Infective Endocarditis by Lactobacillus Species—A Narrative Review

Bacteria of the genus Lactobacillus are microaerophilic or aerotolerant anaerobic Gram-positive non-spore-forming rods. They are considered essential members of the human gut microbiome; however, recent studies have revealed that these microorganisms are less predominant in the gut microbiome than initially thought. Lactobacillus spp. is mainly known for its use as a probiotic in foods and supplements to prevent and treat specific issues such as infectious diseases, irritable bowel syndrome, and diabetes mellitus. However, Lactobacillus spp. may occasionally cause infections such as bacteremia or infective endocarditis (IE). The present study aimed to review all cases of IE by Lactobacillus spp. and describe the epidemiology, microbiology, clinical characteristics, treatment, and outcomes of this infection by collecting relevant data from studies existing in Pubmed and Scopus until 28 September 2023. A total of 77 studies containing data for 82 patients were included. The median age was 56 years, and 69.6% were male. A prosthetic valve was present in 16% of patients, and 17.3% had previously been on probiotics. The aortic valve was the most commonly involved intracardiac site, followed by the mitral valve. Fever, embolic phenomena, sepsis, and heart failure were the most common clinical presentations. Aminoglycosides and penicillin were the most commonly used antimicrobials for definitive treatment. Surgery was performed in 53.7% of patients. Overall mortality was 17.1%. IE in prosthetic valves and presentation with shock were independently associated with overall mortality.


Introduction
Infective Endocarditis (IE) is an infection that involves the endocardium or prosthetic material in the heart, like prosthetic heart valves or cardiac implantable electronic devices (CIED, such as defibrillators and pacemakers).IE carries significant morbidity and mortality [1,2].It is classically caused by aerobic Gram-positive cocci, such as streptococci, staphylococci, and enterococci, that may add up to 75% of the implicated microorganisms in patients with IE [3,4].However, IE may also occur in the context of anaerobic bacteria, Gram-positive rods, or Gram-negative bacteria.The exact characteristics of IE by these pathogens have not been adequately described due to the rarity of the disease that they cause [5][6][7].
Bacteria of the genus Lactobacillus are microaerophilic or aerotolerant anaerobic Grampositive non-spore-forming rods.They are considered essential members of the human gut microbiome, especially the oral cavity and ileum, and the female genital tract [8,9]; however, recent studies have revealed that these microorganisms are not as predominant in the gut microbiome as was initially thought [10].Lactobacillus spp. is widely known for its use as a probiotic in foods and supplements to prevent and treat specific diseases [11,12].These was considered significant.A univariate linear regression analysis was conducted to identify factors associated with all-cause mortality of patients with IE.More specifically, a univariate logistic regression was performed to identify any association between gender, age, presence of prosthetic cardiac valve, of poor teeth and oral hygiene or recent dental work, of previous episode of IE, rheumatic heart disease history, presence of IE at the aortic, mitral, pulmonary, tricuspid valve, presence of IE at multiple valves, presentation with fever, sepsis, embolic phenomena, development of heart failure, treatment with particular antimicrobials and performed surgical management with all-cause mortality.All statistics were calculated with GraphPad Prism 6.0 (GraphPad Software, Inc., San Diego, CA, USA).A multivariate logistic regression analysis evaluated the effect of factors previously identified in the univariate analysis model associated with all-cause mortality with a p < 0.05.Multivariate analysis was performed using the SPSS version 23.0 (IBM Corp., Armonk, NY, USA).

Included Studies' Characteristics
A total of 485 articles from PubMed and Scopus were screened.Finally, 77 met the present study's inclusion criteria [20,.The 77 studies included in the current narrative review involved 82 patients in total.Among these studies, 37 were conducted in North and South America, 32 in Europe, 6 in Asia, 1 in Africa, and 1 in Oceania.There were 70 case reports and seven case series.Figure 1 shows the geographical distribution of Lactobacillus species worldwide and Figure 2 shows the flow diagram of study inclusion.

Treatment and Outcomes of IE by Lactobacillus Species
Definitive treatment of patients is summarized in Table 2 and detailed in Table S1.The median treatment among survivors was six weeks (interquartile range: 6-7 weeks).The most commonly used antimicrobials (as definitive treatment) were aminoglycosides in 67.1% (53 out of 79 patients with available data), penicillin in 59.5% (47), aminopenicillin in 39.2% (31), vancomycin in 24.1% (19), and cephalosporins in 20.3% (16) of cases.Surgical management in combination with antimicrobial treatment was performed in 53.7% (44/82) of cases.Overall mortality was 17.1% (14/82), and mortality directly attributed to the IE episode was 12.2% (10).Overall mortality occurred in a median of 12 days (interquartile range 1-46.5 days) after admission to the hospital.As shown in Figure S1, there was a trend for a relative reduction in mortality of patients with IE by Lactobacillus spp. as decades went by, with an overall mortality of 33.3% in the decade of 1970-1979 and an overall mortality of 11.8% in the current decade (2020 and on).

