Tuesday, 23 July 2019

Bispecific Antibody Development Programs - FDA

Image: Dr Josehp Ndieyira of UCL Medicine

The general regulatory and scientific considerations for bispecific antibodies, is a growing area of interest.
A new guidance document from the FDA, which refers to: “This guidance provides recommendations to assist industry and other parties involved in the development of bispecific antibodies. Discussion includes general considerations and recommendations for bispecific antibody development programs, as well as regulatory, quality, nonclinical, and clinical considerations in the context of bispecific antibody development programs. This guidance does not discuss development considerations for other multitarget therapies that are combinations of monoclonal antibodies or are antibody cocktails or polyclonal antibodies. Although this guidance is specific to bispecific antibodies, the principles discussed in this guidance may also be applicable to the development of other types of bispecific protein products.”

For details, see FDA - https://www.fda.gov/media/123313/download

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Monday, 22 July 2019

Why it’s time to focus on the cleanroom operator

The majority of contamination in a pharmaceutical facility, presuming that the air handling system is functioning as designed, that water systems are low in bioburden and are not leaking, and there is good control of in-coming materials, will derive from people. It follows that an effective contamination control strategy will focus on the control of operators. Control extends to behaviors, gowning and having the correct equipment, and this will be supported by periodic qualifications and underpinned by audits.
In relation to this, Tim Sandle has written a new article:

“This article addresses some of the key concerns relating to operators within cleanrooms, in the context of the risk operators pose in terms of microbial contamination. The article is divided into three sections. The first part looks at means to improve operator behaviors, the second part looks at how regular reviews by plant microbiologists or quality assurance staff can help to reinforce these behaviors, and the third part considers the idea of having ‘environmental control champions’ within the production facility.”

The reference is:

Sandle, T. (2019) Focusing on the Operator: Reducing Facility Environmental Contamination, American Pharmaceutical Review, 22 (3): 12-17

For further details, contact Tim Sandle

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Sunday, 21 July 2019

EMA facilitates engagement with medicine developers to combat antimicrobial resistance

The European Medicines Agency (EMA) is opening up the early dialogue available through its Innovation Task Force (ITF) to all medicine developers who work on therapeutic approaches for the treatment or prevention of bacterial and fungal infections. ITF is a forum for dialogue between regulators and developers of innovative emerging therapies, methods and technologies, in the early stages of research and development. ITF is usually reserved for innovative medicines. Given the growing threat to public health caused by antimicrobial resistance and the need for new treatments, EMA is inviting all developers working on medicines for the treatment or prevention of life-threatening microbial infections to enter into early dialogue with the Agency to help strengthen the drug development pipeline for new antimicrobials.

The emerging and steady increase of microbes that are resistant to antimicrobial treatments threatens the effective treatment of patients with infectious diseases. According to a WHO report, approximately 700,000 people die from drug resistant infections globally each year, a figure that could rise to 10 million deaths globally per year by 2050 under the most alarming scenario if no action is taken. Without a sustained effort to contain antimicrobial resistance, common diseases are becoming untreatable and lifesaving medical procedures riskier to perform.

The ITF will facilitate an early interaction and broad-ranging discussions between innovators and regulatory authorities, which will help developers’ orientation and subsequent use of formal regulatory tools such as EMA’s scientific advice. The service is free of charge and any new medicinal product for the treatment of a life-threatening or debilitating fungal or bacterial infection would be considered for discussion in the ITF.

This platform for early dialogue will ultimately contribute to prioritising and speeding up the development of antimicrobial medicines, which is in line with the European Parliament Resolution of 13 September 2018 on "A European One Health Action Plan against Antimicrobial Resistance".

Interested medicine developers are encouraged to complete the ITF briefing meeting request form and send it to itfsecretariat@ema.europa.eu to discuss their development plans for medicinal products addressing bacterial and fungal infections.

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Saturday, 20 July 2019

Salmonella resistant to antibiotics of last resort

Researchers from North Carolina State University have found a gene that gives Salmonella resistance to antibiotics of last resort in a sample taken from a human patient in the U.S. The find is the first evidence that the gene mcr-3.1 has made its way into the U.S. from Asia.
There are more than 2,500 known serotypes of Salmonella.

