Infections Account for 1/3 of All Deaths on Planet

Imagine the desperation of trying to fight lethal infections when antibiotics fail to work.

That scenario - commonly found with "hospital superbugs" - may well improve thanks to a discovery by a research team at the University of British Columbia, in collaboration with UBC spin-off company Inimex Pharmaceuticals, that has identified a peptide that can fight infection by boosting the body's own immune system.

"Antibiotics are now under threat because of the explosion in antibiotic-resistant bacteria. A third of all deaths on this planet are the result of infection so there is an urgent need to create new therapies," says Robert Hancock, principal investigator and Canada Research Chair in Pathogenomics and Antimicrobials. "The beauty of this peptide is that it acts on the host to trigger a protective response and doesn't act on bacteria directly. That means it's unlikely bacteria will become resistant to it."

The team found that a peptide, or chain of amino acids, they have dubbed innate defense regulator peptide (IDR-1), can increase innate immunity without triggering harmful inflammation, and offer protection both before and after infection is present. The discovery, in animal models, is published in the journal Nature Biotechnology.

Researchers tested the peptide's effectiveness against Staphylococcus aureus including MRSA; a superbug called vancomycin-resistant Enterococcus (VRE); and Salmonella. In Staph and VRE infections, although bacteria were not completely eradicated, IDR-1 significantly reduced bacteria counts and mortality, when given either 24-48 hours before or four hours after infection began. In Salmonella, the peptide offered significant protection when administered prior to infection setting in.

Data showed that IDR-1 activates several signaling pathways to stimulate infection-clearing chemokines - a chemical mediator that mobilizes immune response.

In addition, the peptide did not produce harmful inflammation and toxicity often seen when the immune system is stimulated and, in fact, actually reduced the potentially harmful septic response. Sepsis, a consequence of a ravaging inflammatory response associated with infection, kills as many as 200,000 annually.

The innate immune response is the first line of defense against infection and comprises an interactive network of cellular and molecular systems that recognize and kill pathogens, as well as signaling pathways that trigger biological responses.

The researchers anticipate the therapy may be useful as a supplement to antibiotics in combating common hospital infections such as ventilator associated pneumonia, post-surgical infections, high dose chemotherapy and infections arising from insertion of catheters or other medical devices.

"We now have a powerful new tool that will allow us to stop infection before it starts - it's a new concept in treating infection," says Hancock.

The researchers estimate there are two million cases of antibiotic-resistant infection in hospitals that kill approximately 70,000 people annually in North America. Hospital-based methicillin-resistant Staphylococcus aureus (MRSA) alone causes an estimated 100,000 hard-to-treat infections annually and is now seen in community-based infections, such as boils and abscesses or life-threatening bloodstream infections.

"Salmonella causes 1.3 million infections and up to 100 deaths every year in the U.S. We're looking at a crisis in 10 years as most bugs will be resistant to most antibiotics. There's an urgent need to develop new tools," says Brett Finlay, a UBC microbiologist and an author on the paper. He and Hancock co-founded Inimex, which conducted many of the experiments required for the study.

Researchers expect it will be about 12-15 months before the discovery is introduced into human clinical trials.

Support for the research has been provided by the Canadian Institutes of Health Research (CIHR), Canada's major agency responsible for funding health research, and the Foundation for the National Institutes of Health through the Grand Challenges in Global Health Initiative, a U.S.-based project funded by the Bill & Melinda Gates Foundation, that has offered research grants totaling $436.6 million to achieve scientific breakthroughs against lethal diseases in the world's poorest countries.

Additional support has been provided by Genome Canada and Genome BC. Genome Canada is the primary funding and information resource relating to genomics and proteomics research in Canada. It has established six genome centres across the country, including Genome BC.

Inimex Pharmaceuticals, Inc. is a privately held biopharmaceutical company focused on development and commercialization of Innate Defense Regulator products, novel first-in-class drugs that selectively trigger the body's innate defenses without causing inflammation.

Contact: Hilary Thomson
University of British Columbia

How Biofilm Works

The idea of alien intelligences calmly watching our every move and discussing the right time to take the Earth from us is the stuff of books, movies and nightmares. But how would you feel if you knew thatevery time you sat in the dentist's chair your dentist was fighting a losing battle with exactly such a foe?

One of the most startling discoveries to come out of the burgeoning world of microbiology in the past two decades is the fact that bacteria can communicate. In fact, not just communicate but converse on alevel where they can induce each other to switch on dormant genes that then have the capacity to do you harm.

Dental plaque, it turns out, is the least of our worries. The superbug MRSA is part of the same phenomenon, called 'quorum sensing'. Quorum sensing is the ability of bacteria to communicate and coordinate behaviour using signalling molecules called autoinducers. Autoinducers are continuously produced by bacteria but when their concentration reaches a certain threshold--that is to say, when the bacteria producing it have a quorum—they switch on transcription genes withinthe bacteria's DNA telling it to do two things: to produce more autoinducer and, crucially, to change behaviour.

It is the behaviour change that does the damage. Most bacteria spend their lives as free-swimming, planktonic organisms but when mandated to do so by the autoinducer will switch to a sessile lifestyle, dropping out of the swimming phase and anchoring to the nearest solid surface, be it a tooth, contact lens or the newly-minted plastic ball-joint of a hip replacement. There they form biofilms--bacterial mats that reduce the effectiveness of antibiotics and where the local concentration of autoinducer goes through the roof. Once a biofilm is established it is very difficult to get rid of--witness the ubiquity of dental plaque and the dogged resistance of MRSA to treatment.

Dietrich Mack at the University of Swansea and his group have beenactive in discovering just how quorum sensing works. In Staphylococcus aureus and S. epidermidis--the microbes responsible for both MRSA and implantation rejects--they have identified at least two major gene expression pathwaysresponsible for initiating biofilm formation, one based on a polysaccharide and the other on a peptide. But as Mack acknowledges, 'Our research shows that the expression of these pathways is not straightforward. In certain cases where we inhibit a gene responsible involved in quorum sensing it can actually increase the amount of biofilm formed'.

