Structural and secreted products of Staphylococcus aureus act as virulence factors. Virulence factors of Staphylococcus aureus are shown in Table 18.3. These surface proteins, secreted proteins, and cell wall components help in colonization, immune stimulation, and evasion. The pathogenesis is complex and involves multiple mechanisms. The virulence factors involved in the pathogenesis of Staphylococcus aureus infection are generally not unique for MRSA. So it is important to know the pathogenesis of both Staphylococcus aureus in general and MRSA.

Pathogenesis of Staphylococcus aureus—various factors/enzymes/toxins listed in Table 18.4 are responsible for pathogenesis of infection by Staphylococcus aureus. Adhesins from the MSCRAMMs (“microbial surface components recognizing adhesive matrix molecules”) family mediate intracellular adhesion, aggregation, inflammation, and even immune evasion. Adhesins, enzymes, and toxins also contribute to internalization of bacteria into endothelial cells, invasion, and biofilm formation. Biofilm formation on the abiotic surfaces such as intraocular lenses and sutures may provide survival advantage to bacteria leading to persistent infection. Cytolysins produced by Staphylococcus aureus are involved in pathogenesis of endophthalmitis. In an experimental model, Booth et al. have reported that eyes infected with wild strain had more retinal damage and ocular inflammation as compared to Agr (accessory gene regulator) strain [27]. Experimental infection of vitreous with strains producing alpha and beta toxins seem to have more retinal dysfunction and inflammation compared to infection with mutant strains lacking these toxins [28]. These virulence factors lead to improved evasion of the host immune system or unique toxin production by these organisms.

Pathogenesis of MRSA—MRSA has certain factors and genes responsible for virulence and pathogenesis (Table 18.5) [29–38]. Gene “mec A” carried on a large mobile genetic element called staphylococcal cassette chromosome mec (SCCmec) confers methicillin resistance. SCCmecA gene encodes for an alternative penicillin-binding protein (PBP2a or PBP2b) with a lower affinity for β-lactams and allows survival to MRSA strain in different concentrations of these antimicrobial agents. Twelve major variants of SCCmec have been identified. Types I–II are more commonly associated with healthcare-associated MRSA (HA-MRSA) infections, while types IV–XII are associated with community-associated MRSA (CA-MRSA) infections. Panton-Valentine leukocidin (PVL) helps in tissue destruction and is more commonly associated with CA-MRSA infections. These factors conferring resistance to antibiotics lead to severe infection and inflammation in cases of endophthalmitis caused by MRSA.

Regulation of expression of virulence factors plays an important role in the pathogenesis of Staphylococcus infections. Virulence factor expression in Staphylococcus aureus is controlled by quorum sensing regulatory system such as Agr, SarA, Sae, and Arl [39]. Agr system regulates the production of secreted toxins and virulence factors. SarA system promotes synthesis of toxins (α, β, δ), fibronectin, and fibrinogen-binding adhesion involved in cytolysis and spread of infection. SaeR/S regulates survival of the organism during neutrophil phagocytosis. Arl system downregulates protein A.

Biofilm formation—Agr and SarA systems regulate transition from planktonic to biofilm growth. Loss of Agr enhances the propensity to biofilm formation, while loss of SarA results in reduced biofilm formation [39].

MRSA was traditionally associated with healthcare facilities, but its prevalence has increased in otherwise healthy patients without identified risk factors [5, 10]. MRSA profiles are distinguished into either healthcare-associated MRSA (HA-MRSA) or community-associated MRSA (CA-MRSA) [10, 40, 41]. These types are different from each other clinically, microbiologically, and genetically and are defined as follows:

Healthcare-associated MRSA (HA-MRSA) isolate is confirmed if the original entry criteria of hospitalization for more than 72 h before culture acquisition is met and if in the year before the present hospitalization, the patient had had any one of the following: hospitalization, surgery, residency in a long-term care facility, and hemodialysis or peritoneal dialysis or at the present admission had indwelling percutaneous devices or catheters [42]. These may have multidrug resistance, increased virulence, transmissibility, and the ability to colonize hosts [43]. Genotyping shows that these HA-MRSA are more often associated with SCCmec types I, II, and III.

Community-associated MRSA (CA-MRSA) is confirmed if the patient did not meet any of the above criteria and had an infection at the time of admission and the culture of the infection on admission was taken ≥72 h after admission. These are mainly involved in skin and soft tissue infections, often sensitive to other anti-staphylococcal agents, carry genes for Panton-Valentine leukocidin (PVL), and may present a new acquisition of type IV or type V staphylococcal cassette chromosome mec (SCCmec) DNA [43–45]. CA-MRSA is more commonly associated with SCCmec types IV to type XII on genotyping.

