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Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of sight-threatening infections in the US. These strains pose a significant challenge in managing ocular infections, as they frequently exhibit resistance to first-line empirical antibiotics. To assess the potential of bacteriophages as innovative topical therapies for treatment of recalcitrant ocular infections, we evaluated the in vitro antimicrobial activity of a set of anti-S. aureus phages against a collection of ocular MRSA clinical isolates collected in the US.
Methods
The host range of six phages (V4SA2, V1SA9, V1SA12, V1SA19, V1SA20 and V1SA22) was assessed using the spot assay on a panel of 50 multidrug-resistant (MDR) ocular MRSA isolates selected to be representative of clones circulating in the US. Subsequently, liquid culture-based host range assay was performed for the three most active phages using different multiplicity of infection (MOI of 10–2, 1 or 100 phages/bacteria).
Results
In total, 90.0% of bacterial isolates were susceptible to at least one of the six phages. The spot host range assay showed that phages V1SA19, V1SA20 and V1SA22 had the broadest spectrum, being active against 86%, 84% and 82% of the isolates, respectively, including the MDR-MRSA CC5 and the community-associated CC8 lineages. A phage dose effect was observed across the liquid culture-based host range assay.
Conclusion
Phages V1SA19, V1SA20 and V1SA22 exhibited high antimicrobial activity against ocular MRSA. Bacteriophages represent a promising anti-infective strategy in ophthalmology that could be explored for improved topical therapy of recalcitrant MRSA infections.
Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of sight-threatening infections in the US and pose a major challenge for management of eye infections as they are often resistant to most of the first-line antibiotics used for empirical treatment.
This study investigated the potential of phage therapy to treat recalcitrant sight-threatening infections caused by MRSA.
Our preclinical data on the in vitro activity of three Silviavirus, two Kayvirus and one Rosenblumvirus phage against a collection of ocular MRSA collected in the US showed that bacteriophages could be a promising solution to overcome the growing issue of antimicrobial resistance in ophthalmology to treat ocular surface infections caused by multidrug resistant (MDR) MRSA lineages.
Silviavirus phages had the broadest spectrum, including against the MDR-MRSA CC5 and the community-associated CC8 lineages.
Introduction
Bacteria are the most common etiologies of eye infections, with gram-positive organisms, including Staphylococcus aureus, being among the leading causes [1, 2]. Staphylococcus aureus are well known for their ability to acquire and express various antimicrobial resistance mechanisms leading to multidrug resistance phenotypes (MDRs) that further complicates treatment management [3, 4]. US nationwide surveillance studies have found remarkably high rates of resistance among ocular bacteria, especially for gram-positive pathogens [5]. Thus, ocular staphylococcus isolates display the highest resistance levels among ocular bacteria, with a prevalence of methicillin-resistant S. aureus (MRSA) reaching 34.9% in the US [5]. In addition, MRSA isolates pose a major challenge for management of eye infections as they are also substantially more resistant to first-line antibiotics used for empirical treatment of ocular infections, i.e., fluoroquinolones and aminoglycosides, than methicillin-susceptible S. aureus (MSSA) [5]. Molecular epidemiology studies have shown that the population structure of MRSA causing ocular surface infections, especially keratitis, is dominated by epidemic lineages commonly associated with difficult-to-treat MDR infections in the hospital setting [6, 7]. In this context, a search for non-traditional anti-infective strategies targeting highly resistant MRSA strains associated with sight-threatening and recalcitrant keratitis is urgently needed not only to improve current therapies but also to guarantee our ability to continue treating these infections in the future as ocular MDR MRSA strains become more common.
