Antimicrobial Susceptibility, Minimum Inhibitory Concentrations, and Clinical Profiles of Stenotrophomonas maltophilia Endophthalmitis

Stenotrophomonas maltophilia has been reported in various ocular infections, including keratitis, conjunctivitis, preseptal cellulitis, and endophthalmitis, all of which may lead to vision loss. However, the S. maltophilia strain is resistant to a wide variety of antibiotics, including penicillins, third-generation cephalosporins, aminoglycosides, and imipenem. In this study, we retrospectively reviewed the clinical characteristics, antibiotic susceptibility, antimicrobial minimum inhibitory concentrations (MICs), and visual outcomes for S. maltophilia endophthalmitis. The data of 9 patients with positive S. maltophilia cultures in a tertiary referral center from 2010 to 2019 were reviewed. Cataract surgery (n  =  8, 89%) was the most common etiology, followed by intravitreal injection (n  =  1, 11%). S. maltophilia’s susceptibility to levofloxacin and moxifloxacin was observed in 6 cases (67%). Seven isolates were resistant to sulfamethoxazole-trimethoprim (78%). The MIC90 for S. maltophilia was 256, 256, 256, 8, 12, 12, 12, and 8 μg/mL for amikacin, cefuroxime, ceftazidime, tigecycline, sulfamethoxazole-trimethoprim, levofloxacin, galtifloxacin, and moxifloxacin, respectively. Final visual acuity was 20/200 or better in 5 patients (56%). Fluoroquinolones and tigecycline exhibited low antibiotic MIC90. Therefore, the results suggest that fluoroquinolones can be used as first-line antibiotics for S. maltophilia endophthalmitis.


Introduction
Stenotrophomonas maltophilia is an aerobic, motile, opportunistic, and gram-negative bacillus that is widely distributed in soil, plants, and humid environments [1,2]. S. maltophilia garnered clinical attention as a nosocomial pathogen that can cause serious systemic infections, such as catheter-related bacteremia, pneumonia, and endocarditis; the pathogen is also related to prolonged hospitalization and high mortality rates, especially among patients with compromised immune systems [3][4][5][6]. S. maltophilia has been reported in various ocular infections, including keratitis, conjunctivitis, preseptal cellulitis, and endophthalmitis, all of which may lead to vision loss [7][8][9]. The current treatment protocol for S. maltophilia endophthalmitis is the intravitreal injection of antibiotics with or without pars plana vitrectomy (PPV) [10][11][12]. However, the S. maltophilia strain is resistant to a wide variety of antibiotics, including penicillins, third-generation cephalosporins, aminoglycosides, and imipenem [9,11]. A variable susceptibility to fluoroquinolones and vancomycin has been reported of S. maltophilia [1,13,14]. The multidrug resistance of the bacteria may pose a challenge for clinicians treating S. maltophilia endophthalmitis.
Our literature review of endophthalmitis research on PubMed revealed no specific report of minimum inhibitory concentrations (MICs) for S. maltophilia. Our previous Table 1 presents the demographics, clinical characteristics, management, and visual outcomes of the patients in our study. The patients' average age was 64 (range, 18-83) years. A total of nine eyes belonging to five male and four female patients were involved. The patients' mean follow-up duration was 2.8 years (range, 3 months to 9 years). Additionally, since our hospital was a tertiary referral center, most of the cases were transferred from local clinics or hospitals. Therefore, the medical devices and contaminated solutions responsible for the possible causes of infection were hard to be identified. As far as we understood, there were no risk factors, such as contact lenses uses and keratitis, in our case series.
The causes of endophthalmitis were all exogenous and included cataract extraction (n = 8, 89%) and intravitreal injection (n = 1, 11%). Hypertension and diabetic mellitus were comorbid in five (56%) and four (44%) patients, respectively. Visual acuity (VA) was 20/200 in two patients (22%), counting fingers (CF) in four patients (44%), hand motions (HM) in one patient (11%), and light perception in two patients (22%). The final VA was 20/200 or better in five eyes (56%), CF in two eyes (22%), and HM in one eye (11%). One patient was lost to follow-up after a 3-month interval. Seven patients received vitreous tapping with an intravitreal injection of antibiotics (TAP) as their initial treatment, and two patients received PPV as their primary treatment. One patient (Patient 9) who underwent cataract extraction 2 months earlier received an initial diagnosis of recurrent uveitis. However, the vitreous sample from PPV indicated the growth of S. maltophilia. Five patients received secondary treatment, including TAP for four patients and PPV for one patient. Four patients required additional treatment.

