Mitral Valve Endocarditis with Perforation from a Urinary Source: An Unusual Case and Literature Review

Aerococcus urinae (AU) is a rare pathogen, identified as gram-positive, catalase-negative coccus that grows in pairs and clusters which has been reported to mainly cause urinary tract infections (UTI), especially in elderly males. Treatment for this microorganism is usually with beta-lactams although cultures with antibiotic susceptibility testing are imperative. We present a case of AU endocarditis initially treated with IV antibiotics; nevertheless, the patient required emergent mitral valve replacement due to severe mitral insufficiency and perforation. We also present an analysis with high-yield points summarizing epidemiology, risk factors, microbiology, clinical features, diagnostic workup, and management of AU in general and AU endocarditis. Finally, we post a literature review of relevant cases and the impact of different variables associated with it.


Case Presentation
A 55-year-old male with no significant past medical history presented with a one-week history of nonproductive cough, dyspnea at rest, dysuria, and urinary frequency and urgency. He was diagnosed with a urinary tract infection (UTI) and a viral upper respiratory tract infection by his primary care physician two days prior and was prescribed ciprofloxacin. His symptoms did not improve so he decided to go to the emergency department (ED). Upon presentation, his oxygen saturation was noted to be 90%, with tachycardia and a lowgrade fever. On exam, he had significant bibasilar crackles as well as a holosystolic apical murmur; additionally, he was found to have 2+ lower extremity edema and several punctuate macular lesions on his feet, highly suspicious for vascular emboli phenomena (Figure 1). His laboratory studies demonstrated leukocytosis with neutrophilia (14.7 bil/L and 11.3 bil/L, respectively) and evidence of acute kidney injury. The urinalysis bacteriuria and leukocytes. A chest X-ray (CXR) was unremarkable. Blood and urine cultures were obtained, and he was empirically started on ceftriaxone. A transthoracic echocardiogram revealed a mobile mass on the posterior leaflet of the mitral valve consistent with a vegetation. Ejection fraction was calculated to be 40% ( Figure 2). Preliminary blood cultures reported gram-positive cocci in pairs and clusters. At day 3, AU was identified as the pathogen in both, blood and urine, cultures. The patient was then started on intravenous gentamicin and penicillin G with plans for a 6week therapy. He was medically treated for acute heart failure with aggressive diuresis. At day 5, the patient received a transesophageal echocardiogram (TEE) which confirmed a "1 4 cm × 2 5 cm" vegetation attached to the posterior leaflet of mitral valve (Figure 3(a)), with severe mitral regurgitation and posterior leaflet perforation (Figure 3(b)). On day 8, the patient was acutely decompensated, and he was endotracheally intubated due to hypoxic respiratory failure and consequently underwent emergent prosthetic mitral valve replacement. He had a prolonged complicated postoperative period requiring mechanical ventilation, vasopressor support, and hemodialysis. Repeat blood cultures showed resolution of AU bacteremia. Finally, after 3 months, the patient was discharged to a subacute rehabilitation unit.

Discussion
AU is a rare pathogen, first isolated in 1953 found in lobsters and thought to be of no clinical significance. It was until 1967 when it was first described to cause infection in humans [1]. This organism is a gram-positive, catalase-negative growing coccus in clusters that belongs to a bacterial group referred to as Aerococcus-like organisms (ALO) [2]. It has been associated with UTI mainly, nevertheless there are reports that identify it as the culprit of blood stream infections and endocarditis. Due to difficulties in the biochemical identification, the incidence of infections with this microorganism has likely been underestimated. Currently, it is thought to be the cause of 0.15 to 0.54% of UTIs [1]; additionally, it is responsible for 0.03 to 0.05% of blood stream infections (BSI). There is not enough data regarding the incidence of AU endocarditis as there have been only 45 reports in English literature. Advanced age (>65 years) and underlying urologic conditions are the best-known risk factors for UTI and, potentially, BSI [3] and endocarditis. Both sexes are equally affected [4,5].
The diagnosis is usually challenging due to the rarity of this pathogen. It is commonly mistaken with Staphylococcus sp. and even Streptococcus viridians; for this reason, molecular diagnostic techniques are often needed to identify it. Testing for leucine aminopeptidase, which is positive only for AU, can be used to differentiate it with Staphylococcus [6]. Secure identification also relies on genetic techniques like 16S ribosomal subunit sequencing or mass spectroscopic methods such as MALDI-TOF [7]. To date, there are no guidelines that recommend starting with any of these modalities, even in the presence of the above risk factors, as they are nonspecific, so the diagnostic algorithms remain the same as for the rest of the pathogens.
Due to the current lack of controlled scientific trials and lack of formalized treatment guidelines, therapy is often empiric and guided by expert opinion. In an effort to standardize a treatment, Yabes et al. in 2018 [8] compiled the reported cases and therapies in literature and found that treatment regimens for AU have largely relied on beta-lactams, with the possible addition of synergistic aminoglycosides for endocarditis. In vitro studies regarding the antibiotic susceptibilities of AU have shown susceptibility to amoxicillin, cefotaxime, ceftriaxone, doxycycline, linezolid, meropenem, penicillin, rifampin, and vancomycin. It had variable resistance to clindamycin, erythromycin, and levofloxacin [9][10][11]. It is, however, inherently resistant to sulfonamides and fluoroquinolones [10]. The duration of treatment vary from ten days for UTI and phlegmon to 14 to 28 days for BSI and 42 days (6 weeks) for endocarditis [8]. It is important to mention that treatment for the latter very commonly includes surgical intervention as well, but indications are the same as for other etiologies.
Overall mortality of AU infections, including UTI and BSI, has been shown to be equivalent to that of other etiologies. For endocarditis in particular, a higher rate of complications and mortality has been described, with 27% more when compared to other causes. It is thought that this could be associated with an older patient population with multiple other comorbidities, making their surgical profile highly unfavorable, and dependent on medical management only [8].

