Hospital Reports Europe – Improving the Treatment of Chronic Bone Infections – Bonalive Materials by Global Business Media

SPECIAL REPORT

Improving the Treatment of Chronic Bone Infections Challenges of Treating Bone Infections Plus the Cost and Time Burden of Traditional Patient Treatment What Can Go Wrong with Bones? A Process with Risks Antibiotics and the End of Time The Way Things Are Now and Looking to the Future

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What Can Go Wrong with Bones?

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Bone Infections

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A Process with Risks

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The Prevalence of Bone Infections Bone Injuries

Camilla Slade, Staff Writer

Challenges of Treating Bone Infections Risks of Bone Disease and Treatment

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The Costs of Bone Disease in Life Impact, Time and Money

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Antibiotics and the End of Time

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Peter Dunwell, Medical Correspondent

Antibiotics

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Who is at Risk?

The Way Things Are Now and Looking to the Future

Processes to Treat Bone Trauma and Infection Symptoms, Tests and Diagnosis Treatment Looking Ahead

References 16

Cover image: A septic non-union case pre-op and 2 years post-op, where BonaliveĂ&#x2020; bioactive glass has been used. Courtesy of Galeazzi Institute, Milan Italy. WWW.HOSPITALREPORTS.EU | 1

SPECIAL REPORT: IMPROVING THE TREATMENT OF CHRONIC BONE INFECTIONS

Foreword

IKE ANY infection, bone infections are a

epidemiology as well as what can go wrong with

challenge not only because of their immediate

bones and surgery, and how. Camilla Slade then drills

impact on a patient’s health, but also because the

down a little further to consider the risks associated

weight of treatment and pain will have an impact

with bone infections and current treatment processes

on other aspects of wellbeing.

as well as how infected bones can impact on lives

So, the treatment of bone infections is a very

and, not least, on healthcare systems.

important contributor to a patient’s overall welfare as

Peter Dunwell’s article takes a closer look at one

well as to removing or managing the infection itself.

of the major challenges faced by any surgeons,

There are some well-established methods that can

including those who treat bones; the problem of

be employed to treat bone infections but, for reasons

bacteria evolving to develop resistance to a growing

we’ll cover in the Report, some of those are becoming

number of antibiotics. He looks at the problem itself

less effective. A new approach is called for and we

but also considers how this challenge to our health

will review why that is the case and what might be

has come about and how it might affect us if not

the answer.

dealt with. Finally, we examine how bone infections

We open this Report with an interview. Dr Jan

are discovered, diagnosed and treated with some of

Geurts is an orthopaedic surgeon whose experience

the options available to clinicians. Plus, we take a brief

of treating bone infections makes him well qualified

look at research to address antibiotic resistance and

to talk, from the point of view of a user, about the

to improve treatments for bone infections.

development of Bonalive bioactive glass. Our next article steps back for a broader view of bone disease, looking at prevalence and

John Hancock Editor

John Hancock, an Editor of Hospital Reports Europe, has worked in healthcare reporting and review for many years. A journalist for nearly 30 years, John has written and edited articles, papers and books on a range of medical and management topics. Subjects have included management of long-term conditions, elective and non-elective surgery, wound management, complex health issues, Schizophrenia, health risks of travel, local health management and NHS management.

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SPECIAL REPORT: IMPROVING THE TREATMENT OF CHRONIC BONE INFECTIONS

Challenges of Treating Bone Infections Plus the Cost and Time Burden of Traditional Patient Treatment Words: John Hancock Interviewee: MD Dr Jan Geurts An Interview with Jan Geurts, MD, PhD, Consultant Orthopaedic Surgeon at Maastricht UMC+

O BETTER set the scene for this Report, we first interviewed Jan Geurts, MD, PhD, Consultant Orthopaedic Surgeon at Maastricht UMC+. Because of his experience in the field, we wanted to learn about bone disease and bone trauma from someone who has to deal with real cases every day. As you will see, Jan’s answers offered exactly the insight we were seeking. John Hancock: Tell me something about Bonalive and bioactive glass Dr Jan Geurts: One of the important messages to convey is that Bonalive bioactive glass, in contrast to other contemporary solutions for osteomyelitis or bone infections, uses a modern, antibiotic-free principle, so does not rely on classic antibiotic mechanisms. Another major benefit is that it can be a one-stage solution. The gold standard in bone infection treatment has always been a two-stage treatment with one operation to debride the infected material and a second operation to manage the dead space. That it’s now possible in many cases for treatment to be completed in one stage represents a paradigm shift with very few other void filler products able to achieve that. JH: What are always the big issues with regard to bone trauma and bone infection? Dr JG: As in any sphere of medicine, there will always be matters to which practitioners regularly return, and the treatment of bone disease is no exception. One prime concern is uncertainty as to whether the whole infection has been eradicated. There is a parallel here with oncology, where a

