![]() Season: A letter to the future is coming to PC, PS4, and PS5 on January 31st, 2023.
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12/9/2023 0 Comments Campbell hausfeld air compressor![]() Each month during an equal payments plan you are required to pay in full by the due date that month’s equal payments plan instalment. There is no administration fee charged for entering into a special payments plan. However, if we do not receive the full minimum due on a statement within 59 days of the date of that statement, or any event of default (other than a payment default) occurs under your Cardmember Agreement, all special payment plans on your account will terminate and (i) you will then be charged interest on the balances outstanding on such plans at the applicable regular annual rate from the day after the date of your next statement, and (ii) the balances outstanding will form part of the balance due on that statement. Interest does not accrue during the period of the plan. Dealers may sell for less.įinancing available is “Equal payments, no interest” for 24 months (unless otherwise stated) and is only available on request, on approved credit and on purchases of $150 (unless otherwise stated) or more (Gift Cards excluded) made with your Triangle credit card at Canadian Tire, Sport Chek, Mark’s, L’Équipeur, Atmosphere, Sports Rousseau, Hockey Experts, L’Entrepôt du Hockey and participating Sports Experts. **Online prices and sale effective dates may differ from those in-store and may vary by region. ![]() ±Was price reflects the last national regular price this product was sold for. The tire producer / manufacturer and Canadian Tire uses this fee to pay for the collection, transportation, and processing of used tires.ĬANADIAN TIRE® and the CANADIAN TIRE T riangle Design are registered trade-marks of Canadian Tire Corporation, Limited. △The tire producer / manufacturer of the tires you are buying, and Canadian Tire is responsible for the recycling fee that is included in your invoice. ![]() ![]() ![]() ![]() ![]() Study up and play it as an offline game! IN-GAME ENCYCLOPEDIA! learn all about this strategy game, your enemies and you will be able to plan the best strategy to clash them.PLAY IT AS A OFFLINE GAME! No internet? No problem! You will be able to jump into real action even offline!.Hours of army with OVER 80 ACHIEVEMENTS! what can you expect from Ironhide Games, the creators of Kingdom rush? You will be hooked for hours searching for Easter eggs and epic achievements!.EPIC BOSS FIGHTS! Hey, we told you to get those upgrades.Action like you have never seen before in this tower defense! OVER 40 ENEMIES with epic and unique abilities! Stay on your toes as you fight through desert sandworms, tribal shamans, nomad tribes, and underground terrors.Special units and features on every stage! Watch out for the Black Dragon! DEFEAT THEM ALL.Choose among mighty champions and train their abilities! Each has unique specialties that fit different play styles and strategies! Fortify the frontier in epic news lands - hold the line in deserts, jungles, and even the underworld in this strategy game! TRAIN LEGENDARY HEROES.UPGRADE SYSTEM allows you to min/max your towers towards your preferred strategy.8 SPECIALIZED TOWER UPGRADES! Slice, sizzle, and stomp your foes with Crossbow Forts, Mighty Templars, Necromancers, and even Earthquake Machines - hey, we told you we were shaking things up. ![]() OVER 18 TOWER ABILITIES! Unleash Death Riders, pestilence clouds, or assassins that steal and clash your enemies in this tower defense game!.Whether you're a seasoned strategy game veteran or a newcomer to the tower defense genre, Kingdom Rush Frontiers is a must-play game that will keep you coming back for more! BUILD MIGHTY TOWERS! Embark on an epic journey through new, exotic lands and unlock powerful upgrades to your towers and heroes to stay one step ahead of your foes. With a vast array of flashy towers, levels, heroes, and other goodies at your disposal, you'll be able to crush your enemies to a pulp and emerge victorious. In this strategic tower defense game, you'll take on the challenge of defending exotic lands from dragons, man-eating plants, and ghastly underworld denizens. Get ready for a brand new chapter in the award-winning tower defense game,Įxperience an even more enchanting and furiously fast gameplay that will keep you on the edge of your seat! The furious tower defense battles you love are back! Will you be able to build a mighty empire and conquer your opponents?