Quorum sensing, however, does more than merely initiate biofilm formation. It is a potent weapon of war between bacteria. For example, the four most common strains of S. aureus, including MRSA, use four slightly different autoinducers to initiate biofilm formation, all of which also aggressively inhibit the receptor sites of the other strains. The strain that reaches its critical quorum level first not only gets to put down its biofilm inducing roots first, it also gets to silence its competitors, preventing them from building up more of theirown autoinducer.

Production of orthopaedic implants--from artificial hips to hip and knee joints--is an expanding industry worth $2.5bn in 2005 in Europe, according to Frost & Sullivan. Eighty per cent of hospital-acquired infections are associated with implants or other 'in-dwelling' medical devices, while 60% of hospital infections generally involve biofilms. Since MRSA and other biofilm-infections are frequently fatal, there are compelling financial and ethical reasons to find ways of preventing biofilm formation.

Just how biofilms heighten resistance to antibiotics is not straightforward. It may be simply because the ability of antibiotics to penetrate the biofilm to the bacterial cells themselves is impaired, or it may be that the life-style change from planktonic to sessile changes the metabolic state of the bacterial cell and therefore its resistance to antibiotics. A more extreme suggestion is that the bacteria are fundamentally altered in some way so that they behave more like a multicellular tissue than a loose agglomeration of co-operating single cells.

For years, the approach to tackle biofilms has been incorporate antimicrobial agents in biomaterials that are to be used within the body, but the problem is the incredible ability of bacteria to develop antibiotic resistance. Because of their short generation time and their uncomplicated genomes, the fact is that bacteria can mutate and develop resistance faster than we can develop drugs to combat them. Simply killing bacteria in situ can lead to dead microbial cells and associated detritus fouling the surfaces of crucial implants. Defeating biomaterial biofilm formation requires a different approach, one that does not result in the death of the bacterium but rather in the neutralisation of its malevolence.

There are several possibilities: coating the biomaterial with substances that prevent bioadhesion, developing responsive surfaces that react to bacterial invasion, controlling the orientation of surface-tethered adhesion molecules, or interfering with receptor-ligand specific adhesion. But as Llinos Harris and Geoff Richards of the AO Foundation in Davos, Switzerland, point out: ‘no surface modification or coating fully prevents bacterial adhesion’. This leaves perhaps the most exciting possibility of all: disabling their quorum sensing mechanisms so that the bacteria cannot form biofilms in the first place.
Several signal molecule families involved in quorum sensing have been identified in Gram-negative bacteria—those with two sets of cellmembranes—like Pseudomonas aeruginosa, but the most intensively studied is the N-acylhomoserine lactone (AHL) family.

AHLs contain a homoserine lactone ring attached via an amide bond to an acyl side chaincontaining anything from four to 14 carbon atoms. Once the AHL reaches a critical threshold, concentration members of the LuxR and LuxN family of transcriptional activator genes are switched on, forming proteins that start binding the bacteria to the substrate, thereby beginning biofilm formation. Variations in the chain length and oxidation at the 3-position provide different Gram-negative bacteria with species-specific languages with which they can communicate with their own kind.

Yet, since 75 Gram-negative bacterial species are known to use AHL, and only 25 AHL varieties have been found, it must also be the casethat some of these species share a common tongue and can therefore talk across species boundaries. Since biofilms usually consist of a multitude of different bacterial species—which have different niches and therefore do not compete with each other—this implies that different bacteria co-operate in biofilm formation. It is a frightening thought.
There is some good news, however. Some natural molecules have beenfound to interfere with AHL-mediated quorum sensing and the most important of these are halogenated furanones produced by the large marine alga Delisea pulchra. Halogenated furanones are structurally similar to AHLs and interfere with the ability of AHLs to bond to biomaterial surfaces. An analogy would be the way that carbon monoxide interferes with oxygen’s ability to bond with haemoglobin by occupying the haemoglobin’s receptor sites first.

The Australian firm Biosignal is leading the way in the application of antibiofilm agents to contact lenses. Biosignal’s compounds are based on the naturally occurring furanones from Delisea pulchra. As the trend toward long-wearing disposable contact lenses gathers momentum it is increasingly important to make sure that the lenses do not grow a biofilm and cause eye infection. An initial human safety trial of their furanone-based coating was completed last year and the results look positive. ‘The potential market is enormous’, says Michael Oredsson, Biosignal’s Ceo, ‘somewhere between $5 billion and $6 billion per year. We plan to levy a small but meaningful royalty on the use of Biosignal’s proprietary technology—we aim for around 5%.’

Gram-positive bacteria like S. aureus and Staphylococcus epidermidis—the major cause of implant biofilm infections—use peptides rather than AHLs as signal molecules. In S. epidermidis a single peptide, once it has reached its critical level, activates an accessory gene regulator (agr) operon that results in the synthesis of PolysaccharideIntercellular Adhesin (PIA), a molecular glue that starts the process of biofilm formation.

An inhibiting peptide, appropriately known as RIP, can inhibit biofilm formation in both S. epidermidis and S. aureus and is under investigation as a potential treatment for Staphylococcus-induced infections.

As yet, however, there is no magic bullet for preventing Gram-positive, quorum sensing-induced, biofilm formation, and scaling up thesetechniques to clinical level offers substantial technical challenges. When asked exactly how inhibition of quorum sensing can be used to stop MRSA biofilm formation, Dietrich Mack responded: ‘That is a very good question. I would like to know the answer to that too.’

But there is everything left to play for. Oredsson acknowledges that contact lenses are just the tip of the iceberg, and that the impetus behind quorum sensing remains a cure for serious bacterial infections, including those caused by MRSA.

By Richard Corfield

An HAI Primer (Exhaustive Overview)

DEFINITION: A hospital-acquired infection, also called a nosocomial infection, is an infection that first appears between 48 hours and four days after a patient is admitted to a hospital or other health-care facility.

