Fidaxomicin also exhibits potent antibacterial activity against other CDC “serious threat” bacterial pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Staphylococcus aureus (VRSA), and the tuberculosis bacterium, Mycobacterium tuberculosis. However, the low solubility and low systemic bioavailability of fidaxomicin have precluded use of fidaxomicin for treatment of MRSA, VRSA, and tuberculosis.
To design next-generation fidaxomicin derivatives with improved clinical activity against C. diff and useful clinical activity against MRSA, VRSA, and tuberculosis, it is essential to know how the drug binds to and inhibits its molecular target, bacterial RNA polymerase, the enzyme responsible for bacterial RNA synthesis.
In a paper published in Molecular Cell today, the researchers report results of cryo-electron microscopy (cryo-EM) and single molecule spectroscopy analyses showing how fidaxomicin binds to and inhibits bacterial RNA polymerase.
The researchers report a cryo-EM structure of fidaxomicin bound to Mycobacterium tuberculosis RNA polymerase at 3.5 Å resolution. The structure shows that fidaxomicin binds at the base of the RNA polymerase “clamp,” a part of RNA polymerase that must swing open to allow RNA polymerase to bind to DNA and must swing closed to allow RNA polymerase to hold onto DNA. The structure further shows that fidaxomicin traps the RNA polymerase “clamp” in the open conformation.
The researchers also report results of single-molecule fluorescence spectroscopy experiments that confirm that fidaxomicin traps the RNA polymerase “clamp” in the open conformation and that define effects of fidaxomicin on the dynamics of clamp opening and closing.
The researchers show that fidaxomicin inhibits bacterial RNA polymerase through a binding site and mechanism that differ from those of rifamycins, another class of antibacterial drugs that target bacterial RNA polymerase. The finding that fidaxomicin inhibits bacterial RNA polymerase functions through a different, non-overlapping binding site and mechanism explains why fidaxomicin is able to kill bacterial pathogens resistant to rifamycins and why fidaxomicin is able to function additively when combined with rifamycins.
The new results enable rational, structure-based design of new, improved fidaxomicin derivatives with higher antibacterial potency, higher solubility, and higher systemic bioavailability. Based on the structure of fidaxomicin bound to its target, the researchers identified atoms of fidaxomicin that are not important for binding to the target and thus that can be modified without compromising the ability to bind to the target. The researchers then developed chemical procedures that allow selective attachment of new chemical groups at those atoms, including new chemical groups that can improve potency, solubility, or systemic bioavailability.
“The results set the stage for development of improved fidaxomicin derivatives, particularly improved fidaxomicin derivatives having the solubility and systemic bioavailability needed for treatment of systemic infections, such as MRSA and tuberculosis,” said Ebright, Board of Governors Professor of Chemistry and Chemical Biology and Laboratory Director at the Waksman Institute of Microbiology at Rutgers, who led the research.
In addition to Richard H. Ebright, the research team included Wei Lin, David Degen, Abhishek Mazumder, Dongye Wang, Yon W. Ebright, Richard Y. Ebright, Elena Sineva, Matthew Gigliotti, Aashish Srivastava, Sukhendu Mandal, Yi Jiang, Ruiheng Yin, and Dennis Thomas from Rutgers University; Kalyan Das from KU Leuven; Zhening Zhang and Edward Eng from the National Resource for Automated Molecular Microscopy and the Simons Electron Microscopy Center; Stefano Donadio from NAICONS Srl.; Haibo Zhang and Changsheng Zhang from the Chinese Academy of Sciences Guangzhou.
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The Society for Healthcare Epidemiology of America (SHEA) January 2018 issued guidelines on how long hospitals should continue contact precautions for multidrug-resistant infections and Clostridium difficile infections to avoid the spread of potentially deadly organisms through hospitals.
“Because of the virulent nature of multi-drug resistant infections and C. difficile infections,hospitals should consider establishing policies on the duration of contact precautions to safely care for patients and prevent spread of these bacteria,” said David Banach, MD, MPH, an author of the study and hospital epidemiologist at the University of Connecticut Health Center in Farmington, in a society news release. “Unfortunately, current guidelines on contact precautions are incomplete in describing how long these protocols should be maintained. We outlined expert advice for hospitals to consider in developing institutional policies to more effectively use contact precautions to safely care for patients.”
Dr Banach and members of the SHEA Guidelines Committee, which includes experts in infection control and prevention, studied available evidence and practical considerations and surveyed SHEA members to develop the updated guidance document. The available evidence, however, is insufficient to issue a formal guideline.
The recommendations were published online January 11 in Infection Control & Hospital Epidemiology.
The guidance, which covers methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and carbapenem-resistant Enterobacteriaceae, as well as C difficile, emphasizes the need for clinicians to consider the amount of time since the last positive sample. Specific recommendations include:
For patients not receiving antibiotics with activity against methicillin-resistant S aureus ((MRSA), the committee recommends using negative screening cultures to decide when to stop contact protocols. The optimal number of negative cultures is unclear, but 1 to 3 are often used. Hospitals may want to extend contact precautions for high-risk patients with chronic wounds and those from long-term care facilities. The ideal length of extension is unknown, but 6 months is common.