ĭownload Kingdom Rush Frontiers TD APK now and find out! You can also form alliances with other players, trade resources, and participate in epic battles. With a variety of units to choose from, including infantry, cavalry, and archers, Kingdom Rush Frontiers TD APK provides a realistic combat experience. The latest update on includes bug fixes and performance improvements. Since then, the developers have constantly updated the game to provide users with the best possible gaming experience. Offered by Ironhide Games, this strategy game falls under the category of Strategy Games and was first released on Sep 25, 2013. The game has received 2011141++ downloads and has an impressive rating of 4.7 ⭐ based on 181403+ reviews. With its latest version 5.8.02, this game offers a thrilling experience of building your own empire, managing resources, and leading your army to victory.ĭesigned for Android 4.4 and up, Kingdom Rush Frontiers TD APK has been optimized for seamless gameplay and offers a download size of 250.32 MB. Kingdom Rush Frontiers TD APK - Build Your Empire and Conquer Your OpponentsĮnter the world of strategic warfare with Kingdom Rush Frontiers TD APK, the ultimate strategy game for Android users. ![]() 12/9/2023 0 Comments Red sox tickets game 5![]() ![]() The team was renamed in 1907 and has become one of Major League Baseball’s most popular franchises. There are seven giveaway games on the calendar - most occurring during the week.The Boston Red Sox started out in 1901 as one of the American League's original eight teams. Unlike many teams that offer frequent promotions and giveaways to attract fans, the Red Sox only offer a few such games each year. For fans who haven't been to the ballpark in a while, expect a number of new sights and seating areas.įor fans who have been recently, there weren't many significant changes made in the 2022 off-season. 2023 Changes at Fenway Parkįenway Park has seen a lot of work done over the past 15 years. The biggest downside is that you may be stuck behind one of Fenway's many support poles. If you want an affordable ticket that looks out at Fenway's most distinguishable features, consider the Grandstand. These are outfield seats that don't have a view of the iconic Green Monster. There are two primary options when looking for cheap tickets for a Red Sox game: Bleachers and Grandstand.īleachers tickets can be found for less than $20 for some games. The table below lists top ticket options with the lowest price for the rest of the season (as of Aug. Standing Room tickets are usually sold for less than $100, while seated/reserved tickets are much more expensive. These are less expensive, but still average about $200 for more home games.įinally, the most desirable tickets are the Monster Seats. Pavilion Club tickets are another option for an upscale experience. These are two of the most exclusive seating areas, and it's not uncommon to see tickets priced at $1,000 or more. The best tickets to a Red Sox game are in the Dell Technologies Club or Dugout Boxes. New York Yankees at Boston Red Sox Fenway Park - Boston, MA Tickets In the summer, weekday games against less-popular teams like the Royals, Marlins and Orioles are the most affordable. This year, games against the Pirates and Twins in April are among the lowest-priced. The cheapest games are usually at the beginning of the season when the weather is iffy and the kids are in school. Cheap Red Sox Ticketsįinding a deal on Red Sox tickets is no easy task. Those prices should remain consistent throughout the season - though a post-season run would likely drive up demand for late-season contests. The average get-in price is around $50 and the median price is north of $100. For every month of the 2022 season, Red Sox tickets on ranked among the five most expensive MLB tickets.Īs of early 2023, secondary ticket prices remain high. This is on top of an already-high average ticket price. Red Sox season ticket prices increased by roughly 2% for the 2023 season. How Much are Red Sox Tickets? 2023 Ticket Prices The main Coca-Cola Deck is also a reserved space from which you can watch the game. These spaces cater to fans before the game with packages including food and beverage. The most popular group destinations are the Coca-Cola Decks and the vineyard vines club. ![]() While the ballpark wasn't originally built with that purpose in mind, new spaces have cropped up in recent years that can accommodate up to 200 guests. Each plan comes with a different level of perks, but most include post-season ticket priority and pre-sale opportunities for summer concerts.