In the U.S., Salmonella enterica 4,[5],12:i:- ST34 is responsible for a significant percentage of human illnesses. The drug resistance gene in question -- known as mcr-3.1 -- gives Salmonella resistance to colistin, the drug of last resort for treating infections caused by multidrug-resistant Salmonella.

"Public health officials have known about this gene for some time," says Siddhartha Thakur, professor and director of global health at NC State and corresponding author of the research. "In 2015, they saw that mcr-3.1 had moved from a chromosome to a plasmid in China, which paves the way for the gene to be transmitted between organisms. For example, E. coli and Salmonella are in the same family, so once the gene is on a plasmid, that plasmid could move between the bacteria and they could transmit this gene to each other. Once mcr-3.1 jumped to the plasmid, it spread to 30 different countries, although not -- as far as we knew -- to the U.S."

Thakur's lab is one of several nationally participating in epidemiological surveillance for resistant strains of Salmonella. The lab generates whole genome sequences from Salmonella samples every year as part of routine monitoring for the presence of antimicrobial-resistant bacteria. When veterinary medicine student Valerie Nelson and Ph.D. student Daniel Monte did genome sequencing on 100 clinical human stool samples taken from the southeastern U.S. between 2014 and 2016, they discovered that one sample contained the resistant mcr-3.1 gene. The sample came from a person who had traveled to China two weeks prior to becoming ill with a Salmonella infection.


Daniel F. Monte, Valerie Nelson, Louise Cerdeira, Shivaramu Keelara, Shermalyn Greene, Denise Griffin, Shadia Rath, Robbie Hall, Nichole Page, Paula J. Fedorka-Cray, Siddhartha Thakur. Multidrug- and colistin-resistant Salmonella enterica 4,[5],12:i:- sequence type 34 carrying the mcr-3.1 gene on the IncHI2 plasmid recovered from a human. Journal of Medical Microbiology, 2019; DOI: 10.1099/jmm.0.001012 

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Friday, 19 July 2019

Ebola Outbreak - Global health Emergency

ASTMH (American Society of Tropical Medicine and Hygiene) welcomes the WHO’s declaration of the Ebola outbreak in the Democratic Republic of the Congo as a global public health emergency. The declaration will help to mobilize the additional support necessary for the men, women and children who are suffering from this disastrous and devastating disease, and for the brave health workers and researchers striving tirelessly to stop it.

This new case in Goma is one more of the many warnings of the powder-keg nature of this Ebola outbreak. The West African Ebola outbreak in 2014 was a demonstration of how interconnected we all are. Every country must pay attention to this fragile situation and do more to find solutions to this public health crisis. With new vaccines and the scientific tools available, the WHO’s declaration is a significant step in the right direction.

“While the progress we’ve seen in developing new drugs and vaccines against Ebola is remarkable, we need to make further biological breakthroughs and match them with a political breakthrough,” said ASTMH President Chandy C. John, MD, MS, FASTMH. “ASTMH is eager to work with decision-makers and government leaders in a worldwide collaborative effort to end this outbreak and prevent future outbreaks. As tropical infectious disease experts, we know what is at stake here. We believe it is past time to work together to bring this terrible outbreak to an end.”

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Thursday, 18 July 2019

The Battle to Control HAIs

Floors, often overlooked in the past as a major factor of environmental contamination leading to increased HAI rates, are, in fact, a contributor to this very expensive and life-impacting problem. Studies have shown that floors harbor HAI pathogen organisms. These pathogens may not be neutralized by using mops that bind disinfectants or may be transported through unexpected means, including socks or laundered mops damaged by the laundering process and reducing their ability to effectively clean or disinfect the floor.

New from Infection Control Today:

  • Download this whitepaper, which discusses:

  • Human and financial implications of HAIs.
  • Microfiber laundered mops retain residual pathogens.
  • Impact of laundry processes on microfiber’s structure and efficacy.
  • Moving to single-use mops. 