For highly resistant Enterobacteriaceae, such as carbapenemase-producing carbapenem-resistant Enterobacteriaceae, or Enterobacteriaceae with few treatment options, hospitals should maintain contact precautions indefinitely.
For C difficile infections, contact precautions should be continued for at least 48 hours after the resolution of diarrhea, and clinicians should consider extending precautions if C difficile infection rates remain high despite appropriate prevention and control measures.
With cases of vancomycin-resistant enterococci (VRE) infection, negative stool or rectal swab cultures should be used to determine when to discontinue precautions. One to three negative cultures at least 1 week apart are commonly used.
The authors note that there was insufficient evidence to formally recommend use of molecular testing to help guide decisions on length of contact precautions. However, they said they assume that polymerase chain reaction tests have better sensitivity compared with culture.
Hospitals should carefully gauge their own risks, priorities, and resources when adopting policy on duration of precautions, as costs and practicality of implementation differ, the authors note. In addition, guidance should be reevaluated by infection control leadership, especially when there are outbreaks.
“The duration of contact precautions can have a significant impact on the health of the patient, the hospital, and the community,” coauthor Gonzolo Bearman, MD, MPH, from the Division of Infectious Diseases at Virginia Commonwealth University, Richmond, said in the news release. “This guidance is a starting point, however stronger research is needed to evaluate and optimize the use.”
The guidance was endorsed by the Association for Professionals in Infection Control and Epidemiology, the Society of Hospital Medicine, and the Association of Medical Microbiology and Infectious Disease Canada.
This study was supported in part by the SHEA Research Network. Various coauthors report ties to Springer Nature for book and journal editing and grants from the National Institutes of Health, the Agency for Healthcare Research and Quality, Veterans Affairs’ Health Services Research and Development, the Centers for Disease Control and Prevention, Medimmune, Nanosphere Inc, Techlab, The Children’s Hospital of Philadelphia, Premier EHEC and CHRO-Magar 0157, Pfizer, and the University of Louisville. Coauthors also report consultant roles or fees with Xenex/Clorox, Ecolab and Gilead.
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The federal government has cut payments to 769 hospitals with high rates of patient injuries, for the first time counting the spread of antibiotic-resistant germs in assessing penalties.
The punishments come in the third year of Medicare penalties for hospitals with patients most frequently suffering from potentially avoidable complications, including various types of infections, blood clots, bed sores and falls.
This year – 2016 – the government also examined the prevalence of two types of bacteria resistant to drugs.
Based on rates of all these complications, the hospitals identified by federal officials this week will lose 1 percent of all Medicare payments for a year — with that time frame beginning this past October. While the government did not release the dollar amount of the penalties, they will exceed a million dollars for many larger hospitals. In total, hospitals will lose about $430 million, 18 percent more than they lost last year, according to an estimate from the Association of American Medical Colleges.
The reductions apply not only to patient stays but also will reduce the amount of money hospitals get to teach medical residents and care for low-income people.
Forty percent of the hospitals penalized this year – 2016 – escaped punishment in the first two years of the program, a Kaiser Health News analysis shows. Those 306 hospitals include the University of Miami Hospital in Florida, Cambridge Health Alliance in Massachusetts, the University of Michigan Health System in Ann Arbor and Mount Sinai Hospital in New York City.
Nationally, hospital-acquired conditions declined by 21 percent between 2010 and 2015, according to the federal Agency for Healthcare Research and Quality, or AHRQ. The biggest reductions were for bad reactions to medicines, catheter infections and post-surgical blood clots.
Still, hospital harm remains a threat. AHRQ estimates there were 3.8 million hospital injuries last year, which translates to 115 injuries during every 1,000 patient hospital stays during that period.
Each year, at least 2 million people become infected with bacteria that are resistant to antibiotics, including nearly a quarter million cases in hospitals. The Centers for Disease Control and Prevention estimates 23,000 people die from them.
Infection experts fear that soon patients may face new strains of germs that are resistant to all existing antibiotics. Between 20 and 50 percent of all antibiotics prescribed in hospitals are either not needed or inappropriate, studies have found. Their proliferation — inside the hospital, in doctor’s prescriptions and in farm animals sold for food — have hastened new strains of bacteria that are resistant to many drugs.
One resistant bacteria that Medicare included into its formula for determining financial penalties for hospitals is methicillin-resistant Staphylococcus aureus, or MRSA, which can cause pneumonia and bloodstream and skin infections. MRSA is prevalent outside of hospitals and sometimes people with it show no signs of disease. But these people can bring the germ into a hospital, where it can be spread by health care providers and be especially dangerous for older or sick patients whose immune system cannot fight the infection.
Hospitals have had some success in reducing MRSA infections, which dropped by 13 percent between 2011 and 2014, according to the CDC. AHRQ estimates there were 6,300 cases in hospitals last year.