These MRSA profiles (HA-MRSA and CA-MRSA) are further classified phenotypically or genotypically. In phenotypic classification, demonstrating antibiotic resistance pattern, the HA-MRSA is more resistant to antibiotics (such as aminoglycosides, β-lactam, and fluoroquinolones) as compared to CA-MRSA. In genotypic classification, SCCmec types I–III are associated with HA-MRSA, and types IV–XII are associated with CA-MRSA. Currently, the number of CA-MRSA infections appears to be increasing, and the types responsible are noted in healthcare settings that make the distinction between the two types difficult [46, 47].

MRSA can affect the eye in various forms such as blepharoconjunctivitis, keratitis, corneal flap melt after LASIK, cellulitis, dacryocystitis, endophthalmitis, panophthalmitis, etc. [16, 48–50]. A retrospective cross-sectional, 8-year study reported blepharoconjunctivitis as the most common diagnosis in both MRSA and MSSA groups. The reported incidence of MRSA among all ophthalmic infections has increased from 4.1% to 16.7% from 1990 to 2007 in the United States [16].

Endophthalmitis caused by MRSA—Staphylococcus aureus is an important and frequent cause of acute-onset endophthalmitis [51]. The patients may present with hypopyon, pain, and fibrinous exudates in the anterior chamber. The visual acuity at presentation is generally poor. Experimental (rabbit and rat) model of endophthalmitis has shown that α- and β-toxins contribute significantly to endophthalmitis. Mutation of both SarA and Agr loci lead to almost complete attenuation of intraocular virulence of Staphylococcus aureus.

Exogenous endophthalmitis—acute-onset postoperative endophthalmitis caused by MRSA is a severe and potentially blinding infection; the incidence is increasing [13, 52]. Endophthalmitis with MRSA is reported most commonly after cataract surgery and often has poor visual outcomes [53, 54]. In the EVS, MSSA was reported in 7.4% of isolates, and MRSA was reported in 1.9% of isolates [17]. The reported incidence of postoperative MRSA endophthalmitis between 1990 and 2007 increased from 1.9% to 18.2% in the United States [16]. This may be due to differences in the epidemiological features and geographical distribution [13].

The visual outcomes of endophthalmitis cases caused by MRSA have invariably poor. Deramo reported a retrospective, consecutive, observational series of MRSA-associated acute postoperative endophthalmitis occurring after cataract surgery over a period of 3 years [52]. In this case series, 18% (6/33) cases were culture positive for MRSA and were treated with topical fluoroquinolones during the preoperative period. Occurrence of endophthalmitis despite the use of topical fluoroquinolones is of concern as topical fluoroquinolones (preoperatively or postoperatively) are very commonly used as a measure of endophthalmitis prevention. All these organisms were susceptible to gentamicin and vancomycin but resistant to fluoroquinolone on in vitro antibiotic susceptibility tests. The visual outcomes were poor (hand motions or worse) in four of six eyes with no light perception in two eyes. Similarly, another retrospective series of 32 patients with acute-onset endophthalmitis over a period of 13 years by Major et al. reported higher incidence of fluoroquinolone resistance among MRSA isolates (62%) compared to MSSA isolates (5%) [13]. MRSA was accounted for more than one-third of cases. Cataract surgery was the most common setting. The patients presented with hypopyon, pain, visible exudates in the anterior chamber, and poor presenting vision. All MRSA isolates were susceptible to vancomycin in this series. High rates of pars plana vitrectomy in the management of MRSA vs. MSSA were reported (61% vs. 47%) and possibly explain a more severe clinical presentation that required a vitrectomy. At 3 months follow-up, final visual acuity of 20/400 or better was reported in 36% of MRSA cases compared to 59% of MSSA cases.

Endogenous endophthalmitis—endogenous endophthalmitis caused by MRSA is rare [55]. Patients often have complex and interactive medical conditions such as immunocompromised status, immunosuppression, and chronic medical conditions including hypertension, diabetes mellitus, end-stage renal disease, intravenous drug abuse, lymphoma, and other serious health issues. Delay in the diagnosis, virulence of the causative organism, and the extent of intraocular inflammation are the predictors of final visual acuity [55, 56]. Visual outcomes in endogenous endophthalmitis caused by MRSA are usually poor. Most cases of endophthalmitis can be treated successfully with empirical antibiotics. However, it is important to identify the causative organism as well as the antibiotic susceptibilities in view of increasing antibiotic resistance so that appropriate and timely antibiotics could be used. Treatment includes pars plana vitrectomy, intravitreal, and systemic antibiotics.

Selected reports of MRSA endophthalmitis as reported in literature are shown in Table 18.6 [10, 13, 49, 52, 55–61].