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Wednesday, 17 July 2019

Establishing added benefit of novel therapies

Regulators have a role to play in ensuring that there is a solid evidence base to support the assessment of added therapeutic benefit of novel treatments compared with existing and potentially cheaper therapies, according to the European Medicines Agency.

To help health technology assessment bodies, payers, clinicians and patients to separate merely new from truly better medicines, the regulators, firstly, should provide explicit reasoning on a medicine’s added benefit compared to other treatments at the time of approval. And secondly, they should insist on ‘evidence by design’. This means they must make companies aware of the need to plan the development programmes of medicines upfront, so that they are suitable to address the evidence needs of all relevant healthcare decisions-makers.

These are the main conclusions of an article by EMA’s Senior Medical Officer, Hans-Georg Eichler, Harald Enzmann, Chair of EMA’s human medicines committee (CHMP) and Head of European and International Affairs at the Federal Institute for Drugs and Medical Devices (BfArM) and EMA's Executive Director Guido Rasi, published in Nature Reviews Drug Discovery.

In this article, the authors analyse the benefits and risks of different proposals regarding the role of regulatory agencies in establishing the added therapeutic benefit of novel treatments in light of the ongoing debate about medicines pricing. Health-care payers emphasise that ‘innovation’ is not always synonymous with ‘added therapeutic benefit’ and increasingly resist paying high prices for new medicines with no or only minor added benefit.

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Tuesday, 16 July 2019

Antimicrobial paints have a blind spot

Antimicrobial paints offer the promise of extra protection against bacteria. But Northwestern University researchers caution that these paints might be doing more harm than good.

In a new study, the researchers tested bacteria commonly found inside homes on samples of drywall coated with antimicrobial, synthetic latex paints. Within 24 hours, all bacteria died except for Bacillus timonensis, a spore-forming bacterium. Most bacilli are commonly inhabit soil, but many are found in indoor environments.

“If you attack bacteria with antimicrobial chemicals, then they will mount a defense,” said Northwestern’s Erica Hartmann, who led the study. “Bacillus is typically innocuous, but by attacking it, you might prompt it to develop more antibiotic resistance.”

Bacteria thrive in warm, moist environments, so most die on indoor surfaces, which are dry and cold, anyway. This makes Hartmann question the need to use antimicrobial paints, which may only be causing bacteria to become stronger.

Spore-forming bacteria, such as Bacillus, protect themselves by falling dormant for a period of time. While dormant, they are highly resistant to even the harshest conditions. After those conditions improve, they reactivate.

“When it’s in spore form, you can hit it with everything you’ve got, and it’s still going to survive,” said Hartmann, assistant professor of civil and environmental engineering in Northwestern’s McCormick School of Engineering. “We should be judicious in our use of antimicrobial products to make sure that we’re not exposing the more harmless bacteria to something that could make them harmful.”

The study was published online on April 13 in the journal Indoor Air.

One problem with antimicrobial products — such as these paints — is that they are not tested against more common bacteria. Manufacturers test how well more pathogenic bacteria, such as E. coli or Staphylococcus, survive but largely ignore the bacteria that people (and the products they use) would more plausibly encounter.

“E. coli is like the ‘lab rat’ of the microbial world,” Hartmann said. “It is way less abundant in the environment than people think. We wanted to see how the authentic indoor bacteria would respond to antimicrobial surfaces because they don’t behave the same way as E. coli.”

The study, “Impacts of indoor surface finishes on bacterial viability,” was supported by the Alfred P. Sloan Foundation (award number G-2016-7291) and the Searle Leadership Fund.

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Monday, 15 July 2019

An interview with Dr. Tim Sandle

Dr Tim Sandle is currently Head of Microbiology and Sterility Assurance at Bio Products Laboratory Limited. Here he talks to the Microbiology Society about his current role, his area of research and the importance of antimicrobial resistance (AMR) as a health issue. He also explains why he joined the Microbiology Society and offers advice for anyone thinking about a career change.

You are currently Head of Microbiology and Sterility Assurance: tell us more about your role with Bio Products Laboratory Limited.

