Tag: 23/3/22

It’s in the Mix: Certain Combinations of Pathogens Resist Antibiotics

Pseudomonas
Scanning Electron Micrograph of Pseudomonas aeruginosa. Credit: CDC/Janice Carr

A study has found that much higher doses of antibiotics are needed to eliminate a bacterial infection of the airways when certain other microbes are present. This helps explain why treatment often fails to treat respiratory infections in people with diseases such as cystic fibrosis.

The study’s researchers, whose findings are published in The ISME Journal, say that even a low level of one type of microbe in the airways can have a significant impact on the response of other microbes to antibiotics.

The results highlight the need to consider the interaction between different species of microbe when treating infections with antibiotics – and to adjust dosage accordingly.

“People with chronic infections often have co-infection with several pathogens, but the problem is we don’t take that into account in deciding how much of a particular antibiotic to treat them with. Our results might help explain why, in these people, the antibiotics just don’t work as well as they should,” said Thomas O’Brien, PhD candidate and co-first author.

Chronic bacterial infections such as those in the human airways are very difficult to cure using antibiotics. Although these types of infection are often associated with a single pathogenic species, the infection site is frequently co-colonised by a number of other microbes, most of which are not usually pathogenic in their own right.

Treatment options usually revolve around targeting the pathogen, and take little account of the co-habiting species. However, these treatments often fail to resolve the infection. Until now scientists have had little insight into why this is.

To get their results the team developed a simplified model of the human airways, containing artificial sputum designed to chemically resemble the real thing, packed with bacteria.

The model allowed them to grow a mixture of different microbes, including pathogens, in a stable way for weeks at a time. This is a novel approach, as usually one pathogen will rapidly outgrow the others and spoil the experiment. It enabled the researchers to replicate and study poly-microbial infections in the laboratory.

The three microbes used in the experiment were the bacteria Pseudomonas aeruginosa and Staphylococcus aureus, and the fungus Candida albicans – a combination often found in the airways of cystic fibrosis patients.

The researchers treated this microbial mix with colistin, which kills P. aeruginosa effectively. But when the other pathogens were present alongside P. aeruginosa, the antibiotic didn’t work.

“We were surprised to find that an antibiotic that we know should clear an infection of Pseudomonas effectively just didn’t work in our lab model when other bugs were present,” said Wendy Figueroa-Chavez at the University of Cambridge, joint first author of the paper.

The same effect happened when the microbial mix was treated with fusidic acid – an antibiotic that specifically targets Staphylococcus aureus, and with fluconazole, which specifically targets C. albicans.

The researchers found that significantly higher doses of each antibiotic were needed to kill bacteria when it was part of poly-microbial infection, compared to when no other pathogens were present.

“All three species-specific antibiotics were less effective against their target when three pathogens were present together,” said Professor Martin Welch at the University of Cambridge, senior author of the paper.

Currently, antibiotics are usually only lab tested against the targeted pathogen, to determine the lowest effective dose. But when the same dose is used to treat infection in a person it is often ineffective, and this study helps to explain why. The new model system will enable the effectiveness of potential new antibiotics to be tested against a mixture of microbe species together.

Poly-microbial infections are common in the airways of people with cystic fibrosis. Despite treatment with strong doses of antibiotics, these infections often persist long-term. Chronic infections of the airways in people with asthma and chronic obstructive pulmonary disorder (COPD) are also often poly-microbial.

Genetically analysing the Pseudomonas in their lab-grown mix, the researchers were able to pinpoint specific mutations that give rise to this antibiotic resistance. The mutations were found to arise more frequently when other pathogens were also present.

Comparison with the genetic code of 800 samples of Pseudomonas from around the world revealed that these mutations have also occurred in human patients who had been infected with Pseudomonas and treated with colistin.

“The problem is that as soon as you use an antibiotic to treat a microbial infection, the microbe will start to evolve resistance to that antibiotic. That’s what has happened since colistin started to be used in the early 1990’s. This is another reminder of the vital need to find new antibiotics to treat human infections,” said Prof Welch.

Source: University of Cambridge

Minimally Invasive Hysterectomy Worse in Early Cervical Cancer

Doctors and nurses performing a surgery
Photo by Piron Guillaume on Unsplash

Minimally invasive hysterectomy for patients with early cervical cancer resulted in significantly worse outcomes compared with open surgery, according a clinical trial’s final analysis, a result which confirmed initial findings.

The Laparoscopic Approach to Cervical Cancer (LACC) trial compared disease-free survival (DFS) and overall survival (OS) at 4.5-year follow-up from the initial 631 patients who were randomised to open surgery or to MIS.

In the intention-to-treat population, DFS at 4.5 years – the study’s primary outcome – was 96.0% with the open surgery approach versus 85.0% with minimally invasive surgery (MIS), with similar DFS rates of 97.3% and 86.0% in the per-protocol analysis, reported Pedro T. Ramirez, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“When we presented the data in 2018, the recurrence rate for MIS was four times higher than for open surgery,” Dr Ramirez said at the Society of Gynecologic Oncology annual meeting. “And after completion of 4.5 years follow-up on all of the patients, it still remains the same.”

