First Case of Pleural Empyema Caused by Staphylococcus simulans: Review of the Literature

Staphylococcus simulans is a coagulase-negative organism, mainly an animal pathogen. Reports of human infection have been infrequent, mainly in patients with repeated animal contact. We report the first case of pleural empyema in an elderly woman. S. simulans tends to cause more severe infection because of a biofilm layer which helps in adherence and colonization of smooth surfaces, especially prosthetic devices, shunts, and catheters. The challenging problem even after CoNS isolation and identification is the assessment of their clinical relevance. Major factors that inhibit the penetration of antibiotics is the large-sized effusions/empyema, thickness of pleura, and the nature of antibiotic itself. Source control for septic patients remains the cornerstone of treatment along with optimal antimicrobial coverage. Staphylococcus simulans, a coagulase-negative staphylococcus, is emerging as an important cause of virulent infections with high mortality in humans. Given its propensity for multidrug resistance, including vancomycin, there is an imperative for early and accurate identification of the isolate. Despite aggressive treatment, the patient succumbed to her illness.


Introduction
Staphylococcus simulans is a coagulase-negative staphylococcus. It is mainly an animal pathogen and has been found to cause bovine mastitis. It can occasionally colonize the human skin. Human infections with Staphylococcus simulans have rarely been reported, mainly in patients who have repeated contact with animals. We report the first case of pleural empyema caused by S. simulans.

Case
Report. An 80-year-old woman was admitted to the hospital after a fall. Her prior history was notable for coronary artery disease status post percutaneous intervention, poorly controlled type 2 diabetes mellitus, congestive heart failure, hypothyroidism, and atrial fibrillation. She had had multiple mechanical falls in the past with cervical spine and right-sided rib fractures. She had no recent hospitalization in the last 90 days and has been living at home prior to presentation.
ere was no history of exposure to the farm animals. During this hospitalization, she developed progressive dyspnea and hypoxia. Computed tomography (CT) revealed a bilateral pleural effusion, right more than left, with diffuse interlobular septal thickening. Note was also made of a diffuse, mosaic-like attenuation of the lung parenchyma, likely related to air trapping or obstructive small airway disease. ere was no pleural enhancement, septations, or air noted within the pleural space ( Figure 1(a)). She was noted to have new fracture of right posterior seventh, eighth, and ninth ribs. Laboratory data at admission revealed a white blood cell (WBC) count of 9.7 × 1000/µL (with 83% neutrophils and 1% eosinophils). Her hemoglobin was 11.09 g/dL, hematocrit 40.6%, platelets 143 × 1000/µL, total protein 5.1 g/dL, blood urea nitrogen (BUN) 31 mg/dL, serum creatinine 1.51 mg/dL, serum sodium (Na) 145 mEq/L, chloride (Cl) 102 mEq/L, potassium (K) 3.6 mEq/L, aspartate aminotransferase (AST) 24 IU/L, and lactate dehydrogenase (LDH) 472 IU/L. Serum procalcitonin levels were elevated to 0.59 ng/mL (normal 0.00 -0.08 ng/mL) and hemoglobin A1C (HbA1C) to 8.9%.
Blood cultures prior to initiation of antimicrobial therapy returned negative. Sputum culture was negative for bacteria, including acid-fast bacilli. Transthoracic echocardiography was unremarkable. e patient was treated initially with levofloxacin and ampicillin/sulbactam for a pneumonia and parapneumonic pleural effusion. Despite antimicrobial therapy, her respiratory status continued to deteriorate and within 48 hours of hospitalization required endotracheal intubation and ventilatory support. A thoracentesis yielded 250 ml of pus (WBCs more than 50,000 with 95% neutrophils, elevated protein 3.6 g/dL (normal 0.0-2.4 g/dL), LDH 13461 IU/L, glucose 6 mg/dL, and pH 6.94). A right-sided thoracostomy was performed to facilitate evacuation of the empyema using a 32 French (F) thoracostomy tube. Postprocedure chest X-ray confirmed the optimal placement of the tube ( Figure 2). Gram stains obtained from the pleural fluid collected under sterile conditions revealed gram-positive cocci, and her antibiotics were changed to vancomycin. e final isolate on culture and sensitivity was identified as S. simulans with heavy growth, susceptible to vancomycin and clindamycin only. A repeat CT scan of the chest revealed a persistent collection of right-sided empyema ( Figure 1(b)). Ultrasound imaging of the pleural collections did not demonstrate any septations or loculated pockets on either side. Second attempt was made to evacuate the pleural collection with the use of intrapleural fibrinolytic tissue plasminogen activator (t-PA) with little success. e patient was considered a high-risk candidate for surgical intervention considering her frailty and other medical comorbidities. Her course was further complicated by circulatory shock requiring vasopressor supports and atrial fibrillation with rapid ventricular response requiring multiple rate-controlling drugs. After about 3 weeks of a tenuous course, her family elected to withdraw care and she passed away very shortly thereafter.