Antibiotic Susceptibility and Antimicrobial Minimum Inhibitory Concentrations (MICs)
S. maltophilia was identified in the vitreous samples of five of the nine patients and in the anterior chamber fluid samples of four patients. The S. maltophilia in six isolates (67%) was revealed to be susceptible to both levofloxacin and moxifloxacin. In two isolates, S. maltophilia was revealed to be susceptible to SMX-TMP (22%). The clinical microbial profile of each patient is listed in Table 2. Table 2. Antibiotic susceptibility results of Stenotrophomonas maltophilia.

No.
Levofloxacin S S S S: susceptible, SMX-TMP: sulfamethoxazole-trimethoprim, R: resistant. Table 3 lists the MIC breakpoints of antibiotics. The MIC 50 and MIC 90 of the fluoroquinolones were as follows. The MIC 50 and MIC 90 of levofloxacin were 1 and 12 µg/mL, respectively. The MIC 50 and MIC 90 of moxifloxacin were 0.25 and 8 µg/mL, respectively. The MIC 50 and MIC 90 of gatifloxacin were 0.5 and 12 µg/mL, respectively.

Discussion
To the best of our knowledge, this is the first study to evaluate the MIC of S. maltophilia in eyes with S. maltophilia endophthalmitis. As in previous studies, the primary etiology of S. maltophilia endophthalmitis was cataract extraction. Fluoroquinolones and tigecycline exhibited a low antibiotic MIC 50 and MIC 90 for S. maltophilia isolates, whereas ceftazidime and cefuroxime exhibited high MICs. Although some S. maltophilia isolates exhibited resistance to fluoroquinolones, fluoroquinolones can still be an option for S. maltophilia endophthalmitis. Table 4 presents the data of patients with S. maltophilia endophthalmitis in the literature and the present study. In the present study, the most common etiology of S. maltophilia endophthalmitis was cataract surgery (89%). This finding was in agreement with those of studies conducted in Argentina [2], Turkey [9], Japan [16], Germany [17], China [18,19], and the United States [20]. In our study, only one case (Patient 5) was related to intravitreal injection. Agarwal et al. [10] reported 28 cases of culture-proven S. maltophilia endophthalmitis caused by intravitreal injections; in their study, 23 patients exhibited a VA worse than 20/200 when they received their endophthalmitis diagnosis. However, after 17 patients received intravitreal injections with ceftazidime followed by PPV, they reported that only one patient exhibited a final VA worse than 20/200. In the present study, one patient developed endophthalmitis after receiving an intravitreal injection; however, the patient's VA eventually improved to 20/50 after intravitreal injections of amikacin, vancomycin, and moxifloxacin and subsequent PPV and cataract extraction.
The susceptibility of S. maltophilia to levofloxacin has been widely reported [7,[10][11][12]18,21,22]. Ji et al. [11] reported that 8 of 14 cases (57%) were susceptible to levofloxacin. In our 2010 study [12], we reported 6 cases of S. maltophilia ocular infection susceptible (75% to 100%) to fluoroquinolones. In the present study, we reported 6 cases (67%) susceptible to levofloxacin and moxifloxacin, indicating a greater resistance to fluoroquinolones than that found in our previous study. The higher resistance compared with the previous study may be associated with the use of intracameral and topical fluoroquinolones at the end of and after cataract surgeries in Taiwan. We also identified the MIC breakpoints of the S. maltophilia strain. Fluoroquinolones exhibited the lowest MIC 90 (1, 8, and 12 µg/mL for levofloxacin, moxifloxacin, and gatifloxacin, respectively). Therefore, despite the variable susceptibilities of S. maltophilia, we still recommend fluoroquinolones as the first-line therapy for S. maltophilia endophthalmitis.
We observed high MICs for cefuroxime and ceftazidime. This finding contradicted that reported in 1997 by Hanberger et al. [23], who determined the MIC 50 and MIC 90 of ceftazidime to be 1 and 16 µg/mL, respectively. However, our finding may indicate that the MIC for ceftazidime has increased over this time. Because intracameral cefuroxime is widely used in prophylactic management for cataract surgery [24,25], the increased MIC may also explain the high prevalence of S. maltophilia endophthalmitis after cataract surgery. However, S. maltophilia is typically resistant to cefuroxime and has a high MIC.