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One potential and promising solution to overcome the growing issue of antimicrobial resistance in ophthalmology is using bacteriophages (or phages) to treat ocular surface infections caused by MDR MRSA lineages. Phages are viruses that infect bacteria and are able to kill them while being generally well tolerated as they cause no side effects in human cells [8]. They have been used empirically in Eastern Europe since their discovery in 1917 and remain a common treatment in some of these countries [9]. However, their use was abandoned in Western countries in the 1930s following the discovery of penicillins and their rapid development for clinical use. Only in the past few years has phage therapy experienced a renewal of interest in the West, especially for the treatment of severe S. aureus infections [10‐12]. Unlike antibiotics, which typically kill a broad spectrum of either gram-positive and/or gram-negative bacteria [13], phages are highly specific at the genus, species or strain level, thus limiting the broad range selection of resistant bacteria [14]. In addition, therapeutic phages show no cross-resistance with antibiotics [15]. The anti-S. aureus phages belong to various families and genera, including Herelleviridae (Kayvirus, Silviavirus genera) and Podoviridae (Rosenblumvirus genus), with Silviavirus phages having the broadest spectrum of activity [16‐20]. The PHAGEinLYON program recently established a collection of anti-S. aureus phages with well-characterized activity spectra to rapidly select the most active phage(s) against a given clinical strain [21].
Anti-Staphylococcus aureus phages have not been used widely in ophthalmology, yet they can easily be administrated locally and be highly specific and active against lineages of S. aureus involved in antibiotic-resistant infections of the eye. In this context, we investigated the potential of phage therapy to treat recalcitrant sight-threatening infections caused by MRSA. Here, we present preclinical data on the in vitro activity of three Silviavirus, two Kayvirus and one Rosenblumvirus phage against a collection of contemporary and genomically characterized strains of ocular MRSA collected in the US.
Methods
Bacterial Isolates
A total of 50 MRSA ocular isolates collected from patients presenting with eye infections at the Massachusetts Eye and Ear (MEE) from 2014 to 2021, representative of (1) the major ocular MRSA clones circulating in the US and (2) the clinical diversity of ocular MRSA infections, were included in this study (Supplementary Table S1). Protocols for obtaining discarded isolates with waived informed consent were approved by the MEE Institutional Review Board. This is an experimental laboratory investigation study approved by the Mass General Brigham Institutional Review Board (protocol 2019P001001). Protocols for collection of discarded isolates were approved by the MGB IRB (protocol 2021P000695) for prospective sampling, and the need for informed consent was waived. The study was in adherence to the tenets of the Declaration of Helsinki and is in accordance with HIPAA regulations. Bacterial identification was conducted using the MicroScan WalkAway system (Beckman Coulter, Brea, CA), as previously described [22], following the manufacturer’s protocol.
Antibiotic Susceptibility Testing
Routine antimicrobial susceptibility testing was performed using the MicroScan WalkAway system (Beckman Coulter, Brea, CA) following the manufacturer’s protocol. CLSI-approved interpretive break point criteria were applied [23]. The following representative antibiotics from nine different classes were tested, including ampicillin, oxacillin and penicillin (beta-lactams); clindamycin (lincosamide); erythromycin (macrolide); gentamicin (aminoglycoside); levofloxacin (fluoroquinolone); linezolid (oxazolidinone); tetracycline (tetracycline); trimethoprim/sulfamethoxazole (dihydrofolate reductase inhibitor); and vancomycin (glycopeptide). Multidrug resistance (MDR) was defined as resistance to three or more classes of antibiotics.
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Genome Sequencing and Assemblies
To explore the population structure of MRSA causing ocular infections, whole genome sequencing was performed for the 50 isolates included in this study. Briefly, as previously described [22], total DNA was purified from an overnight pure culture in 5 ml Brain Heart Infusion broth (BHI) using the DNeasy DNA extraction kit (Qiagen, Valencia, CA). Library preparation for Illumina sequencing was carried out using the Nextera XT DNA Library Preparation kit (Illumina, San Diego, CA). The genomes were sequenced as 2 × 250-bp reads on an Illumina MiSeq sequencer, according to the manufacturer’s specifications. Sequence reads were assembled de novo using CLC Genomics Workbench (CLC Bio, Cambridge, MA).