įenway is a popular destination for group outings. Ticket plans are available in different game quantities, including 10, 20 and 40-game plans. If the cost - and commitment - of full season tickets is too high, a multi-game plan is another consideration. The interactive ticket map allows you to compare multiple games and multiple seat locations. There are nearly 70,000 listings available for the 2023 season. ![]() We recommend starting your search on the Fenway Park interactive seating chart. On, tickets are available for all 81 games. Late-summer games will go on sale at a later date. Early-season games are currently for sale, while early-summer games go on sale February 23rd. The Red Sox are phasing their single-game ticket sales for 2023. Through the team's site, full-season plans range from $4,100 to $17,000 per seat. Red Sox season tickets are available in most locations for the 2023 season. Where to Buy Red Sox Tickets Season Tickets Fans are buying tickets for their annual visit and/or planning their summer vacation to Boston.ĭespite playing in a competitive division and having lost one of their stars (Xander Bogaerts), there is some optimism that the team can rebound behind the signing of a few veteran players. East in 2022, Red Sox tickets were the second most popular MLB ticket on .Īs of February, 2023 Red Sox tickets are the most searched-for MLB tickets on the site. No matter how the team is doing, Red Sox tickets will always be in high-demand for games at Fenway Park. ![]() 12/9/2023 0 Comments Free little devil inside![]() ![]() There you’ll be able to talk with NPCs and gather information about your next destination, which is apparently very important as it’ll dictate what kind of gear you’ll need to bring. In between missions, you’ll find yourself at the main town in the game, which acts as the hub. There is also an upgrade system that players can take part in where you can not only upgrade your means of transportation but also your weapons and armor. For a game that doesn’t look very realistic, it seems rather immersive. You use little miniatures to guide your way around obstacles or possible interactions in the world. inside the team. paylines Heartstopper for enhanced free spins Win. outside of the bedroom that Seth was staying in inside the spare house. Traveling across the map involves quite literally traveling across the world map of the game. Lil Devil by Big Time Gaming Free Play Full review of this 6 reels. Apart from a little secret, she is a werewolf, her life was in her control. The gameplay itself looks similar to Legend of Zelda: Breath of the Wild, Bloodborne and Ghost of Tsushima, taking the camera angle from Zelda, the grittiness from Bloodborne and the cinematic swordplay from Ghost.Īs far as braving the wilds are concerned, you have a tent and cooking equipment that you can use to fill up on food and water. Your weaponry is rather diverse, as the developers provide you with a sword, shield, gun, grappling hook and bombs. One of the best Xbox 360 games is free on Xbox Series X and thats not all. Little Devil Inside is a third-person action-adventure game that not only focuses on cinematic combat but also deals with survival elements and open-world exploration. Little Devil Inside is an exploration/survival game with RPG elements and a charming art style. In The Witcher, Geralt gets treated like shit and gets paid like shit despite being one of the most notable monster hunters in the world. Notably, the world of Little Devil Inside seems cruel to its heroes, similar to The Witcher. In one of the trailers, we are introduced to what accepting a job looks like, and that led to almost being sacrificed to some kraken-looking fellow. A nearly five minute long narrated trailer demonstrated the upcoming RPG’s highly unique art style. Just from the trailers alone, we already know that Billy is literally traveling everywhere imaginable, from tropical areas and barren deserts to the middle of the ocean and an icy tundra. It was just a little over a year ago on Octothat Little Devil Inside provided the grand finale of the PlayStation State of Play, which highlighted upcoming third party titles for PS4 and PS5 consoles. ![]() The game will explore the mundane parts of an adventurer’s life, such as financial inequality. When they came home, they realized that the house was not a normal house and that supernatural. His friends went to his new home to look for Jake. Their friends hadnt heard from Jake since he moved in. Jake has bought a house in his new home town. Neostream states that the game is meant to take a satirical angle on the video game cliché of monster hunting, which makes sense given that the trailer looked a lot like if Bloodborne and Monster Hunter had a baby. Little Devil is a horror