DESCRIPTION: About 5–10% of patients admitted to acute care hospitals and long-term care facilities in the United States develop a hospital-acquired, or nosocomial, infection, with an annual total of more than one million people. Hospital-acquired infections are usually related to a procedure or treatment used to diagnose or treat the patient's initial illness or injury. The Centers for Disease Control (CDC) of the U.S. Department of Health and Human Services has shown that about 36% of these infections are preventable through the adherence to strict guidelines by health care workers when caring for patients. What can make these infections so troublesome is that they occur in people whose health is already compromised by the condition for which they were first hospitalized.

Hospital-acquired infections can be caused by bacteria, viruses, fungi, or parasites. These microorganisms may already be present in the patient's body or may come from the environment, contaminated hospital equipment, health care workers, or other patients. Depending on the causal agents involved, an infection may start in any part of the body. A localized infection is limited to a specific part of the body and has local symptoms. For example, if a surgical wound in the abdomen becomes infected, the area around the wound becomes red, hot, and painful. A generalized infection is one that enters the bloodstream and causes systemic symptoms such as fever, chills, low blood pressure, or mental confusion. This can lead to sepsis, a serious, rapidly progressive multi-organ infection, sometimes called blood poisoning, that can result in death.

Hospital-acquired infections may develop from the performance of surgical procedures; from the insertion of catheters (tubes) into the urinary tract, nose, mouth, or blood vessels; or from material from the nose or mouth that is aspirated (inhaled) into the lungs. The most common types of hospital-acquired infections are urinary tract infections (UTIs), ventilator-associated pneumonia, and surgical wound infections. The University of Michigan Health System reports that the most common sources of infection in their hospital are urinary catheters, central venous (in the vein) catheters, and endotrachial tubes (tubes going through the mouth into the stomach). Catheters going into the body allow bacteria to walk along the outside of the tube into the body where they find their way into the bloodstream. A study in the journal Infection Control and Hospital Epidemiology shows that about 24% of patients with catheters will develop catheter related infections, of which 5.2% will become bloodstream infections. Death has been shown to occur in 4–20% of catheter-related infections.

CAUSES: All hospitalized patients are at risk of acquiring an infection from their treatment or surgery. Some patients are at greater risk than others, especially young children, the elderly, and persons with compromised immune systems. The National Nosocomial Infection Surveillance System database compiled by the CDC shows that the overall infection rate among children in intensive care is 6.1%, with the primary causes being venous catheters and ventilator-associated pneumonia. The risk factors for hospital-acquired infections in children include parenteral nutrition (tube or intravenous feeding), the use of antibiotics for more than 10 days, use of invasive devices, poor postoperative status, and immune system dysfunction. Other risk factors that increase the opportunity for hospitalized adults and children to acquire infections are:

- A prolonged hospital stay,

- Severity of underlying illness,

- Compromised nutritional or immune status,

- Use of indwelling catheters,

- Failure of health care workers to wash their hands between patients or before procedures,

- Prevalence of antibiotic-resistant bacteria from the overuse of antibiotics.

Any type of invasive (enters the body) procedure can expose a patient to the possibility of infection. Some common procedures that increase the risk of hospital-acquired infections include:

- Urinary bladder catheterization,

- Respiratory procedures such as intubation or mechanical ventilation,

- Surgery and the dressing or drainage of surgical wounds,

- Gastric drainage tubes into the stomach through the nose or mouth,

- Intravenous (IV) procedures for delivery of medication, transfusion, or nutrition.

INCIDENCES: Urinary tract infection (UTI) is the most common type of hospital-acquired infection and has been shown to occur after urinary catheterization. Catheterization is the placement of a catheter through the urethra into the urinary bladder to empty urine from the bladder; or to deliver medication, relieve pressure, or measure urine in the bladder; or for other medical reasons. Normally, a healthy urinary bladder is sterile, with no harmful bacteria or other microorganisms present. Although bacteria may be in or around the urethra, they normally cannot enter the bladder. A catheter, however, can pick up bacteria from the urethra and give them an easy route into the bladder, causing infection. Bacteria from the intestinal tract are the most common type to cause UTIs. Patients with poorly functioning immune systems or who are taking antibiotics are also at increased risk for UTI caused by a fungus called Candida. The prolonged use of antibiotics, which may reduce the effectiveness of the patient's own immune system, has been shown to create favorable conditions for the growth of this fungal organism.

Pneumonia is the second most common type of hospital-acquired infection. Bacteria and other microorganisms are easily introduced into the throat by treatment procedures performed to treat respiratory illnesses. Patients with chronic obstructive lung disease, for example, are especially susceptible to infection because of frequent and prolonged antibiotic therapy and long-term mechanical ventilation used in their treatment. The infecting microorganisms can come from contaminated equipment or the hands of health care workers as procedures are conducted such as respiratory intubation, suctioning of material from the throat and mouth, and mechanical ventilation. Once introduced through the nose and mouth, microorganisms quickly colonize the throat area. This means that they grow and form a colony, but have not yet caused an infection. Once the throat is colonized, it is easy for a patient to aspirate the microorganisms into the lungs, where infection develops that leads to pneumonia.

Invasive surgical procedures increase a patient's risk of getting an infection by giving bacteria a route into normally sterile areas of the body. An infection can be acquired from contaminated surgical equipment or from the hands of health care workers. Following surgery, the surgical wound can become infected from contaminated dressings or the hands of health-care workers who change the dressing. Other wounds can also become easily infected, such as those caused by trauma, burns, or pressure sores that result from prolonged bed rest or wheel chair use.

Many hospitalized patients need continuous medications, transfusions, or nutrients delivered into their bloodstream. An intravenous (IV) catheter is placed in a vein and the medications, blood components, or liquid nutritionals are infused into the vein. Bacteria from the surroundings, contaminated equipment, or health care workers' hands can enter the body at the site of catheter insertion. A local infection may develop in the skin around the catheter. The bacteria can also enter the blood through the vein and cause a generalized infection. The longer a catheter is in place, the greater the risk of infection.

