Category: Antibiotics

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Faulty ‘Fight or Flight’ Drives C. Diff Infections

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Clostridioides difficile. Credit: CDC

The portion of our nervous systems responsible for the “fight or flight” response can shape the severity of potentially deadly Clostridioides difficile infections, new research from the School of Medicine reveals in Cell Reports Medicine.

The findings suggest that doctors may be able to save patients from the infections – a plague for hospitals and nursing homes – by using drugs to quiet the hyperactive nervous system response, the researchers say.

“Compared to how much we know about immune system influences in C. difficile infections, the field is just scratching the surface in understanding neuronal contributions to disease,” said researcher William A. Petri Jr., MD, PhD, of UVA Health’s Division of Infectious Diseases and International Health. “Newly identifying components of the nervous system that worsen inflammation will allow us to determine potential therapeutic targets and biomarkers for patients at risk of severe disease.”

C. difficile, is a perpetual burden for healthcare facilities. Extensive antibiotic use, particularly among patients who are hospitalised or in nursing care, can allow it to establish dangerous infections. Further, patients who make it through the severe diarrhoea, nausea, fever and colitis C. difficile can cause are not necessarily in the clear: One in six will develop another C. diff infection within eight weeks, according to the federal Centers for Disease Control and Prevention.

The new UVA research reveals the critical role the nervous system plays in severe C. difficile infections. The researchers found that the “sympathetic” nervous system – the branch that responds to dangerous situations – can be a key driver of serious C. diff.

Normally, our “fight or flight” response is helpful for avoiding danger. It helps us respond quickly, improves our eyesight, boosts our strength. It also can stimulate our immune system and help us recover from injury. But in C. difficile cases, the nervous system can have a hyperactive response that becomes part of the problem, and UVA’s new research explains why.

“Neurons are the first responders that coordinate defences against toxic attacks. Sometimes those responders don’t recruit the right size and kind of artillery and that can make things worse,” said researcher David Tyus, a neuroscience graduate student at UVA. “Interestingly, the receptor we identified as important in C. difficile infection [the alpha 2 adrenergic receptor] has also been linked to irritable bowel syndrome. I’m curious to know if there could be a unifying underlying mechanism between the two disease contexts.”

Promisingly, the researchers found that targeting the receptor in lab mice reduced intestinal inflammation and decreased C. difficile severity and mortality. That suggests that, with further research, doctors may be able to take a similar tact to better treat severe C. diff infections in patients. For example, they may be able to surgically remove a portion of nerves in the gut, or they may be able to develop medicines to target the alpha 2 receptor – as Petri and Tyus are attempting to do.

“Our next step is to determine which cells with the alpha 2 receptor are receiving signals from the sympathetic nervous system and play a role in C. difficile-mediated disease,” Petri said. “We are very excited to think about how our findings translate to clinic and how the sympathetic nervous system might play a role in recurrent infection. I hope that this study sets the foundation for future findings of how neurons affect the course of C. difficile infection outcomes.”

Source: University of Virginia Health System

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Transperineal Prostate Biopsy is Safer than the Standard Technique

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Credit: Darryl Leja National Human Genome Research Institute National Institutes Of Health

A multi-institutional clinical trial led by Weill Cornell Medicine and NewYork-Presbyterian investigators showed that a newer technique for collecting prostate biopsy samples reduced the risk of infection compared with traditional biopsy approaches and removed the need for prophylactic antibiotics. The results of the study appear in JAMA Oncology.

The technique, called transperineal prostate biopsy, collects prostate tissue via a needle through the skin of the perineum, the area between the rectum and the scrotum. The procedure, which uses local anesthesia to numb the area, allows physicians to bypass the traditional and more infection-prone route of collecting prostate biopsy tissue with a needle through the rectum.

The PReclude infection EVEnts with No prophylaxis Transperineal (PREVENT) trial, funded by the National Cancer Institute, part of the National Institutes of Health, was conducted at multiple sites, including NewYork-Presbyterian/Weill Cornell Medical Center, NewYork-Presbyterian Queens and NewYork-Presbyterian Brooklyn Methodist Hospital. The study found no infections among 382 men randomised to undergo the transperineal procedure compared with six infections affecting 1.6% of the 370 men randomised to undergo the traditional transrectal biopsy procedure. The lower infection rate is particularly remarkable because the men in the transrectal biopsy group received a targeted course of antibiotics designed to help reduce their infection risk, and the men in the transperineal group received no antibiotics.