The second bacteria measured for the penalties is Clostridium difficile, known as C. diff, It can be spread through contaminated surfaces or hands. ………,
C. diff has challenged infection control efforts. While hospital infections dropped 8 percent from 2008 to 2014, there was a “significant increase” in C. diff that final year, the CDC says. AHRQ estimated there were 100,000 hospital cases last year.
“The reality is we don’t know how to prevent all these infections,” said Dr. Louise Dembry, a professor at the Yale School of Medicine and president of the Society for Healthcare Epidemiology of America.
The Hospital-Acquired Condition Reduction Program also factors in rates of infections from hysterectomies, colon surgeries, urinary tract catheters and central line tubes. Those infections carry the most weight in determining penalties, but the formula also takes into account the frequency of bed sores, hip fractures, blood clots and four other complications.
Specialized hospitals, such as those that treat psychiatric patients, veterans and children, are exempted from the penalties, as are hospitals with the “critical access” designation for being the only provider in an area. Of the remaining hospitals, the Affordable Care Act requires that Medicare penalize the 25 percent that perform the worst on these measures, even if they have reduced infection rates from previous years.
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This is a patient – safety article and quite informative and beneficial for everyone. The topics are highlighted on how to prevent infections prior and during a hospital stay.
The most pertinent information to review and share with others is as follows:
1. Check Up on Your Hospital
See how it compares with others on central line, C. diff, and MRSA infections, as well as other measures of patient safety. To compare hospitals in your area at preventing infections, use our hospital ratings.
2. Have a Friend or Family Member With You
That person can act as your advocate, ask questions, and keep notes. A Consumer Reports survey of 1,200 recently hospitalized people found that those who had a companion were 16 percent more likely to say that they had been treated respectfully by medical personnel. The most important times to have a companion for preventing infections and other medical errors are on nights, weekends, and holidays, when staff is reduced, and when shifts change.
3. Keep a Record
Keep a pad and pen nearby so that you can note what doctors and nurses say, which drugs you get, and questions you have. If you spot something worrisome, such as a drug you don’t recognize, take a note or snap a picture on your phone. You can also use your phone to record thoughts or conversations with staff. Though some may object, “explain that you are recording so you remember later,” McGiffert says.
4. Insist on Clean Hands
Ask everyone who enters your room whether they’ve washed their hands with soap and water. Alcohol-based hand sanitizer is not enough to destroy certain bacteria, such as the dangerous C. diff. Don’t hesitate to say: “I’m sorry, but I didn’t see you wash your hands. Would you mind doing it again?”
5. Keep It Clean
Bring bleach wipes for bed rails, doorknobs, the phone, and the TV remote, all of which can harbor bacteria. And if your room looks dirty, ask that it be cleaned.
6. Cover Wounds
Some hospitals examine incisions daily for infection, but opening the bandage exposes the area to bacteria. Newer techniques—sealing the surgical site with skin glue (instead of staples, which can harbor bacteria) and waterproof dressings that stay on for one to three weeks without opening—are effective at preventing infection.
7. Inquire Whether IVs and Catheters Are Needed
Ask every day whether central lines, urinary catheters, or other tubes can be removed. The longer they’re left in place, the greater the infection risk.
8. Ask About Antibiotics
For many surgeries, you should get an antibiotic 60 minutes before the operation. But research suggests that the type of antibiotic used or the timing of when it’s administered is wrong in up to half of cases.
Listen to one of the educational Podcasts: Using antibiotics wisely, How to help in the fight against antibiotic resistance with Guests Dr. Arjun Srinivassan, MD and Dr. Lauri Hicks, DO
9. Postpone Surgery If You Have an Infection
That increases your risk of developing a new infection and worsening an existing one. So if you have any other type of infection—say, an abscessed tooth—then the surgery should be postponed, if possible, until it’s completely resolved.
10. Say No to Razors
Removing hair from the surgical site is often necessary, but doing that with a regular razor can cause nicks that provide an opening for bacteria. The nurse should use an electric trimmer instead.
11. Question the Need for Heartburn Drugs
Some patients enter the hospital taking heartburn drugs such as Nexium, lansoprazole (Prevacid) or omeprazole (Prilosec) or are prescribed one after they’re admitted. But these drugs, called proton-pump inhibitors, increase the risk of intestinal infections and pneumonia, so consider stopping them before admission and, once there, ask whether you really need one.
12. Test for MRSA
Ask your surgeon to screen you for MRSA, a potentially deadly bacteria that’s resistant to antibiotics, either before you enter or on admission, so that you can address the problem and hospital staff can take extra steps to protect you and others.
13. Watch for Diarrhea
Get tested for C. diff. infection if you have three loose stools within 24 hours. If you test positive, expect extra precautions for preventing infections from spreading to others.
14. Quit Smoking, Even Temporarily
You won’t be allowed to smoke in the hospital anyway, and stopping as long as possible beforehand cuts the risk of infection. Read our advice on how to stop smoking.
15. Wash Up the Night Before Surgery
Ask about taking precautions before entering the hospital, such as bathing with special soap or using antiseptic wipes.
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