Other hospital procedures that may put patients at risk for nosocomial infection are gastrointestinal procedures, obstetric procedures, and kidney dialysis.

SYMPTOMS: Fever is often the first sign of infection. Other symptoms and signs of infection are rapid breathing, mental confusion, low blood pressure, reduced urine output, and a high white blood cell count. Patients with a UTI may have pain when urinating and blood in the urine. Symptoms of pneumonia may include difficulty breathing and inability to cough. A localized infection begins with swelling, redness, and tenderness on the skin or around a surgical wound or other open wound, which can progress rapidly to the destruction of deeper layers of muscle tissue, and eventually sepsis.

DIAGNOSIS: An infection is suspected any time a hospitalized patient develops a fever that cannot be explained by the underlying illness. Some patients, especially the elderly, may not develop a fever. In these patients, the first signs of infection may be rapid breathing or mental confusion.

Diagnosis of a hospital-acquired infection is determined by:

- Evaluation of symptoms and signs of infection,

- Examination of wounds and catheter entry sites for redness, swelling, or the presence of pus or an abscess
- A complete physical examination and review of underlying illness,

- Laboratory tests, including complete blood count (CBC) especially to look for an increase in infectionfighting white cells; urinalysis, looking for white cells or evidence of blood in the urinary tract; cultures of the infected area, blood, sputum, urine, or other body fluids or tissue to find the causative organism,

- Chest x ray may be done when pneumonia is suspected to look for the presence of white blood cells and other inflammatory substances in lung tissue,

- Review of all procedures performed that might have led to infection.

TREATMENT: Cultures of blood, urine, sputum, other body fluids, or tissue are especially important in order to identify the bacteria, fungi, virus, or other microorganism causing the infection. Once the organism has been identified, it will be tested again for sensitivity to a range of antibiotics so that the patient can be treated quickly and effectively with an appropriate medicine to which the causative organism will respond. While waiting for these test results, treatment may begin with common broad-spectrum antibiotics such as penicillin, cephalosporins, tetracyclines, or erythromycin. More and more often, some types of bacteria are becoming resistant to these standard antibiotic treatments, especially when patients with chronic illnesses are frequently given antibiotic therapy for long periods of time. When this happens, a different, more powerful, and more specific antibiotic must be used to which the specific organism has been shown to respond. Two strong antibiotics that have been effective against resistant bacteria are vancomycin and imipenem, although some bacteria are developing resistance to these antibiotics as well. The prolonged use of antibiotics is also known to reduce the effectiveness of the patient's own immune system, sometimes becoming a factor in the development of infection.

Fungal infections are treated with antifungal medications. Examples of these are amphotericin B, nystatin, ketoconazole, itraconazole, and fluconazole.

Viruses do not respond to antibiotics. A number of antiviral drugs have been developed that slow the growth or reproduction of viruses, such as acyclovir, ganciclovir, foscarnet, and amantadine.

PREVENTION: Hospitals take a variety of steps to prevent nosocomial infections, including:

- Adopting an infection control program such as the one sponsored by the U.S. Centers for Disease Control (CDC), which includes quality control of procedures known to lead to infection, and a monitoring program to track infection rates to see if they go up or down,

- Employing an infection control practitioner for every 200 beds,

- Identifying high-risk procedures and other possible sources of infection,

- Strict adherence to hand-washing rules by health care workers and visitors to avoid passing infectious microorganisms to or between hospitalized patients,

- Strict attention to aseptic (sterile) technique in the performance of procedures, including use of sterile gowns, gloves, masks, and barriers,

-Sterilization of all reusable equipment such as ventilators, humidifiers, and any devices that come in contact with the respiratory tract,

- Frequent changing of dressings for wounds and use of antibacterial ointments under dressings,

- Remove nasogastric (nose to stomach) and endotracheal (mouth to stomach) tubes as soon as possible,

- Use of an antibacterial-coated venous catheter that destroys bacteria before they can get into the blood stream,

- Preventing contact between respiratory secretions and health care providers by using barriers and masks as needed,

- Use of silver alloy-coated urinary catheters that destroy bacteria before they can migrate up into the bladder,

- Limitations on the use and duration of high-risk procedures such as urinary catheterization,

- Isolation of patients with known infections,

- Sterilization of medical instruments and equipment to prevent contamination,

- Reductions in the general use of antibiotics to encourage better immune response in patients and reduce the cultivation of resistant bacteria.

Hospitals Look to Improve Infection Prevention Measures

The primary cost to patients with hospital-acquired infections is a prolonged stay and additional therapeutic interventions. But because of the high financial costs, there is increasing outside pressure to decrease infection rates.

Laws have been implemented in at least 15 states to force hospitals to improve their prevention efforts. In Massachusetts, a new law calls for mandatory education of healthcare workers and penalizes facilities that don't comply with prevention measures. In California, a bill signed into law in September imposed new reporting and prevention measures on hospitals beginning in 2007. Pennsylvania and Missouri are among the states that require hospitals to publicly report their rates.

About 2 million patients a year acquire an infection after admission, according to the Centers for Disease Control and Prevention (CDC). The CDC estimates that patients contract 250,000 infections from catheters alone, and that between 12% and 25% of those patients die as a result.

The financial costs of hospital-acquired infections are absorbed by health plans and their payers, members and providers.

A study conducted by the Pennsylvania Health Care Cost Containment Council showed that when looking at private sector insurance reimbursements in the state, the average payment for a case with a hospital-acquired infection was $53,915, while the average payment for a case without a hospital-acquired infection was $8,311.

"It is a difficult area to control," says Victor Caraballo, MD, senior medical director of quality management for Independence Blue Cross in Philadelphia. "The causes are multi-variant and involve different areas of the hospital and different levels of staffing. It's a major patient safety concern."