Statistical Analysis of IE by Lactobacillus Species
Tables 1 and 2 compare patients with IE by Lactobacillus species who survived with those who died.Patients who died were more likely to have a prosthetic heart valve and were also more likely to develop shock in a statistically significant way.
Among the different parameters tested in the univariate regression analysis, IE in a prosthetic valve, polymicrobial IE, development of shock, as well as heart failure were positively associated with overall mortality.A multivariate logistic regression model identified IE in a prosthetic valve and the development of shock to be independently associated with overall mortality.Table 3 shows the results of the regression analysis.

Discussion
The present study described the characteristics of patients who developed IE by Lactobacillus species.The intracardiac site most commonly involved was the aortic valve, followed by the mitral valve.The most common clinical presentation included fever, embolic phenomena, sepsis, and the development of heart failure.Aminoglycosides and penicillin were the most commonly used antimicrobials for definitive treatment.Overall mortality was 17.1%.
The median age of patients diagnosed with IE by Lactobacillus spp. in the present study was 56 years, which is lower than the age in other cohorts of patients with IE, where the mean age is about 70 years [3,4,98].A male predominance was noted, as is also the case in IE by other microorganisms [3,98].A prosthetic valve was present in 16% of patients with IE by Lactobacillus spp., a rate that is comparable to that of other studies of IE, which at times may be as high as 50% [3,4,98].A previous episode of IE was noted in 9.8% of patients in the present study, and the rate of patients with a history of rheumatic fever was 6.1%.Both these rates are similar to those of other studies of patients with IE [4,98].Intravenous drug use was noted in 6.1% of the present patients, which is comparable to that in other studies of IE, where that rate is between 4% and 9.2% [3,4,98].Congenital heart disease was noted in 8.5% in the present study, being comparable to the corresponding rate in another study of IE in the general population [4].Notably, 19% of patients with IE by Lactobacillus spp.had a previous exposure to antimicrobials, which is consistent with the literature that shows that previous exposure to antimicrobials is a risk factor for the development of infection by Lactobacillus spp.[10].Moreover, 17.3% of the present patients had a previous exposure to Lactobacillus spp. in the form of probiotics.Interestingly, the increase in probiotic and dairy consumption and the numerous cases of Lactobacillus spp.infections have led to questions regarding probiotics' safety.The possible relationship between these agents and infection development remains a challenge that has to be proven, since Lactobacillus spp.constitutes part of the normal human flora [76].Indeed, there is ongoing research on the safety of probiotics since, in some cases, mainly in patients with underlying conditions, infections due to probiotics may occur [19,99].
The most commonly infected intracardiac sites were the aortic in 50.7% and the mitral valves in 48.1%, which is similar to other studies of IE, where the aortic valve was the most commonly infected valve, followed by the mitral valve [3,98].In line with the current literature, L. casei and L. rhamnosus were the most frequently identified pathogens.Regarding clinical presentation, the most common symptom was fever, occurring in 65% of patients, sepsis was evident only in 27.8%, while 6.3% developed shock.In other studies describing patients with IE, fever was present in 84% of patients [4], and shock was diagnosed in 9% [3].However, fever is absent in almost 40% of Lactobacillus IE cases.Heart failure was diagnosed in 23.8% of the present patients, a rate lower than the corresponding rate in other studies evaluating patients with IE, where rates were within the range of 33% to 52% [3,98].Embolic phenomena in IE by Lactobacillus spp.were diagnosed in 34.6% of the present patients, a rate similar to that of other studies with IE in the general population, where it ranged from 15% to 45% [3,4].
Lactobacillus species detection by conventional diagnostic methods remains challenging; early clinical suspicion is crucial for an efficient diagnostic approach.Laboratory findings are non-specific and can include thrombocytopenia, monoclonal gammopathy, or a positive rheumatoid factor [93].In the majority of cases, the diagnostic algorithm Lactobacillus IE begins with standard procedures, including blood cultures, transthoracic echocardiogram (TTE), transesophageal echocardiogram (TEE), and application of the Duke's criteria [91].TEE constitutes a valuable tool for prompt imaging of valvular regurgitation or valve vegetations, although active infection versus healing vegetations is not easily differentiated.However, in some cases, TEE might not demonstrate findings of endocarditis and, as a result, should be combined with microbiological studies [82].Valve culture, valves' PCR, or valve histology also aid in the diagnosis.However, Lactobacillus spp.detection in most laboratories is demanding given the problematic culture growth of the pathogen; only 30-50% of the isolates can be identified by conventional methods [69].Thus, advanced molecular techniques such as 16S rRNA combined with MALDI-TOF MS are required for accurate identification [71,92].
