV), composed of five recombinant S. aureus antigens (Hla, SEB, MntC, IsdB, and SpA), has shown promising efficacy in preclinical murine models [65][66]. Another heptavalent vaccine consisting of seven S. aureus toxoids, named IBT-V02, has also been shown to be effective in animal models [66][67][68]. Epitope-based vaccine strategy is also being investigated for vaccine production, and immunization with two S. aureus vaccine candidates, coproporphyrinogen III oxidase (CgoX) and triose phosphate isomerase (TPI), which are essential for heme synthesis and glycolysis, respectively, has been shown to elicit protective immunity against S. aureus. Monoclonal antibodies against these antigens were also shown to be protective against S. aureus infection in mice [69]. Research in this area has been largely pre-clinical [70], and investigations are ongoing to develop a vaccine that would be effective in clinical scenarios.

This entry is adapted from the peer-reviewed paper 10.3390/pathogens13010076

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