Although intracameral cefuroxime is often used as a prophylactic measure for preventing post-cataract endophthalmitis, cefuroxime is not an effective antibiotic for S. maltophilia. Three multidrug-resistant S. maltophilia strains were revealed to be resistant to moxifloxacin and levofloxacin in our study, but rather low MIC 50 and MIC 90 of amikacin, of 4 and 8 µg/mL, were found. Given the retinal toxicity of intravitreal amikacin, amikacin is less effective for treating bacterial endophthalmitis. When a patient with S. maltophilia endophthalmitis exhibits no improvement after receiving intravitreal ceftazidime or fluoroquinolones, amikacin can still be used as an alternative agent.
Notably, resistance to SMX-TMP was identified in 7 of the 9 patients in our study group. This finding differed from that of our previous study [12], which reported that all the S. maltophilia isolates that were investigated were sensitive to SMX-TMP. An increase in resistance to SMX-TMP over the past decade was identified; this increase may be related to the spread of the sul1 gene and class 1 integrins and insertion sequence common region (ISCR) elements linked to the sul2 gene [26,27], which not only explain the increased resistance to SMX-TMP but also suggest treatment options for future S. maltophilia infections.
We observed a low MIC for tigecycline. A similar finding was reported by Wu et al. [28], who determined the MIC 90 for tigecycline to be 1 µg/mL for S. maltophilia. Yue et al. [29] demonstrated that a combination of tigecycline and azithromycin can successfully inhibit the formation of an S. maltophilia biofilm. Given the results of our study, tigecycline may be another effective treatment option for S. maltophilia infections.
PPV is performed when a patient's ocular inflammation persists, or the patient's clinical condition worsens after intravitreal antibiotics. Horio et al. [16] presented two cases of endophthalmitis after intraocular lens implantation; both patients eventually received PPV and exhibited a final VA worse than 20/200. Chhablani et al. [1] also reported four patients who received PPV for dense vitreous opacities; in that study, three patients exhibited a final VA better than 20/80, and one patient's VA remained at the light-perception level. In our study, three patients received PPV as primary or secondary treatment for severe ocular inflammation, and all patients exhibited improved VA after PPV except one excluded for loss to follow-up.
The limitations of our study are its retrospective nature and the limited number of patients who underwent antibiotic testing because of the clinical setting of the study. Because most of the cases were transferred from local clinics or hospitals, the medical devices and contaminated solutions responsible for the possible causes of infection were hard to be identified. Moreover, the inclusion of all patients with positive cultures could have introduced selection bias due to the exclusion of false-negative results. However, our study clarified the etiology, antibiotic susceptibility patterns, MICs, and visual outcomes relating to endophthalmitis caused by S. maltophilia.

Conclusions
S. maltophilia endophthalmitis, which mostly occurs after cataract surgery, is associated with a promising visual outcome when proper clinical management is implemented. Although the investigated S. maltophilia isolates were not fully susceptible to fluoroquinolones, fluoroquinolones were revealed to have lower antibiotic MICs than other antibiotics. Therefore, the results suggest that fluoroquinolones can be used as first-line antibiotics for S. maltophilia endophthalmitis.

Data Availability Statement:
The data analyzed during this study are available on request from the corresponding author, Kuan-Jen Chen. The data are not publicly available due to containing information that could compromise the privacy of the research participants.