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Clinical Microbiology Laboratory, The Baruch Padeh Medical Center, Poriya, Tiberias, IsraelThe Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
We tested the in vitro susceptibility to Tedizolid and Dalbavancin of Methicillin-resistant Staphylococcus aureus strains recovered from blood and wound cultures, and compared our results with studies conducted in the last four years. We examined whether the spa types affect the susceptibility of the different strains.
Methods
We analyzed 275 Methicillin-resistant S. aureus strains recovered from 128 blood and 147 wound samples. For each strain, we performed minimum inhibitory concentration for Tedizolid and Dalbavancin and spa typing. We also performed a non-systematic review of the worldwide literature from the last four years concerning the in vitro activity of Tedizolid and Dalbavancin using the PubMed database; results were restricted by date of publication, between January 2015 and January 2018.
Results
We found one Dalbavancin-resistant isolate (0.36%) and no resistance to Tedizolid. The minimum inhibitory concentration values were dependent in the strain source (wound vs. blood) for both antibiotics. For Dalbavancin, there was also dependence on the spa type.
Conclusion
This study indicates Tedizolid and Dalbavancin have potent in vitro activity against the prevalent S. aureus clones in Israel. Further studies should be performed in order to uncover the factors contributing to reduced susceptibility of S. aureus strains to new drugs.
Staphylococcus aureus is one of the most common causes for human diseases. This Gram-positive bacterium causes various infections, ranging from skin and soft tissue infections, to pneumonia, meningitis, and sepsis (
In vitro susceptibility of methicillin-resistant Staphylococcus aureus isolates from skin and soft tissue infections to vancomycin, daptomycin, linezolid, and tedizolid.
) are a serious health problem worldwide. In addition to the resistance to beta-lactam antibiotics, MRSA strains have developed various forms of resistance to other antimicrobial agents, including for example reduced susceptibility to daptomycin and inducible resistance to macrolides (
In vitro susceptibility of methicillin-resistant Staphylococcus aureus isolates from skin and soft tissue infections to vancomycin, daptomycin, linezolid, and tedizolid.
In vitro activities of Tedizolid and comparator antimicrobial agents against clinical isolates of Staphylococcus aureus collected in 12 countries from 2014 to 2016.
In vitro susceptibility of methicillin-resistant Staphylococcus aureus isolates from skin and soft tissue infections to vancomycin, daptomycin, linezolid, and tedizolid.
). However, the frequent use of Vancomycin has resulted in increased minimum inhibitory concentration (MIC), development of reduced or intermediate susceptibility strains, and increased mortality rates (
In vitro susceptibility of methicillin-resistant Staphylococcus aureus isolates from skin and soft tissue infections to vancomycin, daptomycin, linezolid, and tedizolid.
In 2014, the U.S. Food and Drug administration (USFDA) approved new antimicrobial agents, Dalbavancin and Tedizolid, for treatment of acute bacterial skin and skin-structure infections caused by MRSA (
Dalbavancin is a lipoglycopeptide that inhibits cell-wall synthesis, as is Vancomycin. It is benefited with a long half-life that enables a more convenient dosing regimen. Tedizolid, belonging to the oxazolidinone antimicrobial family, suppresses protein synthesis via binding to the 50S ribosomal subunit. It is more potent than Linezolid, a previously approved oxazolidinone (
In vitro activities of Tedizolid and comparator antimicrobial agents against clinical isolates of Staphylococcus aureus collected in 12 countries from 2014 to 2016.