Each patient on a general floor alone can have upward of 20 different encounters with staff in one day. Patients with compromised defenses and trauma victims on ventilators are most susceptible to infection, but any patient is at risk.

Numerous clinical studies, including one from Johns Hopkins University, show that relatively simple changes in behavior—better hygiene by the hospital staff, for example—can have a profound impact. There appears to be evidence to reinforce the findings of those studies.

Michigan hospitals that rigorously implemented infection-control procedures, such as doctors and nurses washing their hands and cleaning patients' skin with an antibacterial agent before inserting intravenous lines, reduced catheter-related blood stream infections in intensive care units patients from an average of 7.7 per 1,000 days of catheter usage to 1.4 per 1,000 days within 18 months, according to a report in the New England Journal of Medicine in December.

Some hospitals are collaborating to meet the challenge. In Philadelphia, the Healthcare Improvement Foundation, the Delaware Valley Healthcare Council and Independence Blue Cross have created the Partnership for Patient Care (PPC), a quality and patient safety effort by area hospitals.

Those involved in the partnership discuss collaborative ways to encourage the rapid adoption of evidence-based medicine and uniform procedures for preventing infections. Hospitals use a method called Failure Mode and Effects Analysis to analyze processes and outcomes with the aim of finding new and improved ways to prevent infections.

"What we found is that cooperative efforts are very useful," says Charles Wagner, MD, chief medical officer of Holy Redeemer Hospital and Medical Center in Philadelphia, one of the facilities involved in the PPC.

Overall, hospitals involved in the PPC saw a 27% improvement in controlling blood sugar levels in surgical patients, strengthening the ability of a patient's immune system to fight infections; a 21% improvement in the use of antibiotics before surgeries to prevent infections; and a 9% improvement in adopting new safety measures to prevent bloodstream infections from intravenous central lines.

Developing measures for fighting infections must involve the frontline clinicians who have the most contact with patients, says Alexis Elward, MD, medical director of infection control for St. Louis Children's Hospital. One group at Children's Hospital—including nurses, physicians, infection control practitioners, and physical and respiratory therapists—has worked to improve hand hygiene by implementing CDC guidelines that recommend that hospital personnel wash their hands after each contact with a patient. The result is that hand hygiene at Children's Hospital has improved from 60% in mid-2006 to the current level of 94%.

Another multi-disciplinary group, which includes personnel from pharmacy and anesthesia, as well as surgeons, has worked to reduce the number of surgical site infections in cardiothoracic surgery patients.

"We know that getting antibiotics in patients within one hour before an incision is made, and using clippers instead of shaving hair, can decrease the quantity of germs on the skin," Dr. Elward says. "A small group of people got together and created a system where those things are done automatically."

Mar 1, 2007
By: Ken Krizner
Managed Healthcare Executive

Biofilm: A Tale of Slime Cities

Run your tongue over your teeth. Do you detect something more than a just-brushed, slick surface, something maybe just a little slimy? If so, you've just felt a biofilm, a highly organized community of microbes with its own food delivery, waste disposal, communication and defense systems. Not just on teeth, but wherever water, nutrients and a solid surface are available, bacteria and other microbes are likely to put down stakes and form these sticky, slimy structures.

Just two decades ago, most biologists had no idea that microbes prefer living in "cities" of billions to the solitary, free-floating state. "We'd known forever that biofilms existed," says University of Iowa microbiologist Peter Greenberg. "The big advance was learning that they are a major bacterial life-style."

Some biofilms are beneficial. They break down contaminants in water and soil and can form protective coatings that block the growth of disease- causing microbes on the surface of tissues. But mounting evidence suggests that these teeming microbial metropolises also are responsible for many chronic human infections that are difficult-even impossible-to eradicate. Biofilms cause trouble in industrial settings, too, where they clog oil pipelines and water filtration systems, contaminate food- processing equipment and foul the surfaces of computer chips. Altogether, biofilm-related problems cost the United States billions of dollars each year.

To an individual microbe, the biofilm life-style offers many advantages. It provides a safe haven from hostile environments and potential predators, as well as a stable location near a dependable food source. Microbial residents also are protected from assaults by the body's immune system and from antibiotics and chemical disinfectants.

A biofilm may be composed of a single bacterial species or a mixture of anywhere from two to several hundred kinds of bacteria, plus fungi, algae and other microbes. Together these organisms form a highly cooperative community in which each member performs a specialized job. The community has a distinct architecture, consisting of towers of microbes with water channels running among them. Like a primitive circulatory system, the channels let nutrients flow in and waste products flow out. The entire structure is embedded in a slimy web of molecules produced by cells in the biofilm itself. This sticky substrate glues the film to a surface and holds the entire microbial city together.

Dental researchers were the first to realize the role of biofilms in causing disease: Dental plaque (biofilm on teeth) can cause cavities and periodontal disease if not kept in check by regular brushing and flossing. Other chronic infections now known to be caused by biofilms include heart valve and prostate infections, the recurring lung infections that ultimately devastate most people with cystic fibrosis and the chronic middle-ear infections that plague many children.

Biofilms also flourish on nonliving surfaces implanted in the body, such as catheters, artificial joints and dental implants. "Once you establish a biofilm infection on an implanted device it's very difficult to eradicate," says Phil Stewart, a chemical engineer at Montana State University's Center for Biofilm Engineering. Often the only option is surgical removal of the infected device.

Because community life gives microbial inhabitants protection from their enemies-through biological mechanisms that remain largely unknown-researchers estimate that bacteria in biofilms are between 100 and 1,000 times more resistant to antibiotics than their free-floating counterparts. Doctors generally treat biofilm infections with the strongest antibiotics they can get their hands on. Such treatments may reduce symptoms and damp down the disease, but they rarely eliminate it. Eventually the microbes bounce back, and symptoms recur. In some cases, free-floating microbes released from a biofilm trigger a more serious, fast-growing infection. Although antibiotics can usually eliminate these acute infections, the biofilm that spawned them will remain, threatening to repeat the cycle.