Prediction of Sequence Types and Clonal Complexes
Species identification and sequence type (ST) were obtained by using the Center for Genomic Epidemiology (CGE) pipeline. We determined clonal complexes (CC) by using the MLST data and the goeBURST algorithm [24]. cg-MLST phylogenetic relationships among S. aureus isolates was performed using Pathogenwatch v12.0.4 [25]. The phylogeny was visualized and annotated with iTol v4 [26]. We used SCCmecFinder v1.2 [27] to type Staphylococcal Cassette Chromosome mec (SCCmec).
Phage Propagation
Phages included in this study were selected among the PHAGEinLYON phage collection and belonged to three different genera, Silviavirus (V1SA19, V1SA20 and V1SA22), Kayvirus (V1SA9, V1SA12) and Rosenblumvirus (V4SA2). They were previously described by the PHAGEinLYON program (Silviavirus) [21] or reported for the first time in this study (Kayvirus and Rosenblumvirus). They were propagated using low-virulent S. aureus or Staphylococcus capitis strains and, if possible, did not contain any prophages in their genome as previously reported [21]. Briefly, bacterial strains (Supplementary Table S2) and phages were mixed at a multiplicity of infection of 10–2 in Tryptic Soy Broth (TSB) (BD, Franklin Lakes, NJ, USA) medium and incubated for 4–24 h to reach maximum amplification yields. Suspensions were then filtered using a 0.22-µm syringe filter to get rid of bacteria and phage lysates were stored at + 4 °C. Phage genomes were deposited in GenBank under the accession numbers OR602701, OR602702, OR611155, ON814134, ON814135 and ON814136 for V4SA2, V1SA9, V1SA12, V1SA19, V1SA20 and V1SA22, respectively (Supplementary Table S2).
Phage Host Range Agar Overlay Spot Assay
The host range of phages was assessed using the spot assay, as previously described [21], on the panel of 50 ocular MRSAs representative of clinical isolates collected at MEE between 2014 and 2021. The efficiency of plating (EOP) ratio was calculated by dividing the phage titer obtained with the tested strain by the titer obtained with the reference strain (which is the bacterial strain used for phage amplification/production). Strains were considered susceptible to phages if the EOP ratio was ≥ 0.001 [28]. Experiments were performed in biological triplicates. Null EOP values were arbitrarily set to 10−4 for graphical representation purposes.
Microtiter Plate Host Range Assay
For the liquid assay, a bacterial culture in exponential phase (OD600nm = 0.4) in TSB medium was mixed with phages in a final volume of 200 µl of TSB medium in 96-well plates to obtain a final concentration of bacteria of 106 CFU/ml and a multiplicity of infection (MOI) of 10–2,1 or 100 phages per bacteria. Bacterial growth was monitored over 24 h at 37 °C by measuring optical deviation at 600 nm (OD600nm) at 60-min intervals using a LP600 system (Agilent). The liquid assay score (LAS) was calculated as described by Xie et al. as the variation of the area under the bacterial growth curve in the presence of phages compared to the positive control (no phage treatment) [29]. The host range assessed according to this kinetic assay was arbitrary defined with the percentages of strains for which LAS values were ≥ 75% after 12 h or 24 h. All assays were performed using three biological replicates.
Statistical Analysis
Phage activity variations according to the MOI were assessed by comparing LAS distributions using the Kruskal-Wallis test. A p-value < 0.05 was considered significant. Statistical analyses were performed and figures were generated using GraphPad Prism, version 9.5.0 (GraphPad Software, San Diego, CA, USA).