I am responsible for heading up four departments. One is associated with supporting the manufacturing areas in terms of assessing cleanrooms for levels of microorganisms in the air and on surfaces for assessing product bioburden, microbial levels in water, screening samples for bacterial endotoxin and verifying that the finished product is sterile. The second area is associated with the development of novel microbial methods, the qualification of equipment, and dealing with regulatory submissions. The third area is to do with risk assessments, carried out in order to lower microbial contamination risks in process areas and to investigate when high microbial levels are recovered. The fourth area is linked to proactive practices to improve hygiene and to support new technologies. My role is to ensure these different entities connect together and to develop appropriate policies and standards in order to enhance sterility assurance.

Why did you choose to become a microbiologist?

I was always interested in biology: as a child, I was encouraged by my grandfather to take an interest in the natural world. I started off with an interest in biological sciences in general and was encouraged by a teacher to consider the importance of microbiology in health and disease.

Do you have any advice for anyone thinking about a career change and making a brave move from academia to industry?
The key attraction with industry is the ability to research and develop life-saving medicines and see these come to fruition. However, it is a different working experience and there are different types of pressures (these days both academia and industry are subject to increasing cost and time demands). Certainly, in industry there is a need to produce and release on schedule, otherwise this creates financial complexities. However, the work is very varied and there remains opportunities to engage in research and to produce papers. I’ve certainly managed to continue to contribute to peer-reviewed papers and book chapters. There also remains the opportunity to present at conferences.

Tell us about your biggest professional achievement(s) so far.

Some of the recent research I’ve been undertaking has concerned a partly overlooked issue of whether organisms that are resistant to antimicrobials have enhanced resistance to biocides. Although there is no direct evidence that organisms can acquire resistance to disinfectants, organisms that are resistant to antimicrobials may be harder to kill with the disinfectants commonly used in the pharmaceutical or healthcare setting. There is some evidence of this with some organisms, which calls for a renewed focus on aspects of disinfectant efficacy, like the minimum inhibitory concentration.

Tell us about your area of research?

The research is mostly applied. Over the past few years I’ve been working with microbiologists in Saudi Arabia, principally Dr Vijayakumar Rajendran, to determine the frequency of biocide resistant genes (e.g. qacA, qacE and cepA) in multidrug resistant bacteria, such as Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii, and to correlate the presence or absence of resistant genes with biocides susceptibility. We’ve written several papers looking at different organisms and different biocides, assessing whether organisms that are antimicrobial resistant are also more resistant to common disinfectants. The research may have an impact on how pharmaceuticals and healthcare works, such as the need to reassess minimum inhibitory concentrations.

What have you done to try to maximise the impact of your research?

The research is ongoing and the full implications have yet to be realised; however, the research is showing a new dimension to the antimicrobial issue. The main thing in terms of impact is kicking-off discussion about overlooked areas in relation to AMR, which should help to encourage other researchers to consider different perspectives. Outside of this, I publicise where I can the importance of taking steps to reduce AMR, especially when different international campaigns are taking place. Social media provides a great outlet for this.

How important is AMR as a health issue?

It is an issue of great importance. Humans face the very real risk of a future without antibiotics. The implications of this are that life expectancy could fall due to people dying from diseases that are readily treatable today. In the last two decades, the rate at which bacteria are becoming resistant to current antibiotic treatments has substantially increased. For example, this trend is threatening the ability of medical staff to carry out routine operations or transplants in the future.

In your opinion, which areas of research are likely to have greatest impact on tackling AMR in the future?

Scientists have a role in addressing AMR even if they are not directly involved with AMR research or practices. This is by helping to promote best practices, such as avoiding the mis-prescribing of antibiotics to patients or though seeking better practices and alternatives to antibiotics in terms of rearing animals. One key research area that will have the greatest impact is in the search for new antimicrobials. There are some interesting ones in development, such as Dalvance, an intravenous drug that can treat skin and soft tissue infections; Oritavancin, a lipoglycopeptide with bactericidal activity against Gram-positive bacteria; and Teixobactin, a peptide-like secondary metabolite found in some bacteria that kills some Gram-positive bacteria and which has received the most media attention. The search for new antimicrobials, however, needs to continue, and the spectrum of searching needs to extend to areas of low human contact, such as deep in caves or parts of the oceans.

