Extensively drug-resistant Alcaligenes faecalis infection

Background Alcaligenes faecalis is usually causes opportunistic infections in humans. Alcaligenes faecalis infection is often difficult to treat due to its increased resistance to several antibiotics. The results from a clinical study of patients with Alcaligenes faecalis infection may help improve patients’ clinical care. Methods We conducted a retrospective analysis of all patients presenting with Alcaligenes faecalis infection from January 2014 to December 2019. The medical records of all patients were reviewed for demographic information, clinical symptoms and signs, comorbidities, use of intravenous antibiotics within the past three months, bacterial culture, antibiotics sensitivity test, and clinical outcomes. Results Sixty-one cases of Alcaligenes faecalis infection were seen during the study period, including 25 cases of cystitis, nine cases of diabetic foot infection, eight cases of pneumonia, seven cases of acute pyelonephritis, three cases of bacteremia, and nine cases of infection at specific sites. Thirty-seven patients (60.7%) had a history of receiving intravenous antibiotics within three months of the diagnosis. Fifty-one (83.6%) cases were mixed with other bacterial infections. Extensively drug-resistant infections have been reported since 2018. The best sensitivity rate to Alcaligenes faecalis was 66.7% for three antibiotics (imipenem, meropenem, and ceftazidime) in 2019. Two antibiotics (ciprofloxacin and piperacillin/tazobactam) sensitivity rates to A. faecalis were less than 50%. Conclusions The most frequent Alcaligenes faecalis infection sites, in order, are the bloodstream, urinary tract, skin and soft tissue, and middle ear. The susceptibility rate of Alcaligenes faecalis to commonly used antibiotics is decreasing. Extensively drug-resistant Alcaligenes faecalis infections have emerged. Supplementary Information The online version contains supplementary material available at 10.1186/s12879-020-05557-8.


Introduction
Alcaligenes faecalis (A. faecalis) is a Gram-negative, obligate aerobic, oxidase-positive, catalase-positive, and nonfermenting bacterium. It is commonly found in soil, water, and in hospital settings, such as in respirators, hemodialysis systems, and intravenous solutions [1,2]. It is a potentially emerging pathogen and usually causes opportunistic infections in humans. The organism has been isolated from a range of clinical materials, such as urine, blood, wound discharge, stool, cerebrospinal fluid, and respiratory secretions [3][4][5][6]. A. faecalis has been associated with endocarditis, bacteremia, meningitis, endophthalmitis, skin and soft tissue infections, urinary tract infections, otitis media, peritonitis, and pneumonia [1,2,. A. faecalis infection is often difficult to treat due to its increased resistance to several antibiotics, such as anti-pseudomonas penicillin, cephalosporins, carbapenems, aminoglycosides, and quinolones [17,23,24,26]. Optimal antibiotic therapy for A. faecalis has not been well established in the literature. We report the results of a clinical study of patients with A. faecalis infection in this article. This study aims to emphasize the emergence of extensively drug-resistant A. faecalis and to provide local susceptibility data for the same.

Study design
We conducted a retrospective analysis of all patients presenting with A. faecalis infection who were admitted to Dalin Tzu Chi Hospital from January 2014 to December 2019. Patients were diagnosed with A. faecalis infection when their clinical symptoms and signs indicated infection.

Data collection
The data were obtained from the hospital's clinical information system, microbiology laboratory report system, and medical chart review. We obtained details on all A. faecalis infections (including community-onset infection and hospital-acquired infection), patient demographics, clinical symptoms and signs, details of hospital course, comorbidities, prior intravenous antibiotic use within 90 days, bacterial cultures, antibiotics sensitivity tests, and clinical outcomes.

Antibiotic susceptibility
Antibiotic susceptibility was tested using the VITEK® II system with VITEK® II Gram Negative Susceptibility cards (bioMérieux, Marcy-l'Étoile, France) with Clinical & Laboratory Standards Institute interpretive criteria M100-25. One Gram-negative (GN) identification card and another VITEK II AST-N322 card (for susceptibility testing of aerobic GN bacilli against specified antimicrobials) were placed in the neighboring slots, along with the transfer tube and the corresponding suspension tube [29]. The complete list of antibiotics used in susceptibility testing for A. faecalis, including piperacillin, piperacillin-tazobactam, ceftazidime, cefepime, cefotaxime, ceftriaxone, ampicillin-sulbactam, imipenem, meropenem, gentamicin, amikacin, ciprofloxacin, levofloxacin in our microbiology laboratory which was reference from clinical and laboratory standards institute (30th edition). Our microbiology laboratory susceptibility test report for A. faecalis included piperacillin-tazobactam, ceftazidime, cefepime, imipenem, meropenem, gentamicin, amikacin, ciprofloxacin, and ampicillin-sulbactam. If the susceptibility test showed resistant to all antibiotics, tigecycline susceptibility in A. faecalis would be done by the disc diffusion method.
We also searched PubMed and google scholar for topics related to Alcaligenes faecalis with no language restrictions.
The definition of MDR/XDR cites the literature of Maggiorakos et al. [30] Study ethics and consent procedure Our study was a retrospective analysis of medical records. The six-year study represented the lowest risk to the research subjects, and all information was made anonymous before being made available for research. The project was approved by the Buddhist Dalin Tzu Chi General Hospital Research Ethics Committee (Approved IRB No. B10802024), which exempted the study from the requirement for informed consent.