Results
A total of 50 MRSA isolates recovered from common eye infections seen at MEE from 2014 to 2021 and representative of the major ocular MRSA clones circulating in the US were included in this study. Isolates were mainly recovered from periocular infections (n = 19, 38%), keratitis (n = 12, 24%), lacrimal system (n = 10, 20%), conjunctivitis (n = 6, 12%) and endophthalmitis (n = 3, 6%) (Table 1). These ocular MRSA clinical isolates were commonly resistant to erythromycin (86%), levofloxacin (56%) and clindamycin (52%) (Fig. 1A). As shown in Fig. 1B, most MRSA isolates were also resistant to other antibacterial families, with 70.0% of MRSAs considered multidrug resistant based on resistance to three or more antibiotic classes [30]. To correlate the MLST-based population structure findings with the antibiotic resistance phenotype and phage activity, a cg-MLST phylogenetic tree was generated (Fig. 2). The population structure of MRSA isolates covered a large diversity and comprised lineages within CC5 (n = 24), CC8 (n = 15), CC30 (n = 5), CC59 (n = 4), CC88 (n = 1) and ST6 (n = 1) (Fig. 2, Table 1). The occurrence of multidrug resistance was enriched among certain lineages, with 87.5% (21/24) of MRSA CC5 being MDR, whereas 33.3% (5/15) of CC8 were MDR. The CC5 group was mostly comprised of isolates belonging to ST5 (n = 14) and ST105 (n = 7), and CC8 group was mostly comprised of isolates belonging to ST8 (n = 11) (Supplementary Table S1). To characterize our MRSA isolates, we typed the SCCmec cassette, which is a mobile genetic element carrying the mec gene conferring methicillin resistance along with the genes that control its expression. All MRSA CC8 (n = 15) had a SCCmec cassette type IV, a characteristic feature of lineage USA300 [31], whereas 87.5% (21/24) of MRSA CC5 had a SCCmec cassette type II, usually found in lineage USA100 (Supplementary Table S1) [32].
Table 1
Clonal complex of ocular MRSA isolates according to their isolation sites
Clonal complex (no. of isolates)
No. of isolates from:
Periocular infectionsa
n = 19
Keratitis
n = 12
Lacrimal system
n = 10
Conjunctivitis
n = 6
Endophthalmitis
n = 3
CC5 (24)
4
8
6
3
3
CC8 (15)
8
4
2
1
–
CC30 (5)
3
–
2
–
–
CC59 (4)
2
–
–
2
–
CC88 (1)
1
–
–
–
–
ST6 (1)
1
–
–
–
–
aIncludes eyebrow abscess, orbital abscess and cellulitis, subperiosteal abscess and preseptal cellulitis
Fig. 1
Antibiotic resistance profiles of ocular MRSA isolates. A Percentage of resistant strains to clinically relevant antibiotics. B Concurrent resistance to other antibiotics
cgMLST-based phylogenetic relationships among ocular MRSA including phage and antibiotic susceptibility testing. CC5s are represented in pink and CC8s in blue
The host range of the six phages was determined using a collection of 50 ocular MRSA isolates, representative of the clinical diversity and the major ocular MRSA clones circulating in the US. The spot host range assay showed that phages V1SA19, V1SA20 and V1SA22 had the widest activity spectrum covering 86% (43/50), 84% (42/50) and 82% (41/50) of the tested isolates, respectively, while phages V1SA12, V1SA9 and V4SA2 were only active against 40% (20/50), 24% (12/50) and 8% (4/50) of isolates, respectively. The host ranges of the set of six phages were complementary as, in total, 90.0% (45/50) of bacterial isolates were susceptible to at least one of the phages, while 38.0% (19/50) were susceptible to three phages and only 4% (2/50) were susceptible to all six phages (Fig. 3A). Efficiency of plating (EOP) showed that V1SA19, V1SA20 and V1SA22 demonstrated activity against the main lineages of MRSA in our collection (EOP ratio ≥ 0.001) (Fig. 3B). Of note, phages were poorly active against CC59 isolates (EOP ratio < 0.001) (Fig. 3B).