The current study aimed to compare the in vitro susceptibility to two of the new drugs, Tedizolid and Dalbavancin, between MRSA strains recovered from blood and wound cultures. These antibiotics have not yet been used in Israel; therefore, we wanted to evaluate the bacteria’s susceptibility to these new antibiotics prior to their use. We conducted a non-systematic review of the literature in order to compare our results with previously studies published in the four recent years. Additionally, we wanted to test whether spa types and Panton–Valentine leukocidin (pvl) toxin presence affect the susceptibility of the different strains. Spa typing of S. aureus isolates is an important tool for clonal analysis that can indicate on the virulence of specific S. aureus strains (
). The Panton–Valentine leukocidin (PVL) exotoxin encoding gene, one of the bacteria’s virulence factors, is mostly associated with community-acquired MRSA (
The study was performed at the Clinical Microbiology Laboratory of the Baruch Padeh Medical Center, Poriya, in northern Israel and at the Staphylococcus aureus National Reference Center of the Israel Ministry of Health, Jerusalem. The study included 275 MRSA strains that were isolated from blood and wound samples of patients (age range: 0–100 years) admitted to various medical institutes in Israel between May 2015 and February 2017 and sent to the Staphylococcus aureus National Reference Center of the Israel Ministry of Health. These strains, recovered from 128 blood samples and 147 wound samples, were Panton–Valentine leucocidin (pvl)-negative (hospital-acquired strains) and pvl-positive (community-acquired strains), respectively (
). S. aureus ATCC strain 29213 was used as a reference strain.
In vitro antibiotics susceptibility tests (AST)
All MRSA strains were grown at 37 ± 1 °C for 18–24 h before conducting susceptibility tests. Following incubation, several colonies were suspended in saline to a turbidity of 0.5 McFarland. The suspension was seeded on a Mueller–Hinton agar plate (Hy Laboratories Ltd., Rehovot, Israel) and then antibiotic test strips (Liofilchem, Italy, NC) were put on each agar plate for Tedizolid and Dalbavancin. Plates were incubated at 35 ± 1 °C for 16–20 h. MIC values were determined after 16–20 h according to EUCAST 2018 guidelines: resistance to Tedizolid is defined at MIC values >0.5 mg/L; resistance to Dalbavancin is defined at MIC values above 0.125 mg/L. MIC results were determined by two laboratory technician on two different days.
spa typing
Typing of MRSA strains was performed at the National Staphylococcus aureus Reference Center, Central Laboratories, Israel Ministry of Health, as previously described (
Variation of the polymorphic region X of the protein A gene during persistent airway infection of cystic fibrosis patients reflects two independent mechanisms of genetic change in Staphylococcus aureus.
). Briefly, the spa PCR products were sequenced using the BigDye Terminator v1.1 Chemistry (Applied Biosystems, Foster City, CA), according to manufacturer protocol. Cycle sequencing products were purified by gel electrophoresis and analyzed using sequencing Analysis v.5.3.1 software (Applied Biosystems). spa typing analysis was performed using BioNumerics 7.5 software.
Literature review
The literature search was performed in May 2018 using the online database PubMed. We used the following search terms: “Tedizolid” or “Dalbavancin” in combination with “MRSA”. We restricted results to articles published from January 2015 to May 2018. The reference lists of these articles were also reviewed for additional relevant publications. We included articles of all languages, if an English translation was available. Two authors screened the abstracts of all articles (MA, AP). Review articles were excluded. A total of 20 papers were identified.
Statistical analysis
Chi-square test was applied for analyzing the differences in distribution of MIC values between blood and wound MRSA strains as well as between the different spa-types.
The tests were two-tailed and statistical significance was determined with p< 0.05.
The statistical analysis was performed using SPSS 17 software (SPSS Inc., Chicago, IL).
Results
The study included 275 MRSA strains that we divided according to their origin into blood and wound strains. One hundred and twenty-eight blood MRSA isolates were pvl-negative and one hundred and forty-seven wound isolates were pvl-positive.
Figure 1A and B present the distributions of MIC values of MRSA strains for Tedizolid and Dalbavancin, respectively. No resistance to Tedizolid was found. In contrast, one isolate that was recovered from a blood culture was resistant to Dalbavancin, with an MIC value of 0.19 mg/L.