"It's only been in the last couple of years that microbiologists have appreciated that biofilms are a major cause of persistent infection," says Greenberg. The realization has stimulated interest among researchers and biotechnology companies, which are working to develop more effective treatments. By studying the details of how microbial cities form, and what makes cells in a biofilm different from free- floating cells, researchers hope to find clues to new therapies.

One such clue has come from the discovery of chemical signals that bacteria use to "talk" to one another during the carefully orchestrated process of building a biofilm. A 1998 study by Greenberg and his colleagues showed that mutant bacteria that were unable to make one signaling molecule could not form normal biofilms. He and other researchers are teaming up with biotech companies to look for chemical compounds that would interfere with these microbial communication systems.

Biofilms and effects on health and technology
National Wildlife, August-Sept, 2001 by Elia Ben-Ari

Bacterial Biofilm: What it is and What it Does

When he was studying for his doctorate in microbiology, Mark E. Shirtliff thought he knew a lot about bacteria.

Then things got scary.

He discovered that bacteria can band together into sheets - called biofilms. When they do, they alter their behavior. They build complex communities, establish lines of communication and coordinate their actions. Like ants, the microbes find power in numbers. And they're nasty.

"Infections that should respond to antibiotics don't," Shirtliff said. "They become 50 to 500 times more resistant." With drugs often useless against biofilms in the human body, Shirtliff is trying to turn the tables on the slippery infections.

The assistant professor at the University of Maryland Dental School received $1.25 million this month from the National Institutes of Health for research into vaccines that might prevent the deadly films from forming in the first place.

Although the public rarely hears it in popular discussions of health issues, the term "biofilm" was coined in a 1978 Scientific American article by William Costerton, now of the University of Southern California Dental School. He used it to describe microbes that clump together on wet surfaces.

"It came up in dentistry first," Costerton said. "They called it plaque. I just proposed [that] the biofilm isn't just in the mouth, but everywhere."

In fact, biofilms are just about everywhere. They coat everything from Alpine river rocks to neglected teeth. Every year they cause billions of dollars of damage to ship hulls, oil pipelines and machinery by corroding metal surfaces and clogging up the works.

These plaques often contain a variety of microorganisms, including bacteria, protozoa and algae suspended in slimy glue called polysaccharide that holds them together and binds them to surfaces. When enough of the organisms have collected, they undergo metabolic changes that make them better team players.

"We tend to think of them as primitive single-celled organisms," said Phil Stewart, the director of the Center for Biofilm Engineering at Montana State University. "But there is a lot of cooperation and coordination comparable to something more like an ant colony. It allows them to accomplish more than they could on their own."

Particularly vexing is the ability of virulent bacterial infections to resist attack after forming a biofilm. "We could pump bleach into your system," Shirtliff said, "and it probably wouldn't do anything."

That's saying something. Chlorine bleach is the microbiologist's ultimate weapon - it's used to disinfect the labs that house the world's most dangerous germs.

Like soldiers hiding in a castle, the bacteria inside the film are protected from drugs design to kill them. The cells are also starved for nutrients. This makes them grow and divide slowly - providing even more drug resistance, since antibiotics often target fast-growing cells.

The stress also puts biofilm bacteria on the defensive, causing them to release caustic acids and proteins. "They start freaking out," Shirtliff said. "They turn on stress response genes that make them attack the antibiotic."

Compounding the problem, the stress response tricks the natural immune system into using the wrong attack plan. When the macrophages and other white blood cells that form the body's police force arrive on the scene, they're ambushed and destroyed by the biofilm's arsenal of proteins and acids.

Biofilm infections often return because antibiotics kill only the free-floating - or planktonic - bacteria. When a patient stops taking the drug, new free-roaming bacteria emerge from the biofilm and the infection spreads again.

Scientists estimate that 65 percent to 80 percent of chronic infections in industrialized nations linger on because of biofilm formation. Biofilms appear in patients with cystic fibrosis, gum disease and chronic inner ear, urinary tract and bone infections.

Medical devices such dental implants, catheters, artificial joints, breast implants and heart valves are vulnerable to biofilm formation. Central venous catheters, a type inserted into most intensive-care patients in hospitals, are a common source of bacterial biofilms. About 80,000 of ICU patients contract bacterial infections from the catheters each year - and about 35 percent of those die from the infection, according to the Centers for Disease Control and Prevention.

When biofilms grow on bone and metal after joint replacement surgery, the only option may be to start again from scratch. "The only way you can get it out of there is by carving it out," Shirtliff said. "If an artificial knee gets infected, you're going to have to take that knee out and put another one in."

In his research, Shirtliff has focused on one particularly bad actor that has gotten a lot of press lately: methicillin-resistant staphylococcus aureus (MRSA). The antibiotic-resistant bacteria kill about 90,000 people in the United States every year, according to the CDC.

Because MRSA infections are difficult or impossible to eradicate once a biofilm is fully formed, Shirtliff is searching for a way prevent the films from growing.

The trick, he believes, is to hone in on the odd behavior of the biofilm bacteria. He has identified proteins the bacteria produce in abundance as they form a film and hopes to develop antibodies that will target those proteins. Like an army attacking a half-built fortress, the antibodies would attack the immature biofilm and destroy it before its defenses are fully formed.

"The antibodies come in and deactivate the proteins and can destroy the biofilm," he said. "The immune cells could also come in safely then and attack as well."

To test his theories, Shirtliff grows MRSA biofilms in silicon tubing in his lab at the dental school and looks for protein targets.

Anti-biofilm vaccines he has developed have proven effective for treating rabbits with MRSA bone infections. He hopes to move on to clinical trials in humans within four years, he said.

He said a vaccine might be the best way to combat MRSA because the bacteria are so widespread. "Here in the United States," he said, "it's hard to cork that bottle."

