In CF, Low-dose Antibiotics Aid Bacterial Diversity in Airways, But at a Cost

As published on CF News Today, BY JOSE MARQUES LOPES, PHD

Using lower, or suboptimal, doses of antibiotics to treat lung infections in children and young adults with cystic fibrosis (CF) leads to fewer changes in airway bacterial diversity compared to therapeutic (higher) antibiotic exposure.

The findings also suggested, however, that patients receiving therapeutic doses had greater improvements in lung function.

The research, “Changes in microbiome diversity following beta-lactam antibiotic treatment are associated with therapeutic versus subtherapeutic antibiotic exposure in cystic fibrosis,” was published in the journal Scientific Reports.

People with CF often have recurrent lung infections that gradually worsen their lung function. Treatment of these infections, known as acute pulmonary exacerbations (APEs), is typically based on antibiotics directed at pathogens such as Pseudomonas aeruginosa. However, repeated dosing with antibiotics has been suggested as the cause of decreased microbial diversity in the airways, which, in turn, could worsen lung function.

Despite current guidelines recommending higher antibiotic dosing regimens in people with CF, data from the U.S. indicate that beta-lactams — which include penicillin — were given in doses below the guidelines 38–53% of the time.

Although CF patients often do not achieve therapeutic doses of antibiotics to clear infections, which means that their blood levels of antibiotics do not increase sufficiently for effective treatment, it remains to be determined whether short courses of subtherapeutic doses alter microbial diversity, compared to therapeutic doses.

Aiming to address this question, researchers recruited 20 patients, ages 1-21, who were treated for APEs with intravenous infusion of beta-lactam antibiotics at Washington, D.C.’s Children’s National Health System.

Four samples of respiratory fluid were collected from each patient — when they were experiencing an APE, when they were doing well, right after antibiotic treatment, and at least 30 days later. Genetic testing determined the type and relative abundance of bacteria in each sample.

Blood samples and data on lung function were also collected during antibiotic treatment. Plasma antibiotic levels and bacterial minimum inhibitory concentrations (MICs) were used to determine therapeutic versus subtherapeutic antibiotic exposure.

Of note, to achieve effective bacterial killing, the serum concentration of an antibiotic must be above the MIC of the bacteria for a certain amount of time. Subtherapeutic exposure was thereby defined as insufficient time above MIC.

A total of 31 APEs were reported over the study period, from March 2015 to August 2016, and only approximately 14 (45%) of the antibiotic courses given were considered therapeutic. Most treatment regimens (25 out of 31 antibiotic regimens administered) included a single beta-lactam antibiotic.

Patients in the therapeutic group (11 patients, median age 9) had better lung function, and were less likely to receive inhaled antibiotics at study start, compared with the nine patients (median age 14) receiving subtherapeutic doses — 45% versus 100%, respectively.

At exacerbation onset, people in the therapeutic group showed a greater trend toward having a normal flora, compared to the subtherapeutic group (43% versus 12%), as well as increased abundance of Gemella, and a decrease in unclassified Enterobacteriaceae.

There was no significant difference in the presence of Pseudomonas aeruginosa or Staphylococcus aureus between the therapeutic and subtherapeutic groups.

As for antibiotic use, participants in the therapeutic group received ceftazidime (a more narrow spectrum beta-lactam) more often (86% versus 41%), and less frequently meropenem (a broad spectrum beta-lactam; 21% versus 59%) than those in the subtherapeutic group.

Those in the therapeutic group also had a significantly shorter time from end of treatment to post-recovery — 51 versus 79 days.

At both end of treatment and post-recovery, patients in the therapeutic group had decreased bacterial diversity in their airways, which contrasted with those receiving subtherapeutic doses — who showed minimal changes or higher diversity more than one month after treatment.

Unlike participants in the therapeutic group, who showed increased or decreased relative abundance of specific bacterial genera compared to baseline, those in the subtherapeutic group showed no changes.