Fig. 3
Phage activity against the collection of MRSA clinical isolates. A Number and proportion of bacterial strains susceptible to zero, one, two, three, four, five, six or at least one of the six tested phages. B EOP values for phage activity (V4SA2, V1SA9, V1SA12, V1SA19, V1SA20 and V1SA22) against different MRSA clonal complexes. One dot represents the mean of the three biological replicates obtained for one strain. Red bars represent the median EOP for each clonal complex
Interestingly, phage activity did not seem to be correlated to antibiotics resistance phenotype as most of the phages tested were active against MDR CC5 isolates (Fig. 2).
Liquid culture-based host range assay was performed specifically for the three most active phages against our MRSA isolates (V1SA19, V1SA20 and V1SA22) by using the features of an automated plate reader to monitor the culture optical density over time, allowing both determination of the phage host range and emergence of bacterial resistance in a single high-throughput format. The host range assessed according to this kinetic assay was defined with the percentages of strains for which bacterial growth inhibition values were ≥ 75% after 12 h or 24 h. In agreement with the results found in the spot host range assay, V1SA19, V1SA20 and V1SA22 phages displayed a broad host range with percentages of strains for which bacterial growth inhibition values were ≥ 75% varying from 60% (30/50) to 92% (46/50), from 52% (26/50) to 92% (46/50) and from 58% (29/50) to 88% (44/50) for phages V1SA19, V1SA20 and V1SA22, respectively, depending on the MOI (Table 2). For example, V1SA19, V1SA20 and V1SA22 were able to inhibit ≥ 75% of bacterial growth in 88% (44/50) and 92% (46/50) of MRSA isolates at MOI100 after 12 h (Table 2). After 24 h, V1SA19, V1SA20 and V1SA22 phages were able to inhibit ≥ 75% of bacterial growth from 78% (39/50) to 86% (43/50) of MRSA isolates at MOI100 (Table 2). At MOI10−2, the percentage of strains for which the liquid assay score (LAS) values were ≥ 75% after 24 h was equal or superior to those after 12 h. In contrast, at MOI1 and MOI100, the percentage of strains for which LAS values were ≥ 75% was slightly inferior at 24 h compared to 12 h, suggesting bacterial regrowth after 12 h that could correspond to emergence of bacterial resistance to phages (Table 2).
Table 2
Percentage of strains (n = 50) for which LAS values were ≥ 75% after 12 h or 24 h
V1SA19
V1SA20
V1SA22
12 h
24 h
12 h
24 h
12 h
24 h
MOI 10–2
64 (n = 32)
64 (n = 32)
52 (n = 26)
64 (n = 32)
70 (n = 35)
74 (n = 37)
MOI 1
84 (n = 42)
60 (n = 30)
82 (n = 41)
80 (n = 40)
86 (n = 43)
58 (n = 29)
MOI 100
92 (n = 46)
78 (n = 39)
92 (n = 46)
86 (n = 43)
88 (n = 44)
78 (n = 39)
A phage-dose effect was observed across this assay with the highest bacterial growth inhibition observed at MOI100, more pronounced for phage V1SA20 (Fig. 4A–C). For instance, phage V1SA20 could inhibit ≥ 75% of bacterial growth in 52% (26/50) of isolates at MOI10−2 vs. 92% (46/50) at MOI100 after 12 h and in 64% (32/50) at MOI10−2 vs. 86% (43/50) of isolates at MOI100 after 24 h (Table 2). LAS values were statistically higher in the assays at MOI100 (p < 0.0001) after 12 h of incubation (Fig. 4A–C).
Fig. 4
Activity of phages V1SA19, V1SA20 and V1SA22 in the liquid kinetic assay at 12 h and 24 h at MOI = 10–2 (A), MOI = 1 (B) and MOI = 100 (C). One dot represents the mean of the three biological replicates obtained for one strain. Red bars represent the median LAS for each phage
Similar to the results found in the spot host range assay, V1SA19, V1SA20 and V1SA22 demonstrated activity against the main lineages of MRSA in our collection, except CC59 (Fig. 5A–C). In CC5 isolates, V1SA19, V1SA20 and V1SA22 were able to inhibit ≥ 75% of bacterial growth from 45.8% (11/24) to 79.2% (19/24), from 79.2% (19/24) to 91.7% (22/24) and from 58.3% (14/24) to 83.3% (20/24) of isolates, respectively, according to the MOI. In CC8 isolates, V1SA19, V1SA20 and V1SA22 were able to inhibit ≥ 75% of bacterial growth from 80% (12/15) to 86.7% (13/15), from 53.3% (8/15) to 80% (12/15) and from 73.3% (11/15) to 93.3% (14/15) of isolates, respectively, according to the MOI.