Do you have any advice for early career scientists who’d like to work in AMR?

First, research into AMR is a long process and there are many routes that do not lead to anything tangible. Patience is important. Second, potential candidate drugs to address AMR can come from the most unlikely of places, so keeping an open mind is also important.

The Microbiology Society is often seen as a Society for academics. What would you say to disperse this myth? What are the main benefits of being a member?

The Microbiology Society provides topical material for microbiologists in all sorts of occupations, not just academia. In recent years there has been a variety of different topics that connect what is being researched in universities to what needs to be developed by industry in order to meet healthcare demands – the hunt for new antimicrobials being a prime example. The Microbiology Society is so varied, and this richness leads to a range of different subject matter that enhances knowledge across both academia and industry. The sharing of ideas across these two sectors is to the benefit of all professional microbiologists. It provides an important arena for networking and sharing ideas across a range of different microbiological disciplines. It also plays a vital role in promoting the interaction between microbiologists and the general public, helping to educate and to engage.

And finally, why does microbiology matter?

Microbiology matters because it impacts across every aspect of society, from food production to global warming (such as toxic algal blooms); to the development of new medicines through biotechnology; for protecting the manufacture of medicines from contamination; and, of course, in protecting people from disease and with fighting diseases. Through being involved with any of these fields, you can make a difference.

Are you a member and interested in sharing stories about your research journey? Email members@microbiologysociety.org. March 2019

Source: https://microbiologysociety.org/membership/meet-our-members/an-interview-with-dr-tim-sandle.html

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Sunday, 14 July 2019

Artificial intelligence used to identify bacteria accurately

Microscopes enhanced with artificial intelligence (AI) could help clinical microbiologists diagnose potentially deadly blood infections and improve patients' odds of survival, according to microbiologists at Beth Israel Deaconess Medical Center (BIDMC).

The scientists demonstrated that an automated AI-enhanced microscope system is "highly adept" at identifying images of bacteria quickly and accurately. The automated system could help alleviate the current lack of highly trained microbiologists, expected to worsen as 20 percent of technologists reach retirement age in the next five years.

"This marks the first demonstration of machine learning in the diagnostic area," said senior author James Kirby, MD, Director of the Clinical Microbiology Laboratory at BIDMC and Associate Professor of Pathology at Harvard Medical School. "With further development, we believe this technology could form the basis of a future diagnostic platform that augments the capabilities of clinical laboratories, ultimately speeding the delivery of patient care."

Kirby's team used an automated microscope designed to collect high-resolution image data from microscopic slides. In this case, blood samples taken from patients with suspected bloodstream infections were incubated to increase bacterial numbers. Then, slides were prepared by placing a drop of blood on a glass slide and stained with dye to make the bacterial cell structures more visible.

Next, they trained a convolutional neural network (CNN) -- a class of artificial intelligence modeled on the mammalian visual cortex and used to analyze visual data -- to categorize bacteria based on their shape and distribution. These characteristics were selected to represent bacteria that most often cause bloodstream infections; the rod-shaped bacteria including E. coli; the round clusters of Staphylococcus species; and the pairs or chains of Streptococcus species.

"Like a child, the system needed training," said Kirby. "Learning to recognize bacteria required a lot of practice, making mistakes and learning from those errors."

To train it, the scientists fed their unschooled neural network more than 25,000 images from blood samples prepared during routine clinical workups. By cropping these images -- in which the bacteria had already been identified by human clinical microbiologists -- the researchers generated more than 100,000 training images. The machine intelligence learned how to sort the images into the three categories of bacteria (rod-shaped, round clusters, and round chains or pairs), ultimately achieving nearly 95 percent accuracy.