Discussion
Coagulase-negative staphylococcus (CoNS) has become an important cause of nosocomial infections.   de Jesus et al. also reported a case of acute respiratory failure, ARDS with blood culture growing S. simulans [2]. To the best of our knowledge, this is the first case of pleural empyema caused by S. simulans. In our patient, there was no history of contact with animals. Mode of acquisition of infection in our patient remained unclear. S. simulans tends to cause more severe infection because of a biofilm layer which helps in adherence and colonization of smooth surfaces, especially prosthetic devices, shunts, and catheters [8]. S. simulans has also been shown to share virulence factors with S. aureus in infectious animal isolates, including staphylococcal enterotoxins, tissue necrosis cytotoxin Panton-Valentine leukocidin, and the methicillinresistance gene, mecA [5]. e encapsulated forms of S. simulans (i.e., slime layer or biofilm) have an antiphagocytic effect on human polymorphonuclear leucocytes as compared to unencapsulated forms of the pathogen [8]. Sequencing of the tuf gene has been shown to be the most accurate for the species identification of CoNS [9]. e critical event in the establishing the pathogenicity includes formation of multilayered biofilm, especially in foreign body-associated infections caused by CoNS. Members of the genus Staphylococcus produce various proteinaceous and nonproteinaceous adhesins, to mediate attachment to host surfaces, such as plasma extracellular and matrix proteins or even host cells [10,11].
ere are limited data available about how CoNS which are usually common pathogens in veterinary medicine are gaining pathogenicity in human hosts.
ere are some shared virulence factors with Staphylococcus aureus which are documented in Table 2 [5,[12][13][14]. Of note, mecApositive CoNS are capable to horizontally transfer their genes inside the staphylococcal genus with the prospective to contribute increase in new methicillin-resistant strains [12]. e challenging problem even after CoNS isolation and identification is the assessment of their clinical relevance. e major diagnostic question remains as to whether the CoNS isolate represents a contamination of the specimen, physiological colonization of the skin or mucus membranes, or a clinically significant infection. In our case, the absence of other microbiological data and the confidence in the sterile process of procuring the sample from pleural fluid warranted consideration of S. simulans in the pleural fluid as pathogenic. Important considerations include isolation of a strain in pure culture from the site of infection and repeated isolation of the same strain over the course of infection [11,15].
While treating the pleural infections, clinicians need to be cognizant of the choice of antimicrobial therapy and relevant pharmacokinetics. Major factors that inhibit the penetration of antibiotics is the large-sized effusions/empyema, thickness of pleura, and the nature of antibiotic itself; acute inflammation is proven to be a supporting factor due to vasodilation [16,17]. Teixeira et al. demonstrated that penicillin has the best penetration for the treatment of pleural pathologies, followed by metronidazole; gentamicin was found to have poor penetration and considered a poor choice for treatment of empyemas [16].
S. simulans is known to demonstrate resistance to multiple antibiotics including vancomycin [2]. In our case, the organism was resistant to ampicillin/sulbactam, cefazolin, ciprofloxacin, oxacillin, and tetracycline, but it was susceptible to vancomycin in vitro. e use of vancomycin in pleural infections has long been debated due to its suboptimal penetration; however, in our case, the multidrugresistant nature of the isolate required its use. It is debatable in retrospect if continuation of a broader antimicrobial coverage would have changed the outcome for the patient, considering poor biochemical and clinical response with the chosen antibiotic regimen.
Source control for septic patients remains the cornerstone of treatment along with optimal antimicrobial coverage. e MIST-2 study reiterated the fact where use of t-PA and DNase combination therapy in patients with pleural infection improved drainage of pleural empyema, resulting in reduction in hospital stay and need for thoracic surgery intervention [18].

Conclusion
Staphylococcus simulans, a coagulase-negative staphylococcus, is emerging as an important cause of virulent infections with high mortality in humans. Given its propensity for multidrug resistance, including vancomycin, there is an imperative for early and accurate identification of the isolate.