Fig. 5
Activity of phages V1SA19, V1SA20 and V1SA22 in the liquid kinetic assay at MOI10−2 (A) MOI1 (B) and MOI100 (C) depending on the CC. One dot represents the mean of the three biological replicates obtained for one strain. Red bars represent the median LAS for each clonal complex
Antimicrobial resistance is a silent epidemic that represents a serious public health threat worldwide and will only get worse during the next decades [33]. Antibiotic resistance among ocular bacteria is also rapidly increasing [5, 34], resulting in treatment failures with deleterious consequences, such as progressive visual loss and eye evisceration [35, 36]. The development of new antibiotics has not adequately kept pace with the rise of resistance. New therapeutic options are needed. Phage therapy has been suggested by many as a promising alternative among non-traditional antimicrobials [37]. In the present in vitro study, we demonstrated that anti-S. aureus phages are active against a collection of ocular MRSA isolates, including MDR lineages frequently associated with keratitis [6, 7], paving the way to in vivo and clinical studies to determine the positioning of such a therapy for human use.
Ocular infections caused by MRSA have become increasingly common in the last 2 decades, especially in some specific geographical areas including US [5, 22, 38]. In our collection of ocular MRSA isolates composed of primarily community-associated ocular infections that we sampled, two clonal complexes, CC8 and CC5, that are also common causes of MRSA infections in other body sites [39], are highly prevalent. CC8/USA300 lineage is the most common community-acquired MRSA lineage in the US, whereas the CC5/USA100 lineage has been found to be a leading cause of antibiotic-resistant hospital-associated MRSA infections also in the US [40].
In addition, our data highlighted that MRSA isolates associated with CC5 were more likely to display a MDR phenotype and are commonly highly resistant to first-line antibiotics used in ophthalmology, such as fluoroquinolones, macrolides and aminoglycosides [5, 7]. The antimicrobial resistance patterns of the MRSA isolates collected in our service are consistent with other nationwide studies including data generated by the ARMOR study, which showed that approximately 70% of the ocular MRSA isolates collected from 2009 to 2018 in the US were resistant to at least one fluoroquinolone antibiotic and 92.9% of MRSA isolates were resistant to macrolides [5], prompting the use of alternative treatments.
Therapeutic phages have been recently implemented in the treatment of severe infections, especially bone and joint infections in Western Europe [41, 42]; however, their use in ophthalmology remains limited. Only few studies have explored their use in ophthalmology, mainly for infections caused by Enterococcus faecalis [43, 44], Pseudomonas aeruginosa [45] and Streptococcus pneumoniae [46].
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Among the six phages tested against the ocular MRSA collection in the present study, phages V1SA19, V1SA20 and V1SA22 had the widest activity spectrum. Interestingly, our data highlighted that the activity of anti-MRSA phages may be clonal complex dependent, with phages being poorly active against CC59 isolates, in agreement with previously published data [21]. This specificity might be linked to the presence of specific type I restriction-modification systems (associated with this clonal complex) known to be a defense mechanism protecting bacteria from phage invasion, including a restriction endonuclease enzyme and a methylase enzyme [47].
In addition to the spot assay, we also measured the phage host range by microtiter plate assay, which offers the opportunity of multiple comparisons between phage-host associations because of the standardization of the assay and the mathematical transformation of the resulting bacterial growth curves into single numerical values [29]. The results obtained by microtiter plate assay in the present study showed that the activity of bacteriophages against MRSA was MOI dependent and that they were strongly active at MOI100 even after only 12 h of incubation, which is of interest for local use in ophthalmology. This dose effect has also been reported by Xie et al. [29].