Next, the team challenged the algorithm to sort new images from 189 slides without human intervention. Overall, the algorithm achieved more than 93 percent accuracy in all three categories. With further development and training, Kirby and colleagues suggest the AI-enhanced platform could be used as fully automated classification system in the future.

In the meantime, Kirby suggests automated classification can ameliorate the shortage of human technologists by helping them work more efficiently, "conceivably reducing technologist read time from minutes to seconds," he said.

While human technologists routinely provide highly accurate diagnoses, demand for these highly skilled workers exceeds supply in the United States. Nine percent of lab technologists remain unfilled, and that number is expected to dramatically increase as technologists of the Baby Boomer generation begin to retire in droves, according to a 2014 survey from the American Society for Clinical Pathology.

What's more, these images can be sent remotely, bringing the highest level expertise anywhere the internet reaches. That's critical, as rapid identification and delivery of antibiotic medications is the key to treating bloodstream infections, which can kill up to 40 percent of patients who develop them. Each day a patient goes untreated is linked with an increased risk of mortality.

In addition to its clinical uses, the new tool could also have applications in microbiology training and research, Kirby noted.

"The tool becomes a living data repository as we use it," he said. "And could be used to train new staff and ensure competency. It can provide unprecedented level of detail as a research tool."


Kenneth P. Smith, Anthony D. Kang, James E. Kirby. Automated Interpretation of Blood Culture Gram Stains using a Deep Convolutional Neural Network. Journal of Clinical Microbiology, 2017; JCM.01521-17 DOI: 10.1128/JCM.01521-17

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Saturday, 13 July 2019

Paper stickers to monitor pathogens are more effective than swabs

Using paper stickers to collect pathogens on surfaces where antisepsis is required, such as in food processing plants, is easier, and less expensive than swabbing, yet similarly sensitive.

"The porous structure of paper seems able to collect and accumulate [bacterial] contamination," said first author Martin Bobal, technical assistant, Christian Doppler Laboratory for Monitoring of Microbial Contaminants, Department for Farm Animal and Public Health in Veterinary Medicine, The University of Veterinary Medicine, Vienna, Austria. "This requires mechanical contact, for example by hand, or by splashed liquids."

In the study, the investigators, who specialize in monitoring cheese production, chose to target the organism Listeria monocytogenes, a pathogen that commonly contaminates raw milk and other raw dairy products, including soft cheeses such as Brie, Camembert, and Feta. They used qPCR, a method of quantifying DNA samples to determine the numbers of these bacteria, as well as of Escherichia coli.

Surfaces in food processing plants must be cleaned regularly. Unlike swabs, artificially contaminated stickers provided a record of contamination that took place over at least two weeks, despite washing, flushing with water, or wiping with Mikrozid, an alcohol-based disinfectant, to simulate cleansing practices. "Recovery [of DNA] from the stickers was rather variable, at around 30%, but did not distinctly decrease after 14 days of storage," the report stated. "This suggests the possibility of sampling over two weeks as well."

In a proof of concept experiment, the researchers placed stickers at multiple locations that frequently undergo hand contact -- such as on light switches and door handles -- for one to seven days. Both bacterial species were detected repeatedly from these stickers.
Unlike stickers, swabbing is impractical on complex surfaces, such as door handles, light switches, and other fomites (objects likely to be contaminated with, and spread infectious organisms) and does a poor job of taking up bacteria from dry surfaces, according to the report.

"In the food production facility, conventional swabbing as a standard method can only expose a momentary snapshot," the investigators wrote. "For example, it is not possible to reconstruct information about yesterday's status after cleansing has been performed. In addition, when moistened swabs or contact-plate sampling methods are used, they bring with them growth medium into a supposedly clean environment, making subsequent disinfection necessary."

The investigators showed that plain paper stickers could trap not only bacterial pathogens and related DNA, but dead, and viable but non-culturable pathogens, which also can pose a threat to public health.

"A major advantage of stickers is in handling: they are easy to distribute and to collect," the authors concluded. "We put the stickers directly into the DNA-extraction kit's first protocol step. We did not encounter any inhibition or loss of information during DNA-extraction, nor during qPCR," said Mr. Bobal.