By Chris Emery
Baltimore Sun Reporter
March 23, 2007

A Mother’s Letter to a Hospital CEO

(Written by Victoria Nahum after her stepson Josh died from his infection in October 2006)

Our son died in your hospital 7 days ago. He died from a bacterial infection he caught there as a result of his medical care while being treated for something else. It created so much pressure around his brain that it caused part of it to be pushed into his spinal column, leaving him a helpless ventilator-dependent quadriplegic and ending his short but unforgettable life among us all.

In the week since his death, the days I live have small worth to me. I am numb now. I bring my husband coffee in the morning but he doesn’t smile or speak; he doesn’t even look at me. He sits, hands in lap, shoulders rounded, wearing a mask of pain that I have never seen before; it is not a face I recognize when he is wearing it. I wish it would go away.

His voice is low and quiet and I am uncomfortable with its somber tone. We speak infrequently lately because it feels like no good words remain for us. Our son is dead. What good thing can be spoken now? Gentle words that others have for us fall inadequately upon deaf ears. Angry words I rehearse in my head won’t help anything at all; spoken aloud they would change nothing for the better, they just sound mean, even to me. Explanations I seek out and find, full of swaggering, inflated medical terms come far, far, so ridiculously far - too late.

Here, now my husband and I sit. We have too many questions and they are all useless. “Why?” is the most impossible one of them all. How I wish he would just stop asking me that. I have no proper answer to comfort him. I am momentarily lost.

So what then? And is it really, “What then?” or should it rather be, “How then?” How then might we prevent this from happening again to anyone, ever? I wonder.

When our son was ill, I watched your nurses come in and out of his room by the hour and rather than just noticing random women with a regular job to do, I instead saw what angels looked like, masquerading in scrubs with name tags and stethoscopes to complete the disguise, caring for him generously and genuinely with real humanity integrated into their sense and deed of significant duty. I heard endearing compassion in their voices and saw true concern in their eyes that made me want to be like them somehow. Their gestures were warm and their care was competent. To them, my son was their own personal mission. They cared for him well; I would tell anyone – I believe they did their best. I know so.

I got to know your nurses. They are devastated by our son’s death … So that it doesn’t happen again, I want you to empower them to save their patients with appropriate procedures and whatever rock-solid rules that they see fit to execute in the name of safer, better healthcare so they and you, may forego the sadness and futility you all must feel when a patient dies on your shared watch.

I spoke at length with your doctors who treated my son. I felt their frustration when their prescribed treatment did not work. I heard the disappointment in their voices when they spoke of how they did not succeed with their plans for his recovery; the failure they felt was noticeable. It hurt them to lose a patient … So that it doesn’t happen again, I want you to help your doctors to achieve good, quality care with expected medical outcomes they can be proud of, even if it costs you another $10 per patient or surgical procedure for a preventive measure or device you didn’t want to pay for. In the end, the ounce of prevention costs so little in comparison to the loss of another life.

I’ve listened to your administrators who seem ashamed and afraid and go blah, blah, blah, shrinking back at the issue of the death of my son. Shamelessly, instead of offering right words of authenticity and community, I hear cheap words of faked rationalization globbed in paralyzing fear. You do your hospital no good thing to allow them to act in this manner … So that it doesn’t happen again, I want you to teach them to sincerely speak kind, genuine words that suggest shared knowledge of loss. Let them acknowledge fragility; perhaps even responsibility. Do not allow them to suggest that the status quo at your hospital is sufficient when our son is dead from his care. Empower your people to offer hope for a better future of proactive participation with a board of directors willing to improve care on every floor, in every room, for every patient. Demonstrate your honor and regret in appropriate amounts. Leave a significant mark in your community and make a deep imprint of high reputation and of real character that all great men and women do, as you take responsibility for deeds done under your own roof. It’s called stepping up to the plate.

I’ve been a patient as well as a caregiver, advocate and family member. I’ve felt both trusting and helpless; I’ve been a participant and a bystander. I’ve had times when I had full knowledge of an issue and have been ignorant in my lacking of medical understanding … So that it doesn’t happen again, I want you to show my family and me how we can contribute as important members of our own personal medical team so that we all, together with your staff, can effect our own best good, expected outcome. If you are unable to show us how to do that, then identify, invest in and empower those who can and do it as part of your chosen service to the practice of medicine. Respect that we can be capable, thinking, proactive partners in own medical care instead of unsavvy outsiders who never went to medical school. Healthcare needs teamwork to work. We need to know how to “Prepare for Care” and we look to you for direction in doing that.

Dear CEO, I hope you read this letter to your team aloud. Tell your board that we do not want anything for the loss of our dear son but a dramatic and effective plan for change that will make a difference for others who trust healthcare in general and your hospital specifically. We look to you to partner with us as patients and caregivers so that we may all be safe and well, both now, and in the future.

Sincerely, Victoria Nahum

Hospital Acquired Infections

Hospital acquired infections (or healthcare-associated infections aka HAIs) encompass almost all clinically evident infections that do not originate from patient's original admitting diagnosis. Within hours after admission, a patient's flora begins to acquire characteristics of the surrounding bacterial pool. Most infections that become clinically evident after 48 hours of hospitalization are considered hospital-acquired. Infections that occur after the patient's discharge from the hospital can be considered to have a nosocomial origin if the organisms were acquired during the hospital stay.

Within hours of admission, colonies of hospital strains of bacteria develop in the patient's skin, respiratory tract, and genitourinary tract. Risks factors for the invasion of colonizing pathogens can be categorized into 3 areas: iatrogenic, organizational, and patient related.

Iatrogenic risk factors include pathogens that are present on medical personnel hands, invasive procedures (eg, intubation, indwelling vascular lines, urine catheterization), and antibiotic use and prophylaxis.

Organizational risk factors include contaminated air-conditioning systems, contaminated water systems, and staffing and physical layout of the facility (eg, nurse-to-patient ratio, open beds close together).