game with Singleplayer and Multiplayer modes, played with 1 to 5 people. ![]() ![]() ![]() ![]() Pregnant women and children of 6 months or older can use DEET-containing insect repellent.Use DEET-containing insect repellent on exposed parts of the body and clothing.Wear loose, light-coloured long-sleeved tops and trousers.To prevent vector-borne diseases, members of the public need to protect themselves from stings / bites of mosquitoes, mites and ticks, and prevent their proliferation. Mosquitoes are responsible for transmitting dengue fever (Aedes mosquitoes), Japanese encephalitis (Culex mosquitoes) and malaria (Anopheles mosquitoes) while scrub typhus and spotted fever are transmitted by mites and ticks respectively. Most dengue fever and malaria cases recorded are imported from endemic countries via international travel, while most cases of scrub typhus and spotted fever acquired the infection locally and had history of going to vegetated areas in Hong Kong, for example hiking areas, outdoor workplaces, vegetated areas near home or outdoor recreational areas. In Hong Kong, there are several important vector-borne diseases including dengue fever, Japanese encephalitis, malaria, scrub typhus and spotted fever. They can be caused by parasites, bacteria or viruses. The diseases transmitted by vectors are called vector-borne diseases. This has given some Australian producers access to bluetongue-sensitive overseas markets that were not previously available to them.Vectors are living organisms such as mosquitoes, mites and ticks that can carry disease from one infected person (or animal) to another person. Those carried by mosquitoes (such as bovine ephemeral fever, Murray Valley encephalitis, Ross River and Kunjin) are more widely distributed.Ī bluetongue-free zone has been established from surveillance data obtained by the monitoring program. Those carried by Culicoides midges (such as bluetongue and Akabane) are mainly confined to the north and east of Queensland. The distribution of arboviruses is determined by their insect vectors. Insect traps near the animals in these herds show whether insect vectors are present. New animals are selected each year to replace those that develop antibodies to the viruses. They are blood tested at regular intervals to detect the incidence of viral infection. Surveillance carried out under the program provides producers with early warning of movement by these endemic diseases into new areas where cattle that have not previously been exposed are likely to suffer severe symptoms, including abortion, fever, loss of coordination and, in some cases, death.ĭata for the program is gathered by monitoring cattle located in sentinel herds – groups of cattle previously unexposed to arboviral infections. Risk management: Detecting seasonal changes in distribution of the 3 viruses and their vectors.Bluetongue early warning: Detecting incursions of exotic strains of bluetongue virus into North Queensland through surveillance of the northern bluetongue virus endemic area.Trade support: Facilitating the export of live sheep, cattle and goats to countries sensitive to bluetongue, Akabane and bovine ephemeral fever (BEF or three-day sickness) by providing scientific information for the development of export protocols and to meet export certification requirements.The program currently monitors the distribution of the 3 most economically important insect-borne viruses that affect livestock for trade: rhabdoviruses (bovine ephemeral fever).alphaviruses (Ross River, Barmah forest).flaviviruses (Murray Valley encephalitis, Japanese encephalitis, Kunjin).orbiviruses (bluetongue, epizootic haemorrhagic disease).Many arboviruses are present in Australia, especially in the tropical north. The Australian National Arbovirus Monitoring Program (NAMP) is responsible for monitoring the distribution of insect-borne viruses. the Murray Valley encephalitis virus (MVEV) and Kunjin virus). There are 2 types of mosquito-borne viruses, namely Arboviruses (e.g. The main vector-transmitted diseases in cattle are three-day sickness (bovine ephemeral fever) and Akabane disease.