Martin Bobal, Anna Kristina Witte, Patrick Mester, Susanne Fister, Dagmar Schoder, Peter Rossmanith. A novel method for sampling and long-term monitoring of microbes using stickers of plain paper. Applied and Environmental Microbiology, 2019; DOI: 10.1128/AEM.00766-19

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Friday, 12 July 2019

New Liposome Treatment for Community-acquired Pneumonia

The findings are of significance for pharmaceutical companies and the medical sector. This is in the context of a time of great struggle for antibiotic companies given the increase in instances of antibiotic resistant bacteria. What is of particular global concern is the acceleration of resistance. U.S. Centers for Disease Control and Prevention (CDC) data finds that many high-income countries are entering a “post-antibiotic era.”

Tim Sandle has written an article for BioPharma Trends on the subject of liposomes. Here is an extract:

"CAL02 is composed of liposomes engineered to entrap and neutralize a large panel of bacterial toxins, particularly those medically identified as causing severe complications. A liposome is a spherical vesicle having at least one lipid bilayer. In medical research, liposomes are considered one of the most versatile and promising drug-carrier devices."

To read the article, see: https://www.biopharmatrend.com/post/93-new-liposome-treatment-for-community-acquire-pneumonia/

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Thursday, 11 July 2019

New dispersion method to kill biofilm bacteria for wound care

Biofilms are a structured community of bacterial cells that are adherent to inert or living surfaces. What makes these structures special is that living within these biofilm communities makes its resident bacteria resistant to antibiotics. A research team led by Karin Sauer, professor of biological sciences at Binghamton University, demonstrated that two important human pathogens, P. aeruginosa and S. aureus, need pyruvate to form these structured biofilm communities that are inherently resistant to antibiotics. In turn, the research team demonstrated that removal of pyruvate induces a physiological change in biofilm bacteria that has two consequences: 1) it causes them to disassemble the biofilm structure in a process referred to as biofilm dispersion; and 2) it renders biofilm bacteria more susceptible to antibiotics.

Biofilm infections are almost impossible to treat by conventional antibiotic therapy. In that regard, these findings are noteworthy, Sauer said. Inducing biofilm dispersion by depleting pyruvate is an add-on therapy that maximizes the effectiveness of conventional antibiotics in killing biofilms. That this novel therapeutic strategy works was apparent as the combination treatment (inducing biofilm dispersion in addition to conventional antibiotic therapy) was significantly more effective than treatment with antibiotics alone or even with the antimicrobial cream silver sulfadiazine, which is considered the gold standard in wound care.

What this means for wound care is that pyruvate depletion can improve the anti-biofilm activity of conventional antibiotic therapy (which by itself is not working so well), to better treat infected wounds and, ultimately, improve wound healing.

Given that pyruvate depletion not only disperses already established biofilms, but also prevents the formation of antibiotic-resistant biofilms by the two principal pathogens associated with wound infections, pyruvate depletion can also be used to prevent biofilm-related wound infections.


James Goodwine, Joel Gil, Amber Doiron, Jose Valdes, Michael Solis, Alex Higa, Stephen Davis, Karin Sauer. Pyruvate-depleting conditions induce biofilm dispersion and enhance the efficacy of antibiotics in killing biofilms in vitro and in vivo. Scientific Reports, 2019; 9 (1) DOI: 10.1038/s41598-019-40378-z

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Wednesday, 10 July 2019

Standard for Disinfectants and Sterilants (TGO 54)

Previously in this blog we mentioned the Australian TGA consultation for its Standard for Disinfectants and Sterilants (TGO 54). The consultation period has now been completed and the TGA has made the new Therapeutic Goods Order 104: Standard for Disinfectants (TGO 104) to replace the previous TGO 54 'Standard for Disinfectants and sterilants' which sunsets on 1 April 2019.