“Transperineal biopsy should be the new standard of care for prostate biopsy,” said Dr Jim Hu, Professor of Urologic Oncology at Weill Cornell Medicine. “It was as effective as the traditional transrectal biopsy approach at detecting cancer, but without the risk of infection or the need for antibiotics.”

Prostate biopsies are an essential tool for detecting prostate cancer, and about 3 million people worldwide undergo the procedure each year. Dr Hu noted that physicians collect about 90% of these biopsies in the United States via a transrectal procedure. Yet studies have found that 5% to 7% of patients develop infections after biopsy, and 1% to 3% require hospitalisation for these complications, he said. To help prevent infections, physicians typically prescribe a prophylactic course of antibiotics before the procedure.

Dr. Hu noted that the investigators used a personalised approach to prophylactic antibiotics in the patients undergoing the transrectal biopsy procedure. Rather than giving the men a broad-spectrum antibiotic or multiple antibiotics, they matched the antibiotics to cultures obtained from the patient’s rectum during prostate exams before the procedure. This targeted antibiotic approach reduced the infection rate in those undergoing the traditional transrectal procedure substantially compared with the national infection rate for the procedure. Yet, they achieved a statistically significant reduction in infections in the transperineal group by eliminating infections altogether.

 “Transperineal prostate biopsy makes a common diagnostic procedure safer for men,” said Dr Hu, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “It also eliminates the use of antibiotics, helping to reduce the emergence of antibiotic-resistant infections, a growing public health concern.”

Despite the promise of the new procedure, Dr. Hu acknowledged a few hurdles to making it more widely available to men in the United States. He explained that few physicians in the country have been trained in the perineal procedure. Additionally, he noted that US insurers pay the same amount for either procedure but the transperineal biopsy costs more and takes longer to perform, creating a financial disincentive for physicians to make the switch.

However, there is reason to think the status quo will change, Dr Hu said, noting the switch to transperineal prostate biopsies in Norway after a man died after a routine transrectal prostate biopsy. The change virtually eliminated biopsy-related infections and deaths in that country with the nationwide switch to transperineal biopsy, he said.

“There is a strong case to make the switch,” he said. “It will take time. But as more patients request the new procedure, we think it will become more widely available.”

Source: Weill Cornell Medicine

Categories : Antibiotics GastrointestinalTags :

Antibiotic Usage can Damage the Intestine’s Protective Mucus Layer

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Source: CC0

Researchers at Umeå University and Tartu University have found that a history of repeated antibiotic use causes defects in the normally protective mucus barrier of the gut, due to antibiotic-driven alterations in the microbiota. In a further study in a different collaboration, the researchers found a bacteria-independent mechanism through which antibiotics can damage the mucus barrier directly.

The results have been published in the scientific journals Gut Microbes and Science Advances.

“Together, these two studies suggest that antibiotics can damage the mucus layer through at least two independent mechanisms, and that they may have long-lasting effects through an altered gut bacteria. This further supports the notion that antibiotics should be administered in a responsible manner,” says Björn Schröder, Docent in Infection Biology in the Department of Molecular Biology at Umeå University.

Previous research has shown the consequences of short-term antibiotic treatments on the intestinal environment, but it is less clear how repeated antibiotic use in past years can affect our guts.

To address this question, Björn Schröder and his group at Umeå University teamed up with a research group at Tartu University in Estonia, who have built a deeply characterised cohort of individuals that provided stool samples and health records.

The researchers selected individuals who had taken at least five courses of antibiotics in the past, but not within six months before the stool collection, and compared their microbiota composition to individuals who had not taken any antibiotics within the last 10 years.

“The analysis revealed changes to the gut bacteria composition, even though the antibiotics were taken a long time ago. These results indicate that repeated antibiotic use has a lasting effect on gut bacteria composition that can persist at least months after the last treatment,” says Kertu-Liis Krigul, PhD student at Tartu University.