Įquine infectious anaemia is a vector-disease affecting horses that can significantly increase after flooding. Vector-transmitted diseases are spread through the bites of infected arthropods (e.g. ![]() 12/8/2023 0 Comments Pokemon unite switch zeraora![]() To receive the Unite license for Zeraora after the end of this promotional campaign, players will need to complete special missions (scheduled to be implemented at a future date). GG thanks user Alezao for sharing this guide on how to play Zeraora. Be sure to support your favorite creators by upvoting their builds, videos, and anything else they share you find useful. It may contain inaccuracies in the data that is used compared to the current version of 1.9.2.8. GG thanks user IlPato for sharing this guide on how to play Zeraora. Players who download Pokémon UNITE and log in by 14:59 PM UTC Tuesday, August 31, 2021, will be able to claim the Unite license for Zeraora using the in-game mail system. This build was created in the game version of 1.2.1.5. Its Unite Move, Plasma Gale, sends out a powerful electric blast that creates a zone of plasma around the area where the blast hits. Zeraora can close the distance between itself and its opponents in the blink of an eye, just like lightning, and deal massive amounts of damage all at once. To celebrate launch, players who log in to the Nintendo Switch version of Pokémon UNITE by August 31, 2021, will receive a Unite license for Zeraora, which will allow Trainers to use the Pokémon in battle. French, Italian, Spanish, and German language support will be coming later this year. Pokémon UNITE is available in English, Korean, Japanese, Traditional Chinese, and Simplified Chinese. Pokémon UNITE is free-to-start, with optional in-game purchases available.įor more information about Pokémon UNITE, please visit /Unite. Additionally, if you log in using your Nintendo Account or Pokémon Trainer Club account, you’ll be able to use your game data on any device. Cross-platform play between Nintendo Switch and mobile devices is planned, which will allow players on both platforms to battle together and against one another. Pokémon UNITE will become available in September 2021 on mobile devices. Additionally, players who purchase the premium pass will have the chance to earn even more rewards, including the Holowear Hip-Hop Style: Pikachu and Captain Style: Cinderace. Players will need to complete both daily and weekly missions throughout the season to raise their battle pass level and receive rewards based on that level. GG thanks user SnorlaxHealer4100098 for sharing this guide on how to play Zeraora. It may contain inaccuracies in the data that is used compared to the current version of 1.9.2.6. Timed with Pokémon UNITE’s release on Nintendo Switch, players will be able to enjoy the game’s first season, “Welcome to Aeos Island!” The season battle pass will feature many rewards, ranging from in-game currency to Holowear. This build was created in the game version of 1.2.1.5. They will need to defeat their opponents’ Pokémon while trying to earn more points than the opposing team within the allotted time. ![]() During these battles, players will cooperate with teammates to defeat wild Pokémon and level up to evolve their own Pokémon. In Pokémon UNITE, players face off against each other in 5-on-5 team battles. To commemorate the release of the Nintendo Switch version of Pokémon UNITE, Trainers can watch an all-new global launch trailer on the official Pokémon UNITE YouTube channel. Pokémon UNITE AVAILABLE NOW ON NINTENDO SWITCHīellevue, WA-July 21, 2021-Pokémon’s first strategic team battle game, Pokémon UNITE, is now available to download exclusively on Nintendo Switch systems. The move also creates a plasma area that strengthens Zeraora’s basic attacks while within the area.Pokémon UNITE is now available on Nintendo Switch. Its UNITE move is Plasma Gale, which hits any targeted Pokemon and knocks them up. In its second slot, Zeraora has Slash, which is then upgraded to either Discharge or Wild Charge. It also restores Zeraora’s health.įor his first move slot, it starts out with Agility which can upgrade to Volt Switch or Spark as Zeraora levels up in a match. His basic attack becomes enhanced every third attack, dealing increased damage and paralyzing opponents. His passive ability gives it an electric charge when receiving damage and converts that damage into Attack stats. As a Speedster in Pokémon UNITE, Zeraora moves quick and can dole out massive melee damage if needed. ![]() The Speedster is defined as a difficult to master character, according to the game. | Provided by Pokémon UNITE Zeraora’s moves In our Pokémon Unite Zeraora build guide, we offer our recommendations for what battle item you should use, what held items suit Zeraora best, and which moves are worth unlocking. Zeraora is an electric-type Pokemon that can do 'massive damage in the blink of an eye.' Zeraora's special Unite move emits an electric blast that puts out plasma. Players can claim Zeraora in the message and they should own the Speedster. The Pokemon’s UNITE license is in the message called Launch Bonus. ![]() ![]() ![]() After