Regarding treating IE by Lactobacillus spp., there are no established susceptibility breakpoints; recommendations for antimicrobial administration rely on case series in the current literature.Antimicrobial therapy administered after susceptibility testing significantly decreases mortality rates [90].Synergistic intravenous therapy with aminoglycosides and penicillin was the most commonly suggested.This is reasonable, considering that resistance to these two antimicrobials was 15.2% and 8.5%, respectively.Aminoglycosides have been used in the treatment of IE in many pathogens, classically in the context of combination therapy, mostly by Gram-positive pathogens, as well as in the case of Gram-negative pathogens [100][101][102][103].However, there is currently a trend to reduce aminoglycoside use, since it is associated with high morbidity due to kidney injury, while its benefit in mortality is questionable [104][105][106][107][108]. Notably, in the present review, the statistical analysis among patients who survived and those who died did not reveal any statistically significant differences in terms of antimicrobial treatment in general, and for the use of aminoglycosides in the regimen in particular.Furthermore, the univariate linear regression analysis also did not find any association between aminoglycoside use and overall mortality.Thus, it would be tempting to state that aminoglycosides are not necessary in the treatment of this disease.However, only a randomized controlled trial could determine whether aminoglycosides provide any benefit in the treatment of IE by Lactobacillus spp.Moreover, this review includes a small number of patients; thus, it does not have adequate power to draw such solid conclusions.
Interestingly, resistance to vancomycin was 86.2%, which is in line with the literature suggesting that treatment of Lactobacillus spp. with vancomycin is considered generally ineffective, with most strains of Lactobacillus being inherently resistant to this drug [109].Moreover, cases of resistance to tetracyclines, ciprofloxacin, or carbapenems have also been reported [78].A possible mechanism of resistance to these agents is lactic acid production, leading to lower pH levels and decreased effectiveness of antimicrobials [71].Duration of therapy should be per standard guidelines for IE treatment.In the present review, the median intravenous treatment duration was six weeks [78].In some cases, surgical intervention, such as valve replacement or abscess drainage, should accompany antimicrobial therapy [90].The presence of heart failure, large mobile vegetations, abscesses, or multi-drug resistant organisms constitutes strong indications for surgical intervention [93].
In the present review, overall mortality was 17.1%, while in 12.2% of all patients, death was directly attributed to the episode of IE.Overall mortality was comparable to the rates noted in other studies of IE, where it was within the range of 11-40% [3,4,98].Mortality rates are generally attributed to inadequate treatment, polymicrobial infections, and the bacterial pathogenic potential [84].Importantly, statistical analysis of the cases in the present study identified IE in a prosthetic valve and presentation with shock to be independently associated with overall mortality.Interestingly, a reduction in overall mortality was noted in the studies published more recently.In general, the management of IE has changed over the years, with surgery being more commonly indicated and performed in cases where conservative treatment is inadequate [110].However, mortality remains high, at 15-30%, which could be attributed to changes in the epidemiology and the microbiology of the disease [110][111][112].The relative reduction in the overall mortality in patients with IE by Lactobacillus spp.may be linked to a similar epidemiology of the disease over the years, as well as medical improvements in the diagnosis and the medical and surgical management of the disease [113,114].
This study has some limitations.First, it mainly consists of case reports; thus, the evidence may be low, since case reports and case series contain sufficient data the credibility of which mainly depends on the accurate record keeping of each institution.For example, the information on the past medical history oral hygiene of patients, the previous use of probiotics, and the previous use of antibiotics relied on a report by each study's investigator.Inadequate referral could be associated with underreporting of the particular characteristic, leading to bias in the present study.In addition, the heterogeneity among institutions regarding surgical approaches and record-keeping affects information about outcomes and time-to-event analysis.However, given the rarity of this infection, an effort to conduct a prospective or retrospective study evaluating this condition could hardly enroll an adequate number of patients, even if it included cases over many years and from many centers.Finally, this is a narrative, not a systematic review.

Conclusions
To conclude, this narrative review describes the epidemiology, microbiology, clinical characteristics, treatment, and outcomes of IE by Lactobacillus spp.Penicillin and aminoglycosides were the most commonly used antimicrobials for definitive treatment since antimicrobial resistance was low to these antimicrobials.Prosthetic valve IE and presentation with shock were independently associated with mortality.

Figure 1 .
Figure 1.Geographical distribution of studies on infective endocarditis by Lactobacillus species worldwide.

Figure 1 .
Figure 1.Geographical distribution of studies on infective endocarditis by Lactobacillus species worldwide.

Figure 2 .
Figure 2. Flow diagram of study inclusion.

Figure 2 .
Figure 2. Flow diagram of study inclusion.

Table 1 .
Characteristics of patients with infective endocarditis by Lactobacillus species in total and regarding patients' outcomes.

Table 2 .
Clinical presentation and definitive treatment of patients with infective endocarditis byLactobacillus species in total and regarding patients' outcomes.
*: data are among the number of patients mentioned on top unless otherwise described.

Table 3 .
Regression analysis of overall mortality in patients with infective endocarditis by Lactobacillus species.