Figure 1Distribution of MIC values of the different MRSA strains to Dalbavancin (A) and Tedizolid (B).
MIC50 and MIC90 values for tedizolid were 0.25 mg/L and 0.3 mg/L, respectively, in both blood and wound strains (Table 1). For Dalbavancin, MIC50 was 0.047 mg/L for both blood and wound strains. MIC 90 was 0.055 mg/L and 0.06 mg/L for wound and blood isolates, respectively (Table 2).
Table 1Comparison of MIC distribution of MRSA strains for tedizolid in published papers.
In vitro susceptibility of methicillin-resistant Staphylococcus aureus isolates from skin and soft tissue infections to vancomycin, daptomycin, linezolid, and tedizolid.
In vitro activities of Tedizolid and comparator antimicrobial agents against clinical isolates of Staphylococcus aureus collected in 12 countries from 2014 to 2016.
In vitro activities of tedizolid compared with other antibiotics against Gram-positive pathogens associated with hospital-acquired pneumonia, skin and soft tissue infection and bloodstream infection collected from 26 hospitals in China.
Activity of linezolid and tedizolid against clinical isolates of methicillin-resistant and methicillin and linezolid resistant Staphylococcus aureus: an in vitro comparison.
In vitro activities of tedizolid and linezolid against Gram-positive cocci associated with acute bacterial skin and skin structure infections and pneumonia.
In vitro activity of tedizolid against gram-positive bacteria in patients with skin and skin structure infections and hospital-acquired pneumonia: a Korean multicenter study.
In vitro analysis of the minimal inhibitory concentration values of different generations of anti-methicillin-resistant Staphylococcus aureus antibiotics.
Dalbavancin in-vitro activity obtained against Gram-positive clinical isolates causing bone and joint infections in US and European hospitals (2011–2016).
Activity of Dalbavancin tested against gram-positive clinical isolates causing skin and skin structure infections in paediatric patients from US hospitals (2014–2015).
In vitro activity of several antimicrobial agents against methicillin-resistant Staphylococcus aureus (MRSA) isolates expressing aminoglycoside-modifying enzymes: potency of plazomicin alone and in combination with other agents.
In vitro activity of dalbavancin against multidrug-resistant Staphylococcus aureus and streptococci from patients with documented infections in Europe and surrounding regions (2011–2013).
Update on dalbavancin activity tested against Gram-positive clinical isolates responsible for documented skin and skin-structure infections in the US and European hospitals (2011–13).
We investigated whether the source of strain influenced the MIC to each antibiotic agent. We found that there was a dependency of the MIC results in the strain source for both Tedizolid and Dalbavancin (p< 0.01) (Table 3). As shown in Table 3, the prevalence of isolates with each MIC value was different between blood MRSA and wound MRSA strains, for both antibiotics. For example, in Tedizolid, while no (0%) wound strain had a MIC value of 0.5 mg/L, 7.8% (10/128) of the blood strains had this MIC value. However, most isolates from both blood and wound origins had an MIC value of either 0.25 mg/L or 0.38 mg/L.
Table 3Distribution of MIC values of MRSA strains for tedizolid and dalbavancin according to their source.
As for Dalbavancin, the differences in distribution of MIC values were observed in every MIC value. For example, 4.1% (6/147) of wound MRSA strains had an MIC value of 0.094 mg/L. In contrast, 17.2% (22/128) of blood MRSA strains had such an MIC value. Additionally, one blood MRSA isolate was resistant to Dalbavancin, while no resistance was observed among wound MRSA isolates. Most strains from blood and wound origins had an MIC value of either 0.047 mg/L or 0.064 mg/L.
We further wanted to test whether the MIC values are affected by the molecular identity of MRSA strains. For this purpose, we performed spa typing of all MRSA strains and compared the MIC results between the different types of strains. As presented in Table 4, no correlation was found between the molecular identity of MRSA strains and their MIC values for Tedizolid (p> 0.05). In contrast, we found a dependence of MIC values to Dalbavancin and spa type (Table 5). For example, most T001 and T002 strains had high MIC values. In contrast, T437 and T690 showed lower MIC values.