After transplantation of the human microbiota into mice and using specialised methods to analyse the mucus function in the gut, the researchers found that the function of the mucus layer was disrupted in mice transplanted with bacteria from humans with a history of repeated antibiotic use. Expansion of the mucus was reduced, and the mucus layer became penetrable, allowing bacteria to move closer to the intestinal lining.

“Looking at the bacteria present in the gut in more detail, we could see that bacteria known to feed on the mucus layer were present at higher levels in these mice. This further supports a role for the gut bacteria in determining how well the mucus barrier can function,” says Rachel Feeney, PhD student at the Department of Molecular Biology at Umeå University.

A separate study carried out in another international collaboration, further showed that antibiotics can also directly disrupt the mucus barrier in a gut bacteria-independent manner.

By giving the antibiotic vancomycin to normal and ‘bacteria-free’ mice, the researchers were able to show that this antibiotic can act directly on the mucus barrier, independent of the gut bacteria. Complementary experiments on intestinal tissue were carried out at Umeå University and showed that the antibiotic could disrupt the mucus expansion within a few minutes of application.

Source: Umeå University

Categories : AntibioticsTags :

Bacteria able to Overcome Cost of Vancomycin Resistance in Lab Setting

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Compensatory mutations enabled vancomycin resistance to persist through several generations

Methicillin resistant Staphylococcus aureus (MRSA) – Credit: CDC

Staphylococcus aureus has the potential to develop durable vancomycin resistance, according to a study published August 28, 2024, in the open-access journal PLOS Pathogens by Samuel Blechman and Erik Wright from the University of Pittsburgh, USA.

Despite decades of widespread treatment with the antibiotic vancomycin, vancomycin resistance among the bacterium S. aureus is extremely uncommon – only 16 such cases have reported in the US to date. Vancomycin resistance mutations enable bacteria to grow in the presence of vancomycin, but they do so at a cost. Vancomycin-resistant S. aureus (VRSA) strains grow more slowly and will often lose their resistance mutations if vancomycin is not present. The reason behind vancomycin’s durability and the potential for VRSA strains to further adapt have not been adequately explored.

In this study, researchers took four VRSA strains and grew them in the presence and absence of vancomycin to see how the strains would evolve. They found that strains grown in the presence of vancomycin developed additional mutations in the ddl gene, which has previously been associated with vancomycin dependence. These mutations enabled VRSA strains to grow faster when vancomycin was present. Unlike the original strains, which quickly lost vancomycin resistance, the evolved strains maintained resistance through several generations, even when vancomycin was no longer present.

The study shows that durability of vancomycin susceptibility to date should not be taken for granted. The trade-off that often comes with vancomycin resistance can be overcome if the bacteria is allowed to grow in the presence of vancomycin. As antibiotic resistance continues to grow as a public health threat, studies like this underscores the importance of developing new antibiotics.

The authors add: “The superbug MRSA has been held off by the antibiotic vancomycin for decades. A new study shows we will not be able to count on vancomycin forever.”

Provided by PLOS

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Treatment with a Mixture of Antimicrobial Peptides can Impede Antibiotic Resistance

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Pseudomonas exposed to mixtures instead of single peptides did not gain resistance

A common infection-causing bacteria was much less likely to evolve antibiotic resistance when treated with a mixture of antimicrobial peptides rather than a single peptide, making these mixtures a viable strategy for developing new antibiotic treatments. Jens Rolff of the Freie Universitat Berlin, Germany, and colleagues report these findings in a new study publishing July 2nd in the open-access journal PLOS Biology.

Antibiotic-resistant bacteria have become a major threat to public health. The World Health Organization estimates that 1.27 million people died directly from drug-resistant strains in 2019 and these strains contributed to 4.95 million deaths. While bacteria naturally evolve resistance to antibiotics, misuse and overuse of these drugs has accelerated the problem, rendering many antibiotics ineffective. One emerging strategy to combat antibiotic resistance is the use of antimicrobial peptides, which are chains of amino acids that function as broad-spectrum antimicrobial compounds and are key components of the innate immune system in animals, fungi and plants.