Statistical analysis
Continuous variables were expressed as mean ± standard deviation or median (range), whereas categorical variables were expressed as frequencies and percentages. The trend in change of antimicrobial susceptibility analyzed by linear-by-linear association in chi-square test. All statistical analyses were conducted using the statistical package SPSS for Windows (Version 17.0, SPSS, Inc., Chicago, IL, USA). A p-value < 0.05 was considered statistically significant.

Results
Sixty-one cases of A. faecalis infection were identified during the study, including 25 cases of cystitis, nine cases of diabetic foot ulcer with infection, eight cases of pneumonia, seven cases of acute pyelonephritis (APN), three cases of bacteremia, and nine cases of infection at specific sites. There were nine hospitalacquired infections cases, including three cases of diabetic foot ulcer with infection, two cases of pneumonia, one case of pleural empyema, one case of peritonitis, one case of surgical wound infection, and one case of leg burn wound infection. Thirty-one community-onset infection cases (31/52 = 59.6%) had a history of previous hospitalisation within 90 days. Thirty-seven patients (60.7%) had a history of intravenous antibiotic use within the past 90 days. The most commonly used antibiotics were ceftazidime (11 cases) and levofloxacin (ten cases). There were only two cases of receipt of antibiotics during the same hospitalisation but before the onset of A. faecalis infection, including one case of prolonged mechanical ventilation with pneumonia and one case of peritonitis. The length of stay before A. faecalis isolation of the two cases were 190 days and 22 days, respectively. Fifty-one (83.6%) cases were mixed with other bacterial infections. The most common mixed infection pathogens were Enterococcus species (nine cases), Proteus vulgaris (nine cases), and Pseudomonas aeruginosa (eight cases). (Table 1) Twenty-five cases of A. faecalis cystitis were seen during the study period, which accounts for 41% of A. faecalis infections in this report. There were ten females and 15 males in our study. The mean age was 76.9 years (range: 25 to 98 years). Sixteen cases (64%) were catheter related cystitis. One patient had     Table 5.

Cystitis with A. faecalis
The trend in change of antimicrobial susceptibility analyzed by linear-by-linear association in chi-square test ( Table 6). The susceptibility rate of A. faecalis to commonly used antibiotics (except ciprofloxacin and cefepime) is decreasing year by year.  [19]. The use of bird feces by residents as a traditional remedy to prevent ear discharge was related to these A. faecalis chronic otitis media cases. The other infections from A. faecalis that have been reported in prior studies, in order of occurrence, were meningitis, skin and soft tissue infection (SSTI), and UTI. In our series, the most frequent cases were, in order of occurrence, UTI, SSTI, and pneumonia. The cases reported in the literature and our cases indicate that the most frequent A. faecalis infection sites, in order, are the bloodstream, urinary tract, skin and soft tissue (diabetic foot ulcer accounts for 56.5% of skin and soft tissue infections), and middle ear.

A. faecalis isolation in mixed culture as a pathogen or contaminant
In Tena's report, two out of five skin and soft tissue A. faecalis cases were mixed with other bacterial infections [17]. In Filipe's series, all 20 A. faecalis otitis media cases were mixed with other bacterial infections [19]. Kahveci reported a case of A. faecalis peritonitis and concluded that it was important to view A. faecalis as a pathogen rather than a contaminant [15]. Junejo notes that it is evident that any organism found in the culture should not be completely disregarded and marked as a contaminant [23].. Al-Zakhari explains that serious illnesses and  [27]. In 2017, Laham reported a clinical sample study of an A. faecalis strain isolated from two outpatients and three inpatients, including four wounds cultures and one urine culture [47]. However, this study was only conducted for a three-month period. In 2013, Khajuria reported a total of 15 clinical isolates of A. faecalis specimens such as urine, pus, blood, and body fluids [48]. We believe that many cases of A. faecalis infections cases exist but have not been reported in the literature. Our series of A. faecalis infection cases were about 10 cases every year, which was only a small fraction of the infectious diseases in our hospital. We concur with Junejo and believe A. faecalis to be an infectious pathogen rather than contaminant. In our series, the majority of cultures were mixed with other well-established pathogens. However, one should consider that A. faecalis may be a contaminant in some cases, particularly for those who were cured despite lack of active treatment.