Because phages are highly specific at the species and strain level and can be easily instilled locally and at high doses, they have the potential to be used as a topical therapy to treat eye infections. Fadlallah et al. reported the case of a 65-year-old woman with a nosocomial left-eye corneal abscess and interstitial keratitis caused by S. aureus successfully treated by phage therapy in Georgia [48]. Of note, Singh et al. showed that intravitreal injection of the chimeric phage endolysin Ply187 protected mice from S. aureus endophthalmitis [49]. In addition, several studies showed that combination of bacteriophages with antibiotics is synergistic and efficient in treating infections caused by MDR bacteria when treatment by antibiotics alone failed [50, 51]. However, despite its promising clinical potential, phage therapy faces several hurdles that hinder its widespread utilization [52‐54]. Key challenges include regulatory complexities, phage formulation and stability in ocular conditions, as well as concerns about interactions with the immune system including potential antibody responses to phage preparations and the narrow host range specificity of phages necessitating organism identification prior to initiating therapy. Consequently, having access to a collection of purified phages, which could be used in a short delay based on phage susceptibility testing, deserves to be proposed and is pivotal to winning the fight for the limitation of the spread and the eradication of MDR pathogenic bacteria and to curing severe and deleterious infections using innovative treatments.
Conclusion
The emergence of MDR MRSA lineages that are resistant to first-line topical therapies highlights the need for the development of new therapies to treat infections caused by these pathogens. Based on the in vitro activity of phages against a collection of ocular isolates, phages V1SA19, V1SA20 and V1SA22 exhibited an interesting in vitro antimicrobial profile against ocular MDR MRSA collected in the US. We acknowledge some limitations of in vitro models in mimicking ocular physiology such as tear film, immune responses, unknown long-term effects and drug penetration. In the context of emerging multidrug resistances and the need to preserve last resort antibiotics, bacteriophages represent a promising antimicrobial strategy to address antimicrobial resistance that now deserves to be tested in in vivo animal models prior human clinical trials.
Declarations
Conflict of Interest
Camille Andre, Mathieu Medina, Camille Kolenda, Leslie Blazière, Emilie Helluin, Gregory Resch, Paulo J. M. Bispo, and Frédéric Laurent have nothing to disclose.
Ethical Approval
Protocols for obtaining discarded isolates with waived informed consent were approved by the MEE Institutional Review Board. This is an experimental laboratory investigation study approved by the Mass General Brigham Institutional Review Board (protocol 2019P001001). Protocols for collection of discarded isolates were approved by the MGB IRB (protocol 2021P000695) for prospective sampling, and the need for informed consent was waived. The study was in adherence to the tenets of the Declaration of Helsinki and is in accordance with HIPAA regulations.
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Nicht nur Schlaganfälle, sondern auch systemische embolische Ereignisse (SEE) stellen für Menschen mit Vorhofflimmern eine Gefahr dar, wie eine Metaanalyse deutlich macht. Schutz bieten vor allem direkt wirksame orale Antikoagulanzien (DOAK).
Das experimentelle Antikoagulans Abelacimab hat gegenüber Rivaroxaban den Vorteil eines geringeren Blutungsrisikos. Ältere Menschen könnten davon besonders profitieren.
In einer Autopsiestudie aus Japan fand sich in einem substanziellen Anteil der Fälle eine zu Lebzeiten nicht diagnostizierte Krebserkrankung, häufig ein wenig aggressives Prostata- oder Schilddrüsenkarzinom. Einige wenige Tumoren hatten allerdings unbemerkt gestreut.
Ob und wie stark können Infektionen mit dem Respiratorischen Synzytial-Virus kardiorespiratorische Probleme auch in der postakuten Phase verursachen? Eine Studie hat das untersucht.