Table 4Distribution of MIC values of MRSA strains according to their spa typing for tedizolid.
Antibiotic resistance is one of the biggest threats to global health. The emergence of clinical MRSA strains with a reduced susceptibility to glycopeptides or a linezolid resistance (
) underscored the need for improvement of existing antimicrobial agents and development of new antibiotics.
This study investigated the in vitro antibiotic activity of Tedizolid and Dalbavancin, a new oxazolidinone and a lipoglycopeptide, respectively, against MRSA strains isolated from blood and wounds of patients of all ages.
Similar to previous published data, MRSA strains had no resistance to Tedizolid (Table 1). Only one study, performed in the United States in 2016, reported on 1.6% resistance among 302 MRSA isolates (
). In contrast to Israel, where Tedizolid is not yet in use, the United States was the first country that introduced Tedizolid to clinical use, which may explain this resistance rate.
The MIC50 and MIC90 to tedizolid were relatively low (0.25 mg/L and 0.3 mg/L, respectively), compared to previously reported MIC values in other studies. For example, a study conducted in Columbia in 2017 found MIC50 and MIC90 of 0.38 mg/L and 0.5 mg/L, respectively, among 150 MRSA isolates recovered from SSSIs (
In vitro susceptibility of methicillin-resistant Staphylococcus aureus isolates from skin and soft tissue infections to vancomycin, daptomycin, linezolid, and tedizolid.
As with Tedizolid, our MIC values to Dalbavancin were similar to those found in previous studies (Table 2). Furthermore, the MIC50 and MIC90 [0.047 mg/L and 0.055 mg/L (wound)/0.06 mg/L (blood), respectively] in the current study are relatively low. For example, MIC50 and MIC90 of 124 MRSA strains from Poland were 0.094 mg/L and 0.125 mg/L, respectively. The resistance rate to Dalbavancin (0.36%), which is surprising considering the fact that Dalbavancin is not in use in Israel, resembles the resistance rate found in 2015 among MRSA strains collected from the United States, Europe, Russia, and Israel (
Our main question in the current study was whether the source of infection affects the bacterial susceptibility to Dalbavancin and Tedizolid. We found that the Tedizolid and Dalbavancin MIC values of MRSA strains isolated from wounds tend to be lower compared to isolates from blood. To best of our knowledge, this is the first time that MIC values of different source MRSA strains were found to be statistically different. Most of the studies that had evaluated Tedizolid or Dalbavancin activity did not compare MRSA isolates from different clinical samples.
In vitro activities of tedizolid compared with other antibiotics against Gram-positive pathogens associated with hospital-acquired pneumonia, skin and soft tissue infection and bloodstream infection collected from 26 hospitals in China.
presented the Tedizolid MIC values of MRSA strains from hospital-acquired pneumonia (HAP), blood and SSSI samples, did not find any significant difference between these two groups. However, no statistical test was applied for this question. Similarly, another study presented similar Tedizolid MIC values of MRSA strains from HAP and SSSI samples, without statistical analysis (
In vitro activity of tedizolid against gram-positive bacteria in patients with skin and skin structure infections and hospital-acquired pneumonia: a Korean multicenter study.
Another conclusion of this study is that MIC values to Tedizolid and Dalbavancin are not dependent on pvl presence, meaning that we cannot conclude whether community-acquired MRSA strains are more resistant than hospital-acquired MRSA strains and vice versa.
The spa types of the 275 isolates that were tested in this study represent the common S. aureus clones isolated from human bacteremia and SSTI cases in Israel. spa type had no effect on MIC values to Tedizolid but may have affected MIC values to Dalbavancin; for example, higher MIC values can be seen in spa types t001 and t002, but further studies are needed in order to confirm this observation. It is also difficult to compare our results with those of other studies due to differences in the prevalent spa types in different areas.