The trend of antibiotic sensitive rate of A. faecalis
In 1997, Bizet first reported that A. faecalis strains were resistant to amoxicillin, ticarcillin, and gentamicin [1]. Amoxicillin-clavulanic acid and cefotaxime provided a successful treatment outcome for patients with A. faecalis infection. In 2000, Pereira reported that a strain of A. faecalis resistant to expanded-spectrum beta-lactamase cephalosporins was isolated from the urine of an inpatient [2]. In 2005, Dubois described the isolation of A. faecalis with ESBL in a patient with a concurrent urinary tract infection [11]. In 2017 and 2018, two cases of XDR A. faecalis pneumonia were reported by Agarwal and Junejo [22,23]. In 2019, Hasan reported that a 60-yearold female with pandrug-resistant A. faecalis bacteremia who was treated with double-dose tigecycline had a successful treatment outcome [26]. Three articles on pandrug-resistant A. faecalis were published in 2020. Al-Zakhari reported a fatal case of cavitary pneumonia caused by pandrug-resistant A. faecalis. The patient died despite the aggressive antibiotic treatment (linezolid and polymyxin B) [27]. Majewski reported a pandrugresistant A. faecalis hospital acquired urinary tract    infection patient; the patient died in hospital [28]. Ngbede identified mobile colistin resistance genes in Alcaligenes faecalis from human clinical samples [49]. In March 2015, the strain A. faecalis exhibited sensitivity only to imipenem and meropenem in a pneumonia patient in our hospital. In May 2018, a strain of XDR A. faecalis susceptible only to tigecycline was isolated from a pneumonia patient. There were four cases with XDR A. faecalis infection in our series, including two cases of pneumonia and two cases of diabetic foot infection.
In view of individual antibiotics, ciprofloxacin revealed a very low susceptibility rate of A. faecalis from 2014 to 2019. Piperacillin/tazobactam was effective in significantly decreasing the susceptibility rate of A. faecalis since 2016. Emerging resistant strains of A. faecalis to imipenem and meropenem have been found since 2018. A high resistance rate of many antibiotics was also found in 2019. The best sensitivity rate to A. faecalis was 66.7% for three antibiotics (imipenem, meropenem, and ceftazidime). In two antibiotics (ciprofloxacin and piperacillin/tazobactam) sensitivity rates to A. faecalis were less than 50%.
Based on our prior experience, we selected an appropriate antibiotic for a susceptible A. faecalis infection patient according to the results of his or her antibiotics sensitivity test. If the A. faecalis organism is an ESBL strain, carbapenem is an appropriate antibiotic. Four articles mentioned that A. faecalis is susceptible to colistin [8,19,22,23]. Data was not available regarding A. faecalis susceptibility to colistin in this study. If the A. faecalis is an XDR strain, we recommend that tigecycline is effective to XDR A. faecalis.

Treatment failure of A. faecalis infection cases
Among our reported cases of A. faecalis infection, there were seven treatment failure cases, including two cases of pneumonia, two cases of cystitis complicated with sepsis, and three cases of diabetic foot infection. The overall treatment failure rate was 11.5%. A. faecalis is a low virulence bacterium. With adequate intravenous antibiotic therapy, patients with A. faecalis infection will typically experience a positive treatment outcome.
Patients were cured with non-covering regimens Four cases were cured with non-covering antibiotics, including two cases of diabetic foot infection, one case of pleural empyema, and one case of surgical wound infection. The four cases had received appropriate wound care, adequate abscess drainage, and surgical intervention which may be crucial for curing of infections.

Limitations
Our clinical study of A. faecalis infection was a small case series and therefore can provide only minimal clinical experience. Additional case series reports of A. faecalis infection will add to the knowledge of how to treat A. faecalis infection. Misidentification of Acinetobacter baumannii as Alcaligenes faecalis by VITEK II system was reported in the literature [50]. Matrix-assisted laser desorption ionization time of flight mass spectrometry and 16S rRNA sequencing are helpful for the accurate identification between these two species [51]. However, we cannot perform the two methods to confirm the isolates in our hospital. If the culture is XDR A. faecalis, matrix-assisted laser desorption ionization time of flight mass spectrometry and 16S rRNA sequencing can be performed. An accurate distinction between Acinetobacter baumannii and A. faecalis has substantial clinical significance.

Conclusions
A. faecalis exhibited decreasing sensitivity rate to commonly used antibiotics in 2019. Extensively drugresistant Alcaligenes faecalis infections have emerged recently. We select an antibiotic for patients susceptible to A. faecalis infection based on the results of the antibiotics sensitivity test. With adequate intravenous antibiotic therapy, patients with A. faecalis infection will typically experience a positive treatment outcome.