In the new study, researchers investigated whether antimicrobial peptide mixtures synthesised in the lab could reduce the risk of the pathogen Pseudomonas aeruginosa from evolving antimicrobial resistance, compared to exposure to a single antimicrobial peptide. They found that using antimicrobial peptide mixtures carried a much lower risk of the bacteria developing resistance. The mixtures also helped prevent the bacteria from developing cross-resistance to other antimicrobial drugs, while maintaining – or even improving – drug sensitivity.

Overall, the findings suggest that the use of antimicrobial peptide mixtures is a strategy worth pursuing in the search for new, longer-lasting treatments for bacteria. The researchers suspect that using a cocktail of multiple antimicrobial peptides creates a larger set of challenges for bacteria to overcome, which can potentially delay the evolution of resistance, compared to traditional antibiotics. Furthermore, these cocktails can be synthesized affordably, and previous studies have shown them to be non-toxic in mice.

Lead author Bernardo Antunes adds, “Even after four weeks of exposure, a usual treatment duration for Pseudomonas infections, we could not find resistance against our new random peptide, but against other antimicrobials.”

Provided by PLOS

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Which is Better? Prolonged vs Intermittent Infusion of β-Lactams in Sepsis

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Photo by Anna Shvets on Pexels

In adults with sepsis or septic shock, β-lactams are recommended by Surviving Sepsis Campaign guidelines, in a prolonged (after an initial bolus) rather than intermittent infusions – but owing to only moderate quality of evidence this is currently a weak recommendation. Now, a new systematic review and meta-analysis comparing the two approaches across multiple clinical trials has found a survival benefit for prolonged infusion The findings appear in JAMA.

To address whether prolonged infusions of β-lactams improve clinically important outcomes in critically ill adults with sepsis or septic shock, the study investigators searched medical databases for relevant randomised controlled trials comparing β-lactam infusion types in critically ill adults with sepsis or septic shock. The primary outcome was 90-day mortality, with secondary outcomes including intensive care unit (ICU) mortality and clinical cure.

In all, they found 18 eligible trials that included 9108 critically ill adults with sepsis or septic shock (median age, 54 years; 5961 men [65%]), 17 trials (9014 participants) contributed data to the primary outcome.

The pooled estimated risk ratio for all-cause 90-day mortality for prolonged infusions of β-lactam antibiotics compared with intermittent infusions was 0.86, with high certainty and a 99.1% posterior probability that prolonged infusions were associated with lower 90-day mortality. There was high certainty that prolonged infusion of β-lactam antibiotics was associated with a reduced risk of ICU mortality (risk ratio, 0.84) and moderate certainty of an increase in clinical cure (risk ratio, 1.16).

The findings were tempered with the authors’ understanding that, “Potential challenges associated with prolonged infusion administration, including drug instability and incompatibility with other intravenous medications, the need for a dedicated intravenous portal, and the potential effect on clinical workload, require some considerations before broad implementation. Future studies should determine the optimal duration of infusion when β-lactam antibiotics are administered as prolonged infusions.”

The authors concluded that, “Among adults in the intensive care unit who had sepsis or septic shock, the use of prolonged β-lactam antibiotic infusions was associated with a reduced risk of 90-day mortality compared with intermittent infusions. The current evidence presents a high degree of certainty for clinicians to consider prolonged infusions as a standard of care in the management of sepsis and septic shock.”

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Temperature may be a New Weapon in the Battle against Antibiotic Resistance

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Scientists from the University of Groningen in the Netherlands, together with colleagues from other European universities, have tested how a fever could affect the development of antimicrobial resistance. In laboratory experiments, they found that a small increase in temperature from 37 to 40 degrees Celsius drastically changed the mutation frequency in E. coli bacteria, which facilitates the development of resistance. If these results can be replicated in human patients, fever control could be a new way to mitigate the emergence of antibiotic resistance.

There are two ways to fight the threat of antimicrobial resistance: by developing new drugs, or by preventing the development of resistance. ‘We know that temperature affects the mutation rate in bacteria’, explains Timo van Eldijk, co-first author of the paper published in JAC-Antimicrobial Resistance. ‘What we wanted to find out was how the increase in temperature associated with fever influences the mutation rate towards antibiotic resistance.’