Since the initial publication of his team’s findings in 2018, said Dr Ramirez, national and international guidelines have changed their recommendations and now consider open radical hysterectomy as the new standard approach for patients with early cervical cancer. This final analysis confirms that patients with early cervical cancer “should not undergo the minimally invasive approach outside of a clinical trial,” he said.

DFS events occurred in 43 patients in the MIS arm versus 11 patients in the open surgery arm/ Additionally, the MIS arm patients had worse disease-specific survival, cumulative local/regional recurrence and overall survival.

Researchers also found that progression-free survival (PFS) was worse for MIS compared with open surgery, with 48 patients in the MIS arm experiencing events compared with 12 in the open surgery arm, consistent with the 2018 findings.

Since the initial publication of his team’s findings in 2018, said Dr Ramirez, national and international guidelines have altered their recommendations and now consider open radical hysterectomy as the new standard approach for patients with early cervical cancer. This final analysis confirms that patients with early cervical cancer “should not undergo the minimally invasive approach outside of a clinical trial,” he said.

The researchers also assessed outcomes by tumour size, conisation status, and carcinomatosis rates.

They found that 21% of MIS patients with tumours ≥ 2 cm had DFS events compared with about 5% of patients who had open surgery (HR 4.25).

Dr Ramirez emphasised that while the trial was not designed to answer the question of the effect of tumour size on surgical outcomes, “this highlights the fact that for larger tumours, there is clearly a disadvantage to minimally invasive surgery in terms of the difference in recurrence events.”

As for tumours less than 2 cm, the investigators found that no DFS events occurred among 65 patients who underwent open surgery versus seven DFS events among 75 MIS patients.

“It is important to highlight this because comments have been made that if patients have tumours less than 2cm, then perhaps it is appropriate to proceed with minimally invasive surgery,” Dr Ramirez pointed out.

Among those patients who did not have previous conisation, there were worse outcomes for those who underwent MIS. Among patients who did have a previous cone, there was no difference between the two arms.

When there were recurrences in the open surgery arm, no patients manifested with carcinomatosis versus 24% of patients in the MIS arm.

Source: MedPage Today

Access to Medical Marijuana Increases Risks for Abuse

Cannabis plants
Photo by Crystalweed Cannabis on Unsplash

A study found that access to medical marijuana to treat pain, anxiety, or depression symptoms led to cannabis use disorder (CUD) in a significant minority of individuals while failing to improve their symptoms. The Massachusetts General Hospital (MGH) study was published in JAMA Network Open. 

In the US, individuals are able to gain access to cannabis products using medical marijuana cards (MMCs), usually issued by a doctor. Researchers found the greatest risk of developing the addictive symptoms of CUD was in those seeking relief from anxiety and depression. This finding indicates the need for stronger safeguards over the dispensing, use, and professional follow-up of people who legally obtain cannabis through MMCs.

“There have been many claims about the benefits of medical marijuana for treating pain, insomnia, anxiety and depression, without sound scientific evidence to support them,” said lead author Jodi Gilman, PhD, with the Center for Addiction Medicine at MGH. “In this first study of patients randomised to obtain medical marijuana cards, we learned there can be negative consequences to using cannabis for medical purposes. People with pain, anxiety or depression symptoms failed to report any improvements, though those with insomnia experienced improved sleep.”

Dr Gilman was particularly disturbed by the fact that individuals with symptoms of anxiety or depression – the most common conditions which people seek medical cannabis for – were the ones most vulnerable to developing cannabis use disorder. CUD symptoms include a vicious circle of needing more cannabis because of growing tolerance, and seeking out cannabis to treat the psychological problems it causes.

“Medical” cannabis has surged in popularity in the US, as so far 36 of its 50 states have commercialised its use for myriad health conditions through medical marijuana cards. These cards require written approval of a licensed physician who, under the current system, is often not the patient’s primary care provider but rather a ‘cannabis doctor’ who may provide authorisation to patients with only a cursory examination, no recommendations for alternative treatments, and no follow-up. The medical marijuana industry effectively functions outside the regulations that apply to most fields of medicine.

The researchers started their trial in 2017 with 269 adults (average age of 37) who were interested in obtaining a medical marijuana card. One group was allowed to get MMCs immediately, while the second group, designed to serve as a control, was asked to wait 12 weeks before obtaining a card. Both groups were tracked over 12 weeks. The team found that the odds of developing CUD were nearly two times higher in the MMC cohort than in the wait list control group, and that by week 12, 10% of the MMC group had developed a CUD diagnosis, with the number rising to 20% in those seeking a card for anxiety or depression.

“Our study underscores the need for better decision-making about whether to begin to use cannabis for specific medical complaints, particularly mood and anxiety disorders, which are associated with an increased risk of cannabis use disorder,” said Dr Gilman. Regulation and distribution of cannabis to people with medical marijuana cards needs to be greatly improved, no matter the specific condition they are issued for. “There needs to be better guidance to patients around a system that currently allows them to choose their own products, decide their own dosing, and often receive no professional follow-up care.”

Source: Massachusetts General Hospital