The TGA has incorporated stakeholder feedback from consultation, about the proposed new TGO:

  • Updated sections of the previous TGO 54 'Standard for Disinfectants and Sterilants' and clarifies the requirements for hard surface disinfectants;
  • The labelling requirements of the previous and TGO 37 'General Requirements for Labels for Therapeutic Devices' (which sunset on 1 October 2018); and
  • Standards and requirements within the Guidelines for the evaluation of disinfectants.
  • As a result, these regulatory requirements are now contained within one TGO. 

Stakeholder feedback will also inform TGA's review of:
  • the disinfectants pages of the TGA website, to ensure the application processes for inclusion in the Australian Register of Therapeutic Goods (ARTG) are clear for all current and potential sponsors of disinfectants; and
  • the guidance documents for exempt and listed disinfectants (which will be published in late April in response to requests from stakeholders for further amendments). In the interim, the previous guidance documents provide support to sponsors for understanding the TGO.
  • In response to requests from stakeholders, the TGA intends to consult separately on a Standard for sterilants and disinfectants of medical devices during 2019. In the interim, sponsors may continue to comply with the appropriate sections of TGO 104 (which refers to the Guidelines for the evaluation of disinfectants) as 'state of the art'.

The TGA also intends to amend the definition of hospital grade disinfectant to more accurately reflect these products are used outside of a medical setting, at the next review of the regulations.

For details see – TGA https://www.tga.gov.au/therapeutic-goods-order-54-standard-disinfectants-and-sterilants-tgo-54

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Tuesday, 9 July 2019

GDP Office Based Evaluation and Risk Assessment programme (OBERA)

The MHRA GDP Inspectorate is embarking on a pilot of a new inspection approach that will impact holders of a Wholesale Dealer’s Licence (WDA(H)) whose main activities operate from a head office supplied from a number of ‘satellite’ facilities. For the companies selected, their satellite sites will be assessed remotely using information provided by the company in a standardised format.

The Office Based Evaluation and Risk Assessment (OBERA) is targeted at companies that operate from a single head office location, where the majority of the wholesale activity takes place, with a number of satellite sites which perform a very limited range of GDP activity.

Inclusion in the programme will be dependent upon the head office of the company passing an on-site 'Gateway Inspection’.

For the purposes of the pilot, companies with over 100 sites on their Wholesale Dealer’s Licence will be allocated a Gateway Inspection first. These companies will be contacted shortly, with the Gateway Inspections scheduled to commence during spring 2019.

For further details, see MHRA - https://mhrainspectorate.blog.gov.uk/2019/04/16/introducing-the-gdp-office-based-evaluation-and-risk-assessment-programme-obera/

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Monday, 8 July 2019

Disinfectant efficacy testing for bacterial endospores against hydrogen peroxide

Efficacy is demonstrated through performance testing to show that the disinfectant is capable of reducing the microbial bioburden in either suspension (planktonic state) or from cleanroom surfaces to an acceptable level.

The disinfectant efficacy validation should provide documented evidence that the disinfectant demonstrates bactericidal, fungicidal, and/or sporicidal activity necessary to control microbial contamination in the facility. The greater challenges are around sporicidal disinfectants.

To assess the qualification of sporicidal agents, Tim Sandle has written a newpeer reviewed paper. The abstract reads:

Effective cleaning and disinfection of pharmaceutical and healthcare facilities requires effective practices and appropriate biocides. Application is typically through the use of two biocides in rotation. The expectation is that one disinfectant is sporicidal, not least because the presence of spore-forming bacteria poses a contamination risk due to the ability of these organisms to survive harsh environmental conditions. An example sporicide is hydrogen peroxide. It is incumbent upon each user to assess the selected sporicide for efficacy; however, developing a suitable test is not straightforward. This paper provides an approach that can be adopted for developing a sporicidal efficacy test against bacterial endospores, using hydrogen peroxide as the test sporicidal disinfectant.

The reference is:

Sandle, T. (2019) Disinfectant efficacy testing for bacterial endospores against hydrogen peroxide, Chemico Oggi (Chemistry Today), 37 (2): 60-65

To view a copy, see: https://www.teknoscienze.com/tks_article/disinfectant-efficacy-testing-for-bacterial-endospores-against-hydrogen-peroxide/

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

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