‘Most studies on resistance mutations were done by lowering the ambient temperature, and none, as far as we know, used a moderate increase above normal body temperature,’ Van Eldijk reports. Together with Master’s student Eleanor Sheridan, he cultured E. coli bacteria at 37 or 40 degrees Celsius, and subsequently exposed them to three different antibiotics to assess the effect. ‘Again, some previous human trials have looked at temperature and antibiotics, but in these studies, the type of drug was not controlled.’ In their laboratory study, the team used three different antibiotics with different modes of action: ciprofloxacin, rifampicin, and ampicillin.

The results showed that for two of the drugs, ciprofloxacin and rifampicin, increased temperature led to an increase in the mutation rate towards resistance. However, the third drug, ampicillin, caused a decrease in the mutation rate toward resistance at fever temperatures. ‘To be certain of this result, we replicated the study with ampicillin in two different labs, at the University of Groningen and the University of Montpellier, and got the same result,’ says Van Eldijk.

The researchers hypothesized that a temperature dependence of the efficacy of ampicillin could explain this result, and confirmed this in an experiment. This explains why ampicillin resistance is less likely to arise at 40 degrees Celsius. ‘Our study shows that a very mild change in temperature can drastically change the mutation rate towards resistance to antimicrobials,’ concludes Van Eldijk. ‘This is interesting, as other parameters such as the growth rate do not seem to change.’

If the results are replicated in humans, this could open the way to tackling antimicrobial resistance by lowering the temperature with fever-suppressing drugs, or by giving patients with a fever antimicrobial drugs with higher efficacy at higher temperatures. The team concludes in the paper: ‘An optimized combination of antibiotics and fever suppression strategies may be a new weapon in the battle against antibiotic resistance.’

Source: University of Groningen

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New Antibiotic Kills Pathogenic Bacteria but Spares Healthy Gut Microbes

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Gut Microbiome. Credit Darryl Leja National Human Genome Research Institute National Institutes Of Health

Researchers have developed a new antibiotic that reduced or eliminated drug-resistant bacterial infections in mouse models of acute pneumonia and sepsis while sparing healthy microbes in the mouse gut. The drug, called lolamicin, also warded off secondary infections with Clostridioides difficile, and was effective against more than 130 multidrug-resistant bacterial strains in cell culture.

The findings are detailed in the journal Nature.

“People are starting to realise that the antibiotics we’ve all been taking – that are fighting infection and, in some instances, saving our lives – also are having these deleterious effects on us,” said University of Illinois Urbana-Champaign chemistry professor Paul Hergenrother, who led the study with former doctoral student Kristen Muñoz. “They’re killing our good bacteria as they treat the infection. We wanted to start thinking about the next generation of antibiotics that could be developed to kill the pathogenic bacteria and not the beneficial ones.”

“Most clinically approved antibiotics only kill gram-positive bacteria or kill both gram-positive and gram-negative bacteria,” Muñoz said.

The few drugs available to fight gram-negative bacteria, which are protected by their double cell walls, also kill other potentially beneficial gram-negative bacteria. For example, colistin, one of the few gram-negative-only antibiotics approved for clinical use, can cause C. difficile-associated diarrhoea and pseudomembranous colitis, a potentially life-threatening complication. The drug also has toxic effects on the liver and kidney, and “thus colistin is typically utilised only as an antibiotic of last resort,” the researchers wrote.

To tackle the many problems associated with indiscriminately targeting gram-negative bacteria, the team focused on a suite of drugs developed by the pharmaceutical company AstraZeneca. These drugs inhibit the Lol system, a lipoprotein-transport system that is exclusive to gram-negative bacteria and genetically different in pathogenic and beneficial microbes. These drugs were not effective against gram-negative infections unless the researchers first undermined key bacterial defenses in the laboratory. But because these antibiotics appeared to discriminate between beneficial and pathogenic gram-negative bacteria in cell culture experiments, they were promising candidates for further exploration, Hergenrother said.

In a series of experiments, Muñoz designed structural variations of the Lol inhibitors and evaluated their potential to fight gram-negative and gram-positive bacteria in cell culture. One of the new compounds, lolamicin, selectively targeted some “laboratory strains of gram-negative pathogens including Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae,” the researchers found. Lolamicin had no detectable effect on gram-positive bacteria in cell culture. At higher doses, lolamicin killed up to 90% of multidrug-resistant E. coli, K. pneumoniae and E. cloacae clinical isolates.