surgeon might remove a tumour, following which the patient receives chemotherapy or radiation therapy to treat any remaining cancer cells. The same thing applies with bone infections where the surgeon will try to eradicate the infection with radical surgical debridement, following which antibiotics are used in a similar way to chemotherapy. However, as in oncology, there is no certainty that the infection has been completely eradicated [by debridement] because if even one bacterium persists, that one will divide and multiply so that, in the end, there will be a recurrence of the infection. Again, just as no oncologist would ever say in the first five years after resection that a patient is cancer free, an orthopaedic surgeon can never be certain that they have eradicated the infection for up to the first five years following surgery and might never be able to guarantee the patient that the infection has gone. So, any way of being more confident about that, whether from better diagnostics or better treatment, would be a major improvement. For now, there is about a 10% risk of recurrence in the first year, quite high. When bioactive glass is introduced into the body, a surface reaction occurs which makes the local pH and the osmotic pressure rise, and those two lead to an environment where bacteria can not grow. There is also evidence that it has an angiogenetic effect, i.e. supports the formation of new blood vessels; there is in vitro work being conducted on that but there is not yet hard evidence that it also occurs in vivo. Also, because of the surface reactions that occur, there is formation of an hydroxyapatite layer on the glass granules and hydroxyapatite is one of the main constituents of bone; so the body, over time, sees the bioactive glass granules as elements of

Bonalive® granules Bonalive® granules is a CE marked Class III medical device, providing a Smart Healing solution for bone infections and bone reconstruction. Bonalive® granules has been proven to naturally inhibit the bacterial growth of more than 50 clinically relevant bacteria strains, including Methicillinresistant bacteria MRSA, MRSE .** **References on page 16.

Smart Healing

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SPECIAL REPORT: IMPROVING THE TREATMENT OF CHRONIC BONE INFECTIONS

The gold standard in bone infection treatment has always been a twostage treatment with one

normal bone and osteoblasts, bone forming cells, start to form new bone on top of the bioactive glass granules. Bioactive glass, although inert in itself, promotes biological processes as it combines two mechanisms, antibacterial and bone forming.

operation to debride the infected material and a second operation to manage the dead space. That it’s now possible in many cases for treatment to be completed in one stage represents a paradigm shift

BACTERIA TEST WITH PIGMENTED PORPHYROMONAS GINGIVALIS SHOWS THAT BACTERIA CANNOT ADHERE AND GROW ON BONALIVE® GRANULES SURFACE. (STOOR P. ET AL. 1996)

JH: What is the current state of play with regard to bone trauma and bone infection? Dr JG: There is an important distinction between bone infection (osteomyelitis); whether there is an implant involved, PJI (prosthetic joint infection), or infections related to osteosynthesis material – with an implant, the problem is more difficult. Implant related infections and prosthetic joint infections are increasing in the Western World: when one talks about primary replacements, the incidences of infection are about 1% but the absolute numbers are increasing because there are more people treated with implants. Also, because joint replacements are getting better, the reasons for revision are changing. Ten or fifteen years ago, implants were revised because they were worn out or had become loose; nowadays, all the material and fixing related problems are solved and so infection is becoming increasingly important as a reason for revision. Fifteen years ago, infection was the fifth most frequent reason for revision but is now third or second and it might be that, in ten of fifteen years, infection will be the number one reason for revision.

CASE EXAMPLE: CHRONIC OSTEOMYELITIS IN THE DISTAL FEMUR. DEBRIDEMENT OF THE FEMUR WAS PERFORMED. THE DEFECT WAS FILLED WITH BONALIVE® GRANULES. FRACTURE APPEARED 10 DAYS POST-OP DUE TO NONCOMPLIANT WEIGHT-BEARING. AN EXTERNAL FIXATOR WAS APPLIED. BONE HEALING WAS ACHIEVED IN 4 MONTHS FROM IMPLANTATION. THE SOFT TISSUE HEALED WELL, WITH NO CLINICAL OR LABORATORY SIGNS OF INFECTION RECURRENCE. (COURTESY OF INFECTION UNIT, MAASTRICHT UMC+, THE NETHERLANDS)

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SPECIAL REPORT: IMPROVING THE TREATMENT OF CHRONIC BONE INFECTIONS

JH: How would you describe the shortcomings of conventional and traditional treatments? Dr JG: One reason why there is not yet a solution to the issue of infection is because biofilm is involved. When implants get infected, they become covered with biofilm which is very difficult to eradicate. Bacteria have developed biofilm to resist any external influence; it’s how they survive in hostile environments. Another shortcoming is AMR (anti-microbial resistance). Antibiotics have served us well in the last century but we are running into a multitude of problems with bacteria becoming increasingly resistant. Also, of course, one of the other shortcomings is that the gold standard in bone infection treatment is still a two stage treatment (see above). All that said, the treatment of bone disease and trauma hasn’t changed that much: we’re slowly moving to a one-stage protocol that has been possible since the arrival of products such as bioactive glass; but the general concepts have not changed significantly. What has improved is the access to better imaging modalities, which have improved diagnostics, the pre-operative side of things. There is also a tendency to move to shorter antibiotic treatment protocols; whereas patients in the past were on antibiotics for three or six months, there is evidence to support the idea that those treatment periods can be shorter, six weeks, four weeks or less. JH: What are the challenges of dealing with bone disease and bone trauma? Dr JG: One challenge is on the diagnostic side, pre-operative, to evaluate the extent of