Stewart walked to lead off the fifth, Delgado launched a moonshot to the furthest deck in right field-the first to ever go so high in the young history of the then-Skydome-extending the lead to 6-2. However, the slow trickle of runs could not keep up with the onslaught from the Blue Jays bats. The Bombers continued to chip away at Williams, a pair of doubles by Knoblauch and O’Neill in the fifth reducing the deficit to 4-2. The 1988 AL MVP demolished an elevated 2-0 fastball for a grand slam to immediately punish the Yankees for not capitalizing further on their own bases-loaded situation. In the bottom-half, Craig Grebeck got things started with a one-out double, followed by walks from Alex Gonzalez and Shannon Stewart to load the bases for Jose Canseco. A Tino Martinez sac fly to center plated the first run, but that’s all they’d get in the inning. Baltimore Orioles Baltimore Boston Red Sox Boston New York Yankees NY Yankees Tampa Bay Rays Tampa Bay Toronto Blue Jays Toronto. A leadoff Chuck Knoblauch walk followed by back-to-back singles from Derek Jeter and Paul O’Neill loaded the bases with no outs. Team Stats Top Prospects Stats Affiliate Stats Baseball Savant Top Rookies Stats. Box Score Play-by-Play Rizzo slam in 8-run 5th, Yanks rout Jays 12-3 for 8th. Toronto Blue Jays MLB game from Jon ESPN. Box Score Play-by-Play Judge HRs twice, Yankees beat Jays 6-2 to extend. Expert recap and game analysis of the New York Yankees vs. Starting pitcher Yusei Kikuchi had held the New York Yankees. Toronto Blue Jays MLB game from Septemon ESPN. For the first five innings, things were going swimmingly for the Toronto Blue Jays in the opener of their two-game series in the Bronx. They’d even open the scoring in the third, though would instantly rue not pushing across more in the frame. Expert recap and game analysis of the New York Yankees vs. New York’s offense made Woody Williams work, putting a pair on in each of the first and second by drawing three walks and reaching on an error. He was actually cruising early, retiring the side in order in the first and second, inducing four ground outs and striking out a pair. July 19: Yankees 3, Blue Jays 9 ( box score )Įven though the Blue Jays were far removed from their halcyon days in the early 1990s, their lineup still boasted a pair of prodigious sluggers in Jose Canseco and Carlos Delgado, something Andy Pettitte learned the hard way on this particular afternoon at the Rogers Centre. They found themselves temporarily halted, dropping four of five to close out the third week of June while also suffering their first series loss in a month. However, the fatigue of an 11-game road trip to open the second half was perhaps finally catching up with them. The Yankees stormed out of the All-Star break in 1998, winning six of their first seven to start their second half in the same manner with which they finished the first. ![]() 12/8/2023 0 Comments Eddie winslow and sidney starr![]() McCrary also added that while social media is “busy discussing ,” he’s “trying to change the world.” Watch his clip below. That’s what y’all should be focusing on, where that ring is.” “What are we, in high school? You’re going to tell me who I can’t be friends with, who I can’t hang out with?” He added, “I think my fiancé would really have something different to say. Darius McCrary is an actor best known for portraying Eddie Winslow in the. ![]() “While y’all are discussing these rumors that aren’t true, we eating,” he said. Transgender rapper Sidney Starr and Family Matters actor Darius McCrary have fueled dating rumors for over a year. In a video, McCrary is seen sharing a meal with his Family Matters mom, Jo Marie Payton. Sidney, a trans social media personality and actress known for her appearances on Baddies ATL and Love & Hip Hop- and those Chingy rumors-was said to have been carrying on a relationship with McCrary, but after seeing his name become a trending topic, he shared an update to deny the gossip. Starr posted about McCrary and their friendship, leading people to run with the story that they were romantically involved. However, on Monday (October 18), reports surfaced that he and reality star Sidney Starr were together. ![]() Chrisean Rock and Blac Chyna were in the building as special guests. Prescreen judges were Biggie, Rollie, Scotty, Cat, & Lo London. ![]() Nunn served as a judge for the auditions, along with Rubi Rose and Tokyo Toni. We’ve reported on McCrary’s previous romance with Karrine Steffans and the relationship he allegedly has with Kevin Hart’s ex-wife, Torrei Hart. Here’s more on the Baddies East audition fights and brawls that