Anti-infective drug shortages pose 'health threat'

A review in Clinical Infectious Diseases  has indicated that shortages of key drugs used to fight infections represents a public health emergency in the USA, and could lead to patient's lives being put at risk. The review was undertaken by Marc Scheetz and Milena Griffith from Midwestern University Chicago College of Pharmacy and Northwestern Memorial Hospital.

The reasons for this relate to shortages of anti-infective drugs, a slowdown in the development of new anti-infective drugs and the increase of multi-drug resistant pathogens. In the report, the authors point to several supply-side issues which may account for supply issues. These include problems with procuring raw materials, processing, distributing, regulatory compliance, market shortages due to epidemics, new therapeutic indications, and perceived shortages.

The abstract to the study (Clin Infect Dis. (2012) doi: 10.1093/cid/cir954) reads:

"Anti-infective shortages pose significant logistical and clinical challenges to hospitals and may be considered a public health emergency. Anti-infectives often represent irreplaceable life-saving treatments. Furthermore, few new agents are available to treat increasingly prevalent multidrug-resistant pathogens. Frequent anti-infective shortages have substantially altered patient care and may lead to inferior patient outcomes. Because many of the shortages stem from problems with manufacturing and distribution, federal legislation has been introduced but not yet enacted to provide oversight for the adequate supply of critical medications. At the local level, hospitals should develop strategies to anticipate the impact and extent of shortages, to identify therapeutic alternatives, and to mitigate potential adverse outcomes. Here we describe the scope of recent anti-infective shortages in the United States and explore the reasons for inadequate drug supply."

For more about this issue, see Modern Medicine. 

Main sources of food poisioning

Over 90% of cases of a common form of food poisoning seen this year were due to people eating undercooked chicken liver pate, often at weddings.

This is according to a news report by the BBC and based on an analysis by the Health Protection Agency (HPA), who analysed 18 outbreaks of Campylobacter in 2011 across England.

In all, 443 people became unwell and one had to be hospitalised.

The Food Standards Agency (FSA) has reminded caterers to cook poultry livers to prevent infection.

Campylobacter is the most common cause of bacterial food poisoning in Britain - there were estimated to have been more than 600,000 cases in 2010 in England and Wales.

Symptoms include diarrhoea, stomach pains and cramps, fever, and generally feeling unwell. Most people are only ill for a few days.

In 2008 there were just three outbreaks linked to undercooked chicken liver pate, but that rose to nine in 2009 and 14 in 2010.

Poultry livers carry a particularly high risk of Campylobacter as the bacteria can be present throughout the liver, not just the surface as is the case for other poultry meat, and may remain a source of infection if they are not cooked sufficiently.

Of the 18 outbreaks, 14 occurred in catering venues, and 13 of these were linked to chicken or duck liver pate.

Seven were linked to wedding receptions at hotels, banqueting venues or public houses and six were associated with catering at other functions such as hotels, clubs and restaurants.

The HPA found that livers used to make the parfait or pate were undercooked allowing the liver to remain pink in the centre.

It said caterers can reduce the risk of their people becoming infected by ensuring that Campylobacter is killed through proper cooking and by avoiding cross-contamination to other foods.'Inadequate cooking'

Dr Christine Little, an expert in gastrointestinal infections at the HPA, said: "The increase in outbreaks which are due to the consumption of chicken liver pate has been steadily increasing over the last few years.

"Not only is this dish popular in food recipe magazines, it is being served in a variety of different catering venues.

"Illness occurs because the livers are only cooked until they are pink, and inadequate cooking will not be sufficient to kill the bacteria.

"Both the public and the catering industry need to be aware that undercooking this product can result in food poisoning."

She said anyone planning a wedding, or other special event, should be aware of the risks if they were having chicken liver pate to prevent people becoming unwell.

The FSA issued updated advice to caterers on the safe handling and cooking of livers twice in 2010, but Campylobacter outbreaks associated with the consumption of chicken liver pate have continued to occur.

