New study is 'chilling commentary' on future of antibiotics

The health care market is failing to support new antibiotics used to treat some of the world's most dangerous, drug-resistant "superbugs," according to a new analysis by University of Pittsburgh School of Medicine infectious disease scientists.

In a study published today in Antimicrobial Agents and Chemotherapy, a journal of the American Society for Microbiology, investigators used nationwide prescription data to determine that the current annual U.S. sales of new antibiotics to treat carbapenem-resistant Enterobacteriaceae (CRE), one of the world's most insidious drug-resistant bacteria, is about $101 million annually -- significantly short of the $1 billion believed to be necessary to assure the financial viability of a new antibiotic. Even if new anti-CRE agents were used as widely as possible to treat CRE infections, the projected market size is only $289 million.

"New drugs against CRE address a major, previously unmet medical need and are critical to save lives. If the market can't support them, then that is a chilling commentary on the future of antibiotic development," said lead author Cornelius J. Clancy, M.D., associate professor of medicine and director of the mycology program and Extensively Drug Resistant Pathogen Laboratory in Pitt's Division of Infectious Diseases. "Without antibiotics against increasingly resistant bacteria and fungi, much of modern medicine may become infeasible, including cancer chemotherapies, organ transplantation and high-risk abdominal surgeries."

CRE infections are estimated to cause 1.5 to 4.5 million hospitalizations worldwide each year. The Centers for Disease Control and Prevention has classified CRE as urgent threat pathogens and calls them the "nightmare bacteria." The World Health Organization and Infectious Disease Society of America have designated CRE as highest priority pathogens for development of new antibiotics.

Since 2015, five antibiotics against CRE have gained U.S. Food and Drug Administration (FDA) approval and trials have so far shown three of them to be more effective and less toxic than the previous first-line antibiotics. One of the developers of the new anti-CRE drugs -- the biopharmaceutical company Achaogen -- declared bankruptcy in April because of its steep losses.

After reporting earlier this year that new CRE antibiotics are being prescribed in only about a quarter of infections that warrant them, Clancy and senior author M. Hong Nguyen, M.D., Pitt professor of medicine and director of UPMC's Antimicrobial Management Program, investigated the market needed to make antibiotic development sustainable. They found a shortfall in revenue potential, evidenced by the financial difficulties faced by drug companies that created the new anti-CRE drugs.

"The prudent approach when fighting bacteria is to have multiple treatment options in the pipeline so that when resistance is inevitably developed to the current drug, a new antibiotic is waiting in the wings," said Nguyen. "But we found that market prospects will become even more daunting if more anti-CRE drugs are approved, which is bad news for infectious disease physicians and, more importantly, our patients."

Clancy and Nguyen propose a combination of "push" and "pull" incentives to encourage sustainable antibiotic development, starting with approval of the bilateral DISARM Act, which currently is under consideration in Congress. DISARM would assure full Centers for Medicare and Medicaid Services reimbursement for use of new antibiotics against resistant infections in hospitalized patients, rather than subsuming antibiotic costs into the discounted bundled payment hospitals receive. This would remove the disincentive hospitals face in using more effective but more expensive new agents rather than cheaper, older agents.

There also needs to be a cultural and behavioral change among hospitals and clinicians to encourage faster adoption and appropriate use of new antibiotics, the researchers said. Infectious disease physicians and pharmacists need to take responsibility for educating the wider clinical community about the importance of quickly updating and following guidelines on the best possible antibiotics to be using for their patients.

There was no funding for this study. Clancy and Nguyen report unrelated research funded by various pharmaceutical and medical device companies, detailed in the study manuscript.


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Materials provided by University of Pittsburgh. Note: Content may be edited for style and length.


Antibiotics not effective for clinically infected eczema in children

Estimates suggest that 40 percent of eczema flares are treated with topical antibiotics, but findings from a study led by Cardiff University suggest there is no meaningful benefit from the use of either oral or topical antibiotics for milder clinically infected eczema in children.

Eczema is a common condition, especially in young children, and affects around 1 in 5 children in the UK. Eczema sometimes gets worse, or 'flares', and having particular bacteria on the skin may contribute to causing some of these flares. Quite often eczema flares are treated with antibiotics, although there was very little research to show whether antibiotics are helpful or not.

The CREAM study was designed to find out if oral (taken by mouth) or topical (creams and ointments applied to the skin) antibiotics help improve eczema severity in children with infected eczema. All children also received standard eczema treatment with steroid creams and emollients (moisturiser) from their doctor.

Results from the analysis of data from 113 children with non-severely infected eczema, published in the Annals of Family Medicine journal, showed no significant difference between the groups in the resolution of eczema symptoms at two weeks, four weeks or three months.

Researchers found rapid resolution in response to mild-to-moderate strength topical corticosteroids and emollient treatment, and ruled out a clinically meaningful benefit from the addition of either oral or topical antibiotics.

Dr Nick Francis, Clinical Reader at Cardiff University and practicing GP, who led the study said: "Topical antibiotics, often in combination products with topical corticosteroids, are frequently used to treat eczema flares. Our research shows that even if there are signs of infection, children with milder eczema are unlikely to benefit from antibiotics, and their use can promote resistance and allergy or skin sensitization."

"Providing or stepping up the potency of topical corticosteroids and emollients should be the main focus in the care of milder clinically infected eczema flares."

How bacteria survive antibiotic treatment

Multiresistant bacteria Scientists around the world are working hard to win the battle against multi-resistant bacteria. A new publication from the BASP Centre, University of Copenhagen now presents how even sensitive bacteria often manage to survive antibiotic treatment as so-called 'persister cells'. The comprehensive perspective on this phenomenon may help to improve current options of drug treatment and could even inspire the discovery of novel antibiotics targeting these notoriously difficult-to-treat persister bacteria.

In the current issue of the journal Science, Alexander Harms and colleagues from the BASP Centre, Department of Biology, University of Copenhagen summarise newly discovered molecular mechanisms explaining how bacteria manage to survive antibiotic treatment and cause chronic and recurrent infections.

Post-Doc Alexander Harms explains: "This amazing resilience is often due to hibernation in a physiological state called persistence where the bacteria are tolerant to multiple antibiotics and other stressors. Bacterial cells can switch into persistence by activating dedicated physiological programs that literally pull the plug of important cellular processes. Once they are persisters, the bacteria may sit through even long-lasting antibiotic therapy and can resuscitate to cause relapsing infections at any time after the treatment is abandoned."

Using novel detection methods, recent work in the field has uncovered the molecular architecture of several cellular pathways underlying the formation of bacterial persisters -- and these results confirmed the long-standing notion that persistence is intimately connected to slow growth or dormancy. Bacterial persistence can therefore be compared to hibernation of animals or the durable spores produced by many mushrooms and plants.

Across many different bacteria, these programs are controlled by a regulatory compound known as "magic spot" that plays a central role in the persistence phenomenon. These important discoveries, many of which were accomplished by the BASP Centre, may in the future facilitate the development of improved drug treatment regimens and eventually lead to the development of novel antibiotics.


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