went viral on social media. ![]() 12/8/2023 0 Comments Synergy gas vermont![]() ![]() aureus VISA) or daptomycin exhibit the seesaw effect, and for most such clinical isolates, the emergence of the seesaw effect cannot be assessed due to absence of the parent strain. Not all MRSA with reduced susceptibility to vancomycin ( i.e., vancomycin intermediate S. There are a few well-characterized examples of such clinical strain pairs, but this is not something that can be easily determined through routine monitoring by clinical laboratories ( Vignaroli et al., 2011 Werth et al., 2013a). While the seesaw effect is assumed to be a common feature of strains with reduced susceptibility to vancomycin or daptomycin, to measure it requires the comparison between a parent strain that is initially susceptible to vancomycin or daptomycin and isogenic strains that develop reduced susceptibility. ![]() While it is intuitive that the seesaw effect between beta-lactams and glyco-, lipo-, and lipoglycopeptides could be related to synergy between these agents, this association has not been rigorously tested. Some investigators have attributed this synergy to the “seesaw effect” ( Renzoni et al., 2017 Molina et al., 2020), a phenomenon where the susceptibility to beta-lactams increases with declining vancomycin or daptomycin susceptibility ( Sieradzki and Tomasz, 1997 Ortwine et al., 2013). Further work is warranted to characterize strains that don’t exhibit beta-lactam synergy to identify which strains should be targeted with combination therapy and which ones cannot and to further investigate the potential role of CLs in mediating synergy.Īll MRSA are resistant to traditional beta-lactams, but when combined with glycopeptides, lipopeptides, or lipoglycopeptides, synergistic antimicrobial activity is commonly observed, especially among strains with reduced susceptibility to the latter antimicrobial classes ( Mehta et al., 2012 Werth et al., 2013b Xhemali et al., 2018). This suggests that the emergence of the seesaw effect may not have clinical importance in terms of predicting synergy. In conclusion, the beta-lactam-glycopeptide seesaw effect and beta-lactam-glycopeptide synergy are distinct phenomena. Lipidomic analysis of all strains exposed to individual beta-lactams at subinhibitory concentrations suggested that in general, the abundance of cardiolipins (CLs) and most free fatty acids (FFAs) positively correlated with the presence of synergistic effects while abundance of phosphatidylglycerols (PGs) and lysylPGs mostly negatively correlated with synergistic effects. Interestingly N315-D1 and N315-DAL0.5 both had mutations in vraTSR and walKR despite their differences in the seesaw effect. Synergy was more common among the resistant mutants than the parent strain. Among the beta-lactams, cefoxitin and nafcillin were the most likely to exhibit synergy using the concentrations tested, while cephalexin was the least likely to exhibit synergy. Synergy was more commonly observed with vancomycin and daptomycin based combinations than dalbavancin in time-kills. We observed that the seesaw effect with each beta-lactam was variable and the emergence of the seesaw effect for a particular beta-lactam was not necessary for synergy between that beta-lactam and vancomycin, daptomycin, or dalbavancin. We used whole genome sequencing to identify genetic variants that emerged and tested for synergy between vancomycin, daptomycin, or dalbavancin in combination with 6 beta-lactams with variable affinity for staphylococcal penicillin binding proteins (PBPs), including nafcillin, meropenem, ceftriaxone, ceftaroline, cephalexin, and cefoxitin, using time-kills. We selected for three isogenic strains with reduced susceptibility to vancomycin, daptomycin, and dalbavancin by serial passaging the MRSA strain N315. The objective of this study was to determine whether the seesaw effect is necessary for synergy and to measure the impact of beta-lactam exposure on lipid metabolism. Many have attributed this synergy to the beta-lactam-glycopeptide seesaw effect however, this association has not been rigorously tested. aureus (MRSA) are resistant to beta-lactams, but synergistic activity between beta-lactams and glycopeptides/lipopeptides is common. 3Department of Laboratory Medicine and Pathology, School of Medicine, University of Washington, Seattle, WA, United States.2Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, WA, United States.1Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, WA, United States.Ashford 2 Kelsi Penewit 3 Adam Waalkes 3 Elizabeth A. ![]() |
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