Bob Martin, head of foodborne disease strategy at the FSA, said: "Unfortunately, levels of Campylobacter in most raw chicken are high, so it's really important that chefs cook livers thoroughly to kill any bacteria, even if recipes call for them to be seared and left pink in the middle.

"The only way of ensuring the pate or parfait will be safe to serve to your guests or customers is by cooking the livers the whole way through.

"Caterers should also follow good general hygiene practices when cooking and handling poultry livers, to avoid cross contamination with Campylobacter."

Posted by: Dr. Tim Sandle

Hot microbiology and pharma topics!

Listed below are the mist popular microbiology, quality assurance, pharmaceutical and healthcare related items on this blog during the past month. Please have a look through, they will probably be something of interest.

If you have any suggestions for news items or comments on this site - pharmaceutical microbiology - please contact me.

Advances in cleanroom technologies  The gorgeous molecular biology movie UK bacteraemia reports Quality Management #1: Quality Management Systems Laboratory data tables Quality Control Laboratories: An Inspector's Guide Air Quality and Cleanrooms (free on-line paper) Bacillus anthracis and Anthrax: history Evaluation of contact plates for environmental monitoring

Posted by: Dr. Tim Sandle

Quality Risk Management documents

A blog reader has asked me for a list of documents pertaining to Quality Risk Management. Quality Risk Management allows process and products, and in some cases personnel, to be better protected and it can be used to help to meet regulatory expectations and to meet cost demands or to seek process efficiency.

Here are the key ones (together with some relevant links):

1. US FDA document "Pharmaceutical cGMPs forthe 21st Century: A Risk-Based Approach";
2. ICH Q9 Quality RiskManagement guideline;
3. ISO/IEC Guide 73:2002 - Risk Management - Vocabulary -Guidelines for use in Standards; 
4. ISO/IEC Guide 51:1999 - Safety Aspects -Guideline for their inclusion in standards; 
5. AS/NZS 4360:2004 - Risk Management; 
6. WHO Technical Report Series No 908, 2003, Annex 7 Application of HazardAnalysis and Critical Control Point (HACCP) methodology to pharmaceuticals; 
7. ENISO 14971: Application of risk management to medical devices; 
8. PharmaceuticalDevelopment (ICH Q8) and Annex (ICH Q8(R1);
9. FDA Guidance for Industry PAT -A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance; 
10. Pharmaceutical Quality Systems (ICH Q10);
11. FDA Guidancefor Industry Quality Systems Approach to Pharmaceutical cGMP Regulations.

Posted by: Dr. Tim Sandle

Choosing Cleanroom Clothing

Cleanroom clothing is an important part of contamination control, particularly in preventing operators from shedding skin (and thereby microorganisms).

Pharmaceutical Technology Europe have an interesting interview with Jaime Cassar, cleanroom category manager at Kimberly-Clark Professional Europe, about the importance of sterile garments for cleanroom environments.

Here is an extract:

How can the protection provided by sterile clothing help to create process improvements?






The cleanliness of sterile clothing is important to consider in order to prevent the clothing from itself becoming a source of contamination. For example, sterile gloves that have been washed in di-ionised water, cleanroom packed, sterile validated and specified for low endotoxin levels can help lower the risk of particle, microbiological and endotoxin contamination. Sterile apparel that is laundered, cleanroom packed in individual vacuum packaging, double-bagged and provided with periodic sterile validation will also contribute to lower contamination risks. Sterile gloves made from synthetic materials are beneficial because they can eliminate the risk of contaminating the final product with rubber latex proteins, which can be a problem for patients with latex allergies.


Another crucial point is the barrier performance of the clothing. Continuous improvement can come from better control or elimination of variability in attributes that impact barrier performance. For example, disposable apparel eliminates the risk of variability in filtration efficiency and material strength that may come from re-wearing, re-washing and re-sterilising apparel many times and over a long period of time. Sterile apparel made from stronger materials and sterile gloves with a higher quality film formation will be more resistant to breakage and are more likely to be free from any pinhole type defects.