Patient risk factors include the severity of illness, underlying immunocompromised state, and length of stay.

In the US, nosocomial infections (HAIs) are estimated to occur in more than 2 million cases per year, resulting in an added expenditure in excess of $20+ billion annually. Internationally, HAI impact on the health care systems of developed countries is significant and proportionate to that of the United States. Nosocomial infections are estimated to more than double the mortality and morbidity risks of any admitted patient, and they result in at least 90,000 deaths a year in the United States.

Patient Safety: "Do No Harm"

by Sir Liam Donaldson

The maxim "First, do no harm" is attributed to Hippocrates. Scholars debate whether he actually said it, but it endures as an elegantly simple expression of what should be the cardinal rule in health care: We health care providers are called to improve patients' health, not to make it worse by our errors.

Yet in fact, medical errors and other adverse events in health care are major contributors to the global burden of disease and death. A 1999 study by the Institute of Medicine in the United States found that medical errors cause as many as 98,000 U.S. deaths annually—more than the number of deaths due to breast cancer, car accidents or AIDS. Studies in the United Kingdom indicate that one in 10 patients suffers an adverse event while hospitalized. Similar rates are found in New Zealand and Canada, and in Australia, the rate is 16.6 percent.

Data are more difficult to come by in developing countries. But according to the World Health Organization (WHO), half or more of medical equipment in those countries is unsafe, and 77 percent of all reported cases of counterfeit and substandard drugs are in poorer countries. There's little doubt that millions of adults and children in the developing world suffer prolonged illnesses, permanent disabilities or death because of unsafe vaccinations and blood, poor-quality drugs, unsafe equipment, inadequate infection control, and generally unreliable practices performed in ill-equipped settings.

Failures in patient safety exact an enormous human toll, but they have an important economic impact as well. Studies have shown that individual countries lose between $6 billion and $29 billion a year as a result of prolonged hospitalizations, litigation claims, lost income, disability and medical expenses.

Human error is only part of the problem of lapses in patient safety. Although a more conscientious approach by medical staff would prevent many medical errors, there are also chronic problems with medical systems and procedures. For example, thousands of patients every year are given the wrong drugs—sometimes with fatal results—because of hand-written prescriptions and hospital orders that are difficult to read. Yet electronic reporting and medical recording are widely available, though not yet standard.

New alliance
The issue of patient safety has been a growing public concern in recent years, and a growing number of medical practitioners, public health experts and patient advocates have been working to address it. In October 2004 at the headquarters of the Pan American Health Organization, WHO launched a new World Alliance for Patient Safety in the presence of ministers of health, senior officials, academics and patients groups from around the world. The goal of the new alliance is to galvanize and coordinate global and national efforts to improve patient safety around the world.

What needs to be done?
First, we need more research on the nature and scope of the problem. What exactly is happening, to whom, where and why? In developed countries, considerable research has already been done in this area, but more is needed. In the developing world, we need to start by carrying out baseline studies on the prevalence and nature of adverse events.

Second, to aid both research and the search for solutions, we need a taxonomy on patient safety issues, that is, a common set of concepts, principles and norms for reporting and analysis. We also need to create and coordinate reporting systems that can track adverse events and "near misses," to facilitate learning and to serve as the basis for preventive action.

In addition, we must develop guidelines based on best practices and facilitate early learning from information as it becomes available.

And we need to begin to deliver solutions, promoting interventions that have already been shown to be effective and coordinating our activities internationally to ensure that new interventions are widely disseminated.

We also need to involve patients and patients' organizations in all this work, so that we can learn lessons from their firsthand experiences and capitalize on their energy and motivation to find solutions.

One of the first initiatives of the new World Alliance for Patient Safety is a Global Patient Safety Challenge for 2005–06, whose theme is "Clean Care Is Safer Care." This campaign will focus on nosocomial infections. These hospital-acquired infections result in prolonged or aggravated illnesses, extended hospital stays, and even long-term disability and death for millions of patients worldwide. Research in the United States has found that U.S. hospitals lose from $583 to $4,886 for every nosocomial infection. A study in Thailand found that hospital-acquired infections consume up to 10 percent of some hospitals' total budgets. The campaign will promote five action areas: clean hands, clean practices, clean products, clean environment and clean equipment.

The focus of the first Global Patient Safety Challenge was chosen in part because it presents all the main characteristics of a patient safety problem: It affects large numbers of patients worldwide; it has multiple causes, relating to systems and procedures as well as human error; there are proven ways to reduce it, yet many health care institutions have not yet adopted the proven practices; and it offers a clear agenda for research and for monitoring and evaluation of the effectiveness of remedial actions.

We are inviting countries around the world to join in our efforts to document the scale and nature of health care–associated infections, analyze their root causes and develop solutions to reduce the risk of these infections as a first step toward improving patient safety overall. We hope that ministries of health, other government agencies, nongovernmental organizations, and patient and consumer groups will join in this challenge.

Patient and consumer groups are particularly critical to the success of not only the Global Patient Safety Challenge but also all our future efforts. Patients and their families are the ones who suffer when things go wrong. Yet in the past, health care providers have tended to resist their involvement in corrective efforts. It is essential that patients and their families take an active role, and that we in the health professions listen to what they have to say. Their natural concerns—to find out what happened, to hold someone accountable, and to see to it that similar errors don't happen again—should be our concerns as well.

The biggest challenge for patient safety is not to place blame or to punish, but to prevent errors—both human and systemic—from occurring. That requires both greater transparency in health care systems and greater willingness on the part of health professionals to confront our failings. To err, after all, is human. But to cover up is unforgivable, and to fail to learn is simply inexcusable. We all make mistakes, but it is our duty to learn from them and find ways to make sure they never again cause harm.

Sir Liam Donaldson is chief medical officer of the United Kingdom and chair of the new World Alliance for Patient Safety, launched at Pan American Health Organization headquarters in October 2004.