Overall, both antibiotics showed potent in vitro activity against MRSA strains from different infection types and different patients (with different morbidity and age), as was shown in previous studies (
In vitro susceptibility of methicillin-resistant Staphylococcus aureus isolates from skin and soft tissue infections to vancomycin, daptomycin, linezolid, and tedizolid.
In vitro activity of tedizolid against gram-positive bacteria in patients with skin and skin structure infections and hospital-acquired pneumonia: a Korean multicenter study.
In vitro activities of tedizolid compared with other antibiotics against Gram-positive pathogens associated with hospital-acquired pneumonia, skin and soft tissue infection and bloodstream infection collected from 26 hospitals in China.
). Moreover, both antibiotics were effective against different spa types and pvl presence did not affect susceptibility. Thus, these results indicate that both antibiotics are promising and useful for treatment of infections other than the approved indication – SSSIs.
To conclude, this study indicates Tedizolid and Dalbavancin potency against the prevalent S. aureus clones in Israel. Further studies should be performed in order to uncover the factors contributing to reduced susceptibility of MRSA strains to new drugs.
Ethical committee
This study was approved by The Baruch Padeh Medical Center, Poriya Ethics Committee.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflict of interest
The authors declare that they have no competing interests.
Authors’ contribution
Avi Peretz, Maya Azrad, Yish Levi and Motti Baum out most of the laboratory detections and wrote the manuscript. Assaf Rokney and Avi peretz conceived of the study and revised the manuscript. Maya Azrad and Motti Baum collected the data. Maya Azrad performed the statistical analysis. All authors read and approved the final manuscript.
References
Aktas G.
In vitro activity of ceftriaxone combined with newer agents against MRSA.
In vitro activities of tedizolid and linezolid against Gram-positive cocci associated with acute bacterial skin and skin structure infections and pneumonia.
In vitro analysis of the minimal inhibitory concentration values of different generations of anti-methicillin-resistant Staphylococcus aureus antibiotics.
In vitro activity of dalbavancin against multidrug-resistant Staphylococcus aureus and streptococci from patients with documented infections in Europe and surrounding regions (2011–2013).
Variation of the polymorphic region X of the protein A gene during persistent airway infection of cystic fibrosis patients reflects two independent mechanisms of genetic change in Staphylococcus aureus.
In vitro activities of Tedizolid and comparator antimicrobial agents against clinical isolates of Staphylococcus aureus collected in 12 countries from 2014 to 2016.
In vitro activity of tedizolid against gram-positive bacteria in patients with skin and skin structure infections and hospital-acquired pneumonia: a Korean multicenter study.
In vitro activities of tedizolid compared with other antibiotics against Gram-positive pathogens associated with hospital-acquired pneumonia, skin and soft tissue infection and bloodstream infection collected from 26 hospitals in China.
In vitro activity of several antimicrobial agents against methicillin-resistant Staphylococcus aureus (MRSA) isolates expressing aminoglycoside-modifying enzymes: potency of plazomicin alone and in combination with other agents.
Update on dalbavancin activity tested against Gram-positive clinical isolates responsible for documented skin and skin-structure infections in the US and European hospitals (2011–13).
In vitro susceptibility of methicillin-resistant Staphylococcus aureus isolates from skin and soft tissue infections to vancomycin, daptomycin, linezolid, and tedizolid.
Activity of linezolid and tedizolid against clinical isolates of methicillin-resistant and methicillin and linezolid resistant Staphylococcus aureus: an in vitro comparison.
Dalbavancin in-vitro activity obtained against Gram-positive clinical isolates causing bone and joint infections in US and European hospitals (2011–2016).
Activity of Dalbavancin tested against gram-positive clinical isolates causing skin and skin structure infections in paediatric patients from US hospitals (2014–2015).
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