“With the subtherapeutic treatment group, this could represent a ‘basement effect’ where it is harder to decrease diversity when it is already low to start,” Andrea Hahn, MD, the study’s lead author, said in a press release.

Also, “patients in the subtherapeutic group had more advanced disease than those in the therapeutic group, which may influence the findings,” Hahn said.

Data further showed that receiving therapeutic antibiotics was associated with a trend toward greater improvement in lung function.

“Thus, the conclusion should not be drawn that because subtherapeutic antibiotics have less impact on changes in microbial diversity, it could be used as a strategy to prevent declining lung function,” the scientists said. “This is likely a reflection of disease severity, antibiotic exposure, and antibiotic resistance.”

The researchers believe that repeated subtherapeutic courses of antibiotics could lower microbial diversity without clearing infections, causing progressive lung dysfunction. Closer monitoring of antibiotic levels in blood to ensure that each exacerbation is treated with therapeutic-level dosing could be an effective answer, Hahn said.

“What this study shows is that levels of the antibiotics we give probably play a role in patients’ ability to recover baseline diversity,” Hahn said. “If we pay more attention to drug levels when using these types of antibiotics to ensure that dosing is sufficient, we could potentially improve patients’ clinical outcomes over time.”

Insufficient antibiotics available for cystic fibrosis patients: Study

Turns out, the majority of patients with cystic fibrosis may not achieve blood concentrations of antibiotics sufficiently high enough to effectively fight bacteria responsible for pulmonary exacerbations, thus leading to worsening pulmonary function.

Cystic fibrosis, a genetic condition that affects about 70,000 people worldwide, is characterised by a buildup of thick, sticky mucus in patients’ lungs. There, the mucus traps bacteria, causing patients to develop frequent lung infections that progressively damage these vital organs and impair patients’ ability to breathe.

A recent study led by researchers at Children’s National Health System shows that it’s impossible to predict solely from dosing regimens which patients will achieve therapeutically meaningful antibiotic concentrations in their blood. The findings were published online in the Journal of Pediatric Pharmacology and Therapeutics.

These infections, which cause a host of symptoms collectively known as pulmonary exacerbations, are typically treated with a combination of at least two antibiotics with unique mechanisms. One of these drugs is typically a Beta-lactam antibiotic, a member of a family of antibiotics that includes penicillin derivatives, cephalosporins, monobactams and carbapenems.

Although all antibiotics have a minimum concentration threshold necessary to treat infections, Beta-lactam antibiotics are time-dependent in their bactericidal activity. Their concentrations must exceed a minimum inhibitory concentration for a certain period. However, study’s lead author Andrea Hahn explained that blood concentrations of Beta-lactam antibiotics aren’t typically tracked while patients receive them.

Since antibiotic dosing often doesn’t correlate with cystic fibrosis patients’ clinical outcomes, Dr. Hahn and other researchers examined whether patients actually achieved serum antibiotic concentrations that are therapeutically effective.

In addition, all the patients underwent pulmonary function tests at the start of their exacerbations and about once weekly until their antibiotic therapy ended.

Using the data points, the researchers constructed a model to determine which patients had achieved therapeutic concentrations for the bacteria found in their respiratory secretions. They then correlated these findings with the results of patients’ pulmonary function tests. Just 47 per cent of patients had achieved therapeutic concentrations. Those who achieved significantly high antibiotic exposure had more improvement on their pulmonary function tests compared with patients who didn’t.

Paradoxically, they discovered that although each patient received recommended antibiotic doses, some patients had adequately high serum antibiotic concentrations while others did not.

Another way to ensure patients receive therapeutically meaningful levels of antibiotics is to develop new models that incorporate variables such as age, gender, and creatinine clearance–a measure of kidney function that can be a valuable predictor of metabolism–to predict drug pharmacokinetics.

Using findings from this research, Dr. Hahn adds, Children’s National already has implemented an algorithm using different variables to determine antibiotic dosing for patients treated at the hospital.

Original article here.