As well as protecting the process from contamination, sterile clothing should also protect the wearer from the health and safety risks presented by chemicals and APIs. Sterile gloves tested to show longer resistance times to permeation by cytotoxic chemicals and sterile clothing certified to provide protection against chemical splashes can contribute to better protection for the wearer. In Europe, sterile gloves and apparel should be Category III certified under the personal protective equipment (PPE) directive 89/686/EEC, if there is risk of exposure to chemicals and APIs. There are also other ways to protect wearers from health and safety risks. For example, sterile clothing that is biocompatible can mitigate the risk of the clothing causing irritation to the wearer, and sterile gloves that are free from natural rubber latex will eliminate the risk of latex allergies.


Posted by: Dr. Tim Sandle

Sustainable water-treatment process using tree seeds

A material derived from seeds of a tree, sometimes called the "miracle tree", could purify and clarify water inexpensively and sustainably in the developing world, where many millions of people lack access to clean drinking water. Research, led by Stephanie Velegol, on the potential of a sustainable water-treatment process requiring only tree seeds and sand has been reported in the journal Langmuir.

Velegol looked to Moringa oleifera, also called the "miracle tree," a plant grown in equatorial regions for food, traditional medicine and biofuel. Past research showed that a protein in Moringa seeds can clean water, but using the approach was too expensive and complicated. So Velegol's team sought to develop a simpler and less expensive method.

To achieve this, the researchers added an extract of the seed containing the positively charged Moringa protein, which binds to sediment and kills many microorganisms, to negatively charged sand. The resulting "functionalized," or "f-sand," proved effective in killing harmful E. coli bacteria and removing sediment from water samples. The results could lead to applications using f-sand to provide a simple, locally sustainable process for producing storable drinking water.

The moringa tree is grown mainly in semi-arid, tropical, and subtropical areas, corresponding in the United States to USDA hardiness zones 9 and 10. While it grows best in dry sandy soil, it tolerates poor soil, including coastal areas. It is a fast-growing, drought-resistant tree that is native to the southern foothills of the Himalayas in northwestern India.

The journal reference is: Huda A. Jerri, Kristin J. Adolfsen, Lauren R. McCullough, Darrell Velegol, Stephanie B. Velegol. Antimicrobial Sand via Adsorption of Cationic Moringa oleifera Protein. Langmuir, 2011
Posted by: Dr. Tim Sandle

Cleanroom cleanliness classes

Here is a table showing the comparison between EU GMP cleanroom grades and ISO 14644 cleanroom classes.

	At Rest
	0.5 µm				5.0 µm
Grade	Annex 1		ISO 14644-1 (Class) Count		Annex 1		ISO 14644-1 (Class) Count
A	3,520		(5) 3,520		20		(4.8) 20
B	3,520		(5) 3,520		29		(5) 29
C	352,000		(7) 352,000		2,900		(7) 2,930
D	3,520,00		(8) 3,520,000		29,000		(8) 29, 300
		Operational
		0.5 µm				5.0 µm
Grade		Annex 1		ISO 14644-1 (Class) Count		Annex 1		ISO 14644-1 (Class) Count
A		3,520		(5) 3,520		20		(4.8) 20
B		352,000		(7) 352,000		2,900		(7) 2,930
C		3,520,000		(8) 3,520,000		29,000		(8) 29,300
D		Not Defined				Not Defined

Posted by: Dr. Tim Sandle

Can intestinal bacteria influence mood?

Many of the bacteria which reside in the human gut, are beneficial, helping people with digestion and keeping the intestines in good working order. This is fairly well established in scientific research.

From this starting point, there is a small, but steadily growing, body of evidence which suggests that bacteria dwelling in the gut can affect the brain, too, and thereby influence an individual’s mood and behaviour. A recent paper on the topic was recently published in the  Proceedings of the National Academy of Sciences. The study reports on results in mice.