When given orally to mice with drug-resistant septicemia or pneumonia, lolamicin rescued 100% of the mice with septicemia and 70% of the mice with pneumonia, the team reported.

Extensive work was done to determine the effect of lolamicin on the gut microbiome.

“The mouse microbiome is a good tool for modeling human infections because human and mouse gut microbiomes are very similar,” Muñoz said. “Studies have shown that antibiotics that cause gut dysbiosis in mice have a similar effect in humans.”

Treatment with standard antibiotics amoxicillin and clindamycin caused dramatic shifts in the overall structure of bacterial populations in the mouse gut, diminishing the abundance several beneficial microbial groups, the team found.

“In contrast, lolamicin did not cause any drastic changes in taxonomic composition over the course of the three-day treatment or the following 28-day recovery,” the researchers wrote.

Many more years of research are needed to extend the findings, Hergenrother said. Lolamicin, or other similar compounds, must be tested against more bacterial strains and detailed toxicology studies must be conducted. Any new antibiotics also must be assessed to determine how quickly they induce drug resistance, a problem that arises sooner or later in bacteria treated with antibiotics.

The study is a proof-of-concept that antibiotics that kill a pathogenic microbe while sparing beneficial bacteria in the gut can be developed for gram-negative infections – some of the most challenging infections to treat, Hergenrother said.

Source: University of Illinois at Urbana-Champaign, News Bureau

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Milk Samples From the 1940s Reveal Antibiotic Resistance in the Pre-antibiotic Era

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Photo by Robin Worrall on Unsplash

Using stored milk samples as a kind of time capsule, veterinary researchers at the University of Connecticut have uncovered insights about the presence of antibiotic resistance even in the pre-antibiotic era.

Sometime in the 1940s or so, someone in what is now the Department of Pathobiology and Veterinary Science got a lyophiliser, a piece of equipment that freeze-dries samples, says Director of the Connecticut Veterinary Medical Diagnostic Laboratory (CVMDL) Dr Guillermo Risatti. Risatti explains that at that time, the microbiology lab was very active in testing milk for the dairy farms in the region. With an exciting new piece of equipment, it seems they started lyophilising hundreds of samples.

The samples have been in storage ever since. Beyond the scant details that these are milk samples containing Streptococcus bacteria from the 1940s, Risatti explains that he and his colleagues – CVMDL Research Associate Dr. Zeinab Helal, Ji-Yeon Hyeon and Dong-Hun Lee – were interested in exploring their microbial history.

Risatti says that over the years, the data was lost, so researchers don’t have precise details of the provenance of the samples. But knowing a bit of history about the department, they can deduce some information.

“We believe that most of them came from Connecticut or perhaps from cases from the region, but we cannot say which parts,” Risatti says. “Most likely, this lab provided a testing service to locals, as this was mainly a pathology lab. Now it’s more like a diagnostic lab, and we receive samples from all over the region, including New York and New Jersey.”

Learning about what these historical samples hold could help with research in unexpected ways, but the first step is piecing together the lost details. To do this, Risatti explains that the team established a workflow using standard techniques to streamline processes to analyse the visual characteristics, called phenotype, and to analyse their genotype with genomic sequencing.

Different species of Streptococcus use different strategies to inflict disease in the organisms they infect. These virulence factors are used to differentiate one species of Streptococcus from another and are one way to distinguish samples through phenotypic analysis. Another phenotypic analysis includes testing bacteria for their susceptibility to antibiotics.

The researchers started with 50 samples collected from 1941 to 1947, and they found that the samples contained seven different Streptococcus species, including two subspecies of S. dysgalactiae. Interestingly, the researchers found some of the samples were resistant to the antibiotic tetracycline and did not carry antibiotic resistance genes typically seen in today’s antibiotic-resistant bacterial strains. Since these samples were collected prior to the antibiotic era, the results add to a growing body of literature showing that antibiotic resistance occurred naturally before humans discovered and began to use antibiotics.