Triclosan, often maligned, may have a good side — treating cystic fibrosis infections

By Chris Waters

Maybe you’ve had the experience of wading in a stream and struggling to keep your balance on the slick rocks, or forgetting to brush your teeth in the morning and feeling a slimy coating in your mouth. These are examples of bacterial biofilms that are found anywhere a surface is exposed to bacteria in a moist environment.

Besides leading to falls in streams or creating unhealthy teeth, biofilms can cause large problems when they infect people. Biofilms, multicellular communities of bacteria that can grow on a surface encased in their own self-produced matrix of slime, can block immune cells from engulfing and killing the bacteria or prevent antibodies from binding to their surface.

On top of this, bacteria in a biofilm resist being killed by antibiotics due to the sticky nature of the matrix and activation of inherent resistant mechanisms, such as slow-growing cells or the ability to pump antibiotics out of the cell.

Biofilms are one of the primary growth modes of bacteria, but all antibiotics currently used clinically were developed against free-swimming planktonic bacteria. This is why they do not work well against biofilms.

My laboratory studies how and why bacteria make biofilms, and we develop new therapeutics to target them. Because antibiotic resistance is the most problematic aspect of biofilms during infections, we set out to identify novel molecules that could enhance antibiotic activity against these communities.

We discovered that an antimicrobial that has recently obtained a bad reputation for overuse in many household products could be the secret sauce to kill biofilms.

The hunt for antibiotic superchargers

To find such compounds, we developed an assay to grow plates of 384 tiny biofilms of the bacterium Pseudomonas aeruginosa. We did this to screen for molecules that enhance killing by the antibiotic tobramycin. We chose this bacterium and this antibiotic as our test subjects because they are commonly associated with cystic fibrosis lung infections and treatment.

People with cystic fibrosis (CF) are at particular risk from biofilm-based infections. These infections often become chronic in the lungs of cystic fibrosis patients and are often never cleared, even with aggressive antibiotic therapy.

After we screened 6,080 small molecules in the presence of tobramycin, we found multiple compounds that showed the antibiotic enhancement activity we were searching for. Of particular interest was the antimicrobial triclosan because it has been widely used in household products like toothpaste, soaps and hand sanitizers for decades, indicating that it had potential to be safely used in CF patients. Triclosan has also garnered a bad reputation due to its overuse, and states like Minnesota have banned it from these products. The Food and Drug Administration banned its use from hand soaps in September 2016. This ruling was not based on safety concerns, but rather because the companies that made these products did not demonstrate higher microbial killing when triclosan was added, compared to the base products alone.

Another fact that piqued our interest is that P. aeruginosa is resistant to triclosan. Indeed, treatment with either tobramycin or triclosan alone had very little activity against P. aeruginosa biofilms, but we found that the combination was 100 times more active, killing over 99 percent of the bacteria.

We further studied this combination and found that it worked against P. aeruginosa and other bacterial species that had been isolated from the lungs of CF patients. The combination also significantly enhanced the speed of killing so that at two hours of treatment, virtually all of the biofilm is eradicated.

Our efforts are now focused on pre-clinical development of the tobramycin-triclosan combination. For CF, we envision patients will inhale these antimicrobials as a combination therapy, but it could also be used for other applications such as diabetic non-healing wounds.

Although questions about the safety of triclosan have emerged in the mainstream media, there are actually dozens of studies, including in humans, concluding that it is well tolerated, summarized in this extensive EU report from 2009. My laboratory completely agrees that triclosan has been significantly overused, and it should be reserved to combat life-threatening infections.

The next steps for development are to initiate safety, efficacy and pharmacological studies. And thus far, our own studies indicate that triclosan is well tolerated when directly administered to the lungs. We hope that in the near future we will have enough data to initiate clinical trials with the FDA to test the activity of this combination in people afflicted with biofilm-based infections.

We think our approach of enhancing biofilm activity with the addition of novel compounds will increase the usefulness of currently used antibiotics. Learning about how these compounds work will also shed light on how bacterial biofilms resist antibiotic therapy.

Original article here.

OWN IT: MCR-1 is Here

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