The researchers, led by Javier Bravo of University College, Cork, split their rodent subjects into two groups. One lot were fed a special broth containing Lactobacillus rhamnosus, a gut-dwelling bacterium often found in yogurt and other dairy products. The others were fed an ordinary diet, not fortified with microbes.

The team then subjected the mice to a battery of tests that are used routinely to measure the emotional states of rodents. Most (though not all) of these tests showed significant differences between the two groups of animals.

One test featured a maze that had both enclosed and open tunnels. The researchers found that the bacterially boosted mice ventured out into the open twice as often as the control mice, which they interpreted to mean that these rodents were more confident and less anxious than those not fed Lactobacillus.

In another test the animals were made to swim in a container from which they could not escape. Bacteria-fed mice attempted to swim for longer than the others before they gave up and had to be rescued. Such persistence is usually interpreted by students of rodent behaviour as evidence of a more positive mood.

Direct measurements of the animals’ brains supported the behavioural results. Levels of corticosterone, a stress hormone, were markedly lower in the bacteria-fed mice than they were in the control group when both groups were exposed to stressful situations. The number of receptors for gamma-aminobutyric acid, a natural chemical messenger that helps dampen the activity of certain nerve cells, varied in statistically significant ways between the brains of the two groups, with more in some parts of the treated animals’ brains and fewer in others. Most intriguing of all, when Dr Bravo cut the animals’ vagus nerves—which transmit signals between the gut and the brain—the differences between the groups vanished.

 Some doubts, however, remain. Dr Bravo and his colleagues do not yet know the precise mechanisms at work. The key question which emerges from the research is whether a similar effect occurs in people. Studies which use  bacterial treatments to help with mental symptoms of illnesses such as irritable-bowel syndrome would suggest so.

All this is forcing a reassessment of people’s relationship with the bacteria that live on and in them, which have long been regarded mainly as a potential source of infections.

Reference: Bravo, Forsythe, Chew, Escaravage, Savignac, Dinan, Bienenstock & Cryan. 2011. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. PNAS http://dx.doi.org/10.1073/pnas.1102999108

For further information: University of Cork

Posted by: Dr. Tim Sandle

Hepatitis drug developments

Two new drugs have recently been approved to help those suffering from the virus hepatitis C. The FDA have approved Incivek (telaprevir) from Vertex Pharmaceuticals and Merck’s Victrelis (boceprevir). Both pills are protease inhibitors that interfere with the liver-infecting virus's ability to replicate, and each drug can be combined with existing treatment to make the life of the patient easier and closer to 'normal'. The development was reported in The New York Times.

Further in relation to hepatitis treatment, the pharmaceutical company Gilead recently purchased the biotech company Pharmasset and its hepatitis C development program for $11 billion. Also on the subject of acquisitions, Johnson & Johnson and Bristol-Myers Squibb are jointly working on a hepatitis C drug combination, which is set to begin Phase III clinical trials in 2012

Read more: see a special report on the Digital Journal site  

Posted by: Dr. Tim Sandle

WHO HVAC Document (revised edition)

The World Health Organization has revised their guidance on Heating Ventilation and Air Conditioning (HVAC) systems. This forms part of Technical Report 961, as Annex 5.

The document covers the following topics: products and personnel, air filtration, unidirectional airflow, infiltration, cross-contamination, displacement concept (low pressure differential, high airflow), pressure differential concept (high pressure differential, low airflow), physical barrier concept, temperature and relative humidity, protection of the environment, design of HVAC systems and components and commissioning, qualification and maintenance.

The introduction to the document reads:

“This document aims to give guidance to pharmaceutical manufacturers and inspectors of pharmaceutical manufacturing facilities on the design, installation, qualification and maintenance of the HVAC systems. These guidelines are intended to complement those provided in Good manufacturing practices for pharmaceutical products and should be read in conjunction with the parent guide. The additional standards addressed by the present guidelines should, therefore, be considered supplementary to the general requirements set out in the parent guide”

The document can be found at: WHO HVAC

Posted by: Dr. Tim Sandle