“Antibiotic resistance is a very big area of research, and it has been for many years,” says Risatti. “We did not go any further with our analysis because we don’t have the tools here, but we hope to bring this information to the public. I think it could be the jumpstart for somebody to study further.”

Risatti explains the hope is to partner with large agencies like the CDC and the Department of Public Health to help bolster antibiotic resistance research.

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Supply Shortage Reveals that a Common Antibiotic has Unintended Consequences

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Photo by Marcelo Leal on Unsplash

Clinicians often have to make split-second decisions about which antibiotics to give a patient when a life-threatening infection is suspected. By taking advantage of a shortage of a common antibiotic, researchers at U-M found that antibiotic selection may have unintended consequences for patient outcomes.

Beginning in 2015, a 15-month national shortage of a commonly prescribed antibiotic, piperacillin/tazobactam (Zosyn), provided a unique opportunity to compare rates of death in hospitalised patients with sepsis who were administered two different types of antibiotics – one that spares the gut microbiome and one that profoundly alters it.

Piperacillin/tazobactam is a broad-spectrum antibiotic that is commonly administered for sepsis, a life-threatening complication from infection. In its absence, clinicians commonly instead use another antibiotic, cefepime, which has similar activity against common sepsis pathogens but, unlike piperacillin/tazobactam, has minimal effects on anaerobic gut bacteria. The results, published in JAMA Internal Medicine, were surprising.

“We saw this Zosyn shortage as a one-of-a-kind opportunity to ask whether this antibiotic, which we know depletes the gut of anaerobic bacteria, makes a difference in terms of patient outcomes,” said Robert Dickson, MD of the Department of Medicine’s Division of Pulmonary & Critical Care Medicine and Deputy Director of the Weil Institute for Critical Care Research & Innovation.

In health, the gut microbiome is largely populated by anaerobic bacteria that rarely cause disease. Prior work by the study team has revealed that even a single dose of piperacillin/tazobactam kills most of these anaerobic gut bacteria, which play important roles in the body’s metabolism, immunity, and prevention of infections.

Dickson, Rishi Chanderraj, MD of the Division of Infectious Disease, Michael Sjoding, MD of the Division of Pulmonary & Critical Care Medicine and their multidisciplinary team at U-M and the VA Ann Arbor used patient record data to look at outcomes in 7569 patients. The team compared 4523 patients who were treated were piperacillin/tazobactam with 3046 patients who received cefepime.

They found marked differences: treatment with piperacillin-tazobactam was associated with a 5 percent increase in 90-day mortality, more days on a ventilator, and more time with organ failure.

“These are powerful antibiotics that are administered to patients every day in every hospital nationwide,” said Chanderraj. “Clinicians use them because they are trying to treat every possible pathogen that might be causing their patients’ illness. But our results suggest that their effects on the microbiome might also have important effects on patient outcomes.”

The study builds on previous work by the researchers that suggested critically ill patients may do worse when given antibiotics that deplete the gut of anaerobes. They have also seen similar effects when studying animal models.

“Our prior work suggested that there might be harm with piperacillin/tazobactam, but it was an observational study that had some limitations,” said Sjoding, the study’s senior author. “That’s why the drug shortage was such an amazing opportunity. It created an almost perfect natural experiment that let us test the difference between these two drugs on patient outcomes in a very rigorous manner.”

A recent clinical trial pitted these two antibiotics against each other and compared side effects and mortality after two weeks. That trial did not find any differences in the short term – a finding that the U-M team also observed in their analysis.

“When we looked at two-week outcomes in our study, we didn’t find differences either,” said Chanderraj. “But the differences at three months were dramatic.”

Overall, the new findings suggest that treatment with piperacillin/tazobactam instead of cefepime may contribute to one additional death per every 20 septic patients treated.

“A 5% mortality difference has enormous implications because sepsis is so common,” said Dickson. “Every day, thousands of clinicians are deciding which of these drugs to use in septic patients.”

Physicians should give more thought about whether anti-anaerobic antibiotics are warranted before prescribing them, added Chanderraj. “We need to think about antibiotics like chemotherapy. In the right context, treatment can be lifesaving, but in the wrong context, it can be quite harmful.”

Source: Michigan Medicine – University of Michigan