Literature Review
Between 2000 and 2012, the incidence of endocarditis in the United States increased from 11 per 100,000 population to 15 per 100,000 population [12,13]. Nowadays, the precise incidence is difficult to ascertain because case definitions have varied over time between authors and between clinical centers. In addition, the presence of predisposing conditions such as rheumatic heart disease or injection drug use is variable over time and between regions and in low-and high-income countries [14,15].
A literature search on PubMed, Web of Science, Cochrane, and Google Scholar databases revealed 45 cases of AU endocarditis in English literature (Table 1). We present a summary with a mathematical analysis and  calculations involving all reports in an effort to identify patterns regarding risk factors, clinical course, treatment modalities, and prognosis.
3.1. General Statistics. The general statistics are as follows: (i) 85% (39) of the patients were male and only 15% female (7) (ii) The average age was 72 years, with the youngest patient being 42 years and the oldest 91 years (2) (iii) Of the forty patients, only three had no reported associated risk factors or comorbidities (6.5%), 93.5% did have risk factors which are as follows: (a) 69% of the patients had urologic comorbidities while only four patients (9.5%) had an underlying known cardiac condition (one patient with aortic stenosis, one patient with atrial septal defect, and one patient with pacemaker (b) Five patients were also reported to have a nonurologic associated malignancy (11.9%) (c) Only two patients (4.6%) had a different risk factor other than the ones mentioned above, a case with untreated hepatitis C and other case with liver failure (2.3% each) (iv) Regarding urologic risk factors: (a) Current or recent presence of indwelling urinary catheter was seen in eight patients (19%), benign prostatic hypertrophy was also seen in eight patients (19%)   3.3. Analysis. As seen in previous reports, most of the patients were elderly males. The majority had underlying urologic comorbidities; baseline cardiac anomalies like valvular diseases were very seldom seen. Additionally, mitral and aortic valves were equally affected. All of the patients received treatment with beta-lactam antibiotics. In most of them, aminoglycosides were used in combination; other less commonly used add-on therapies were vancomycin and rifampin. More than half of the patients did not undergo surgery, as they were deemed as poor surgical candidates or did not meet criteria for intervention. Interestingly enough, 100% of the patients that received beta-lactam as monotherapy in combination with surgery survived.
Aerococcus urinae endocarditis is associated with a 28% mortality from our calculations, deeming a high grade of aggressiveness to this microorganism. It is unclear at this time if this high mortality is due to the bacteria itself or the fact that most of the patients were elderly and had other comorbidities. Lack of surgical intervention in most patients possibly plays a role as 80% of the patients that underwent a surgical procedure survived. An underlying urologic condition was commonly seen in the patients that died, although it was recurrently seen in patients that survived as well. The affected valve does not seem to have an impact on mortality.

Conclusion
AU is an extremely unusual cause of human disease; it has been described to cause urinary tract infections, blood stream infections, and infective endocarditis. We do believe, however, that its actual incidence is higher than reported. Reliable data regarding clinical presentation, diagnosis, and potential treatments of AU are becoming more available to health-care workers making this a promising era in its management. With this case report and literature review, we aim to add critical data to the current medical literature regarding this rare pathogen. We urge health-care professionals to share related experiences in order to build up literature and treat patients in a more appropriate manner; at this time evidently, randomized studies are univariably defiant as with any rare disorder.

Conflicts of Interest
The authors declare that they have no conflict of interest