debridement needed to remove an infection. A surgeon wants to know how aggressive they have to be. Again, the parallel is with oncological surgery, how far to go to get rid of the cancer or the tumour? Bone infection is the same: how far to go? A surgeon knows that the more aggressive they have to be, the more bone that has to be excised, that can give rise to other problems with reconstruction and maintaining the length and/or strength of a bone. So, the better they are informed about how far to go with debridement, the better they can predict the post-operative regime. Another challenge with regard to bone infections and infected non-unions, is when a fracture does not heal which, if it results from an infection, is very difficult because the clinician is treating two problems at the same time – a fracture that doesn’t want to heal and an infection. In the Western world, that issue of having two problems to address is faced increasingly. Although genuine osteomyelitis is not seen that often in the West, we do treat a lot of fractures with implants, i.e. osteosynthesis material; infected non-unions are a growing problem and another major challenge.

For professionals Our solutions aim to minimize the complexity and amount of procedures that medical professionals perform, increasing the capacity of hospital organizations and their personnel to provide better care for more patients.

JH: How does Bonalive bioactive glass help address these challenges? Dr JG: There are two important points to be made in this respect. First, it enables the surgeon to offer a one-stage treatment, a major benefit of bioactive glass, which means a lot less impact as far as morbidity is concerned and, second, the product treats infection in a nonantibiotic way. In my opinion, we are already in the

BONALIVE® GRANULES IS A UNIQUE BONE REGENERATION TECHNOLOGY THAT NATURALLY INHIBITS BACTERIAL GROWTH AND STIMULATES BONE FORMATION. (© BONALIVE BIOMATERIALS)

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SPECIAL REPORT: IMPROVING THE TREATMENT OF CHRONIC BONE INFECTIONS

Another challenge with regard to bone infections and infected non-unions, is when a fracture does not heal which, if it results from an infection, is very difficult because the clinician is treating two problems at the same time – a fracture that doesn’t want to heal and an infection

post-antibiotic era by which, I mean that it is necessary to find solutions that do not rely on antibiotics. No resistance to bioactive glass has yet been reported. JH: Are there any research programmes or trials recorded about bioactive glass or about bone trauma and bone infection? Dr JG: There are a few. Lorenzo Drago from Milan has published some data on in vitro antibiofilm activity of bioactive glass1 in vitro as well as in vivo. There is also a multi-centre study, by Nina Lindfors and myself2 which proved that you don’t really need a strict protocol to use bioactive glass, so different hospitals used it with different protocols and they all got the same result, which makes a strong case because it proves that the product itself or the mechanism of action is good enough for it to be used in different protocols. JH: What benefits might a clinician be able to realise immediately using bioactive glass? Dr JG: It’s a bone void filling solution as well as an infection treatment, that’s the main benefit. Where the surgeon is confident that debridement has thoroughly removed any infection, Bonalive bioactive glass can be used right away, i.e. making a one-stage treatment. JH: Are there any benefits that a clinician might realise in the medium to long-term? Dr JG: There is a growing body of evidence that the eradication rate can be improved in the medium to long term. Whereas the two stage treatment had eradication rate of about 85-88 percent, Bonalive bioactive glass has up to 95 percent eradication rate. The second medium

to long-term benefit is cost reduction; it’s a cost-effective solution. And the third one is that it’s actually a biological solution – bioactive glass is turned into normal bone in the medium to long-term. JH: What future improvements would you like to see in the treatment of bone trauma and bone infection? Dr JG: Better solutions for specifically non-union and prosthetic joint infection issues because that is the main problem that we face now. JH: Is there anything else on which you’d like to comment? Dr JG: One important message is that, even with all the products and solutions available nowadays, debridement is still the key to a successful outcome. Bonalive or any other product is not a ‘get out of jail’ card to guarantee a good result from bone infection treatment. Debridement will eradicate, say, 95 percent of the infection and the infection left behind can be well treated with solutions such as bioactive glass; but if the debridement has not been conducted correctly, then even Bonalive bioactive glass cannot guarantee a good result. That’s also a good reason for centralising this kind of care in referral centres or specialised centres. I always make a strong case for centralising bone infections in dedicated units, in hospitals that do a lot of these cases where there is experience and dedication rather than in every hospital. With all of our questions answered and answered well, we bade Jan goodbye, first thanking him for his time and his informative answers.

Even with all the products and solutions available nowadays, debridement is still the key to a successful outcome. Bonalive or any other product is not a ‘get out of jail’ card to guarantee a good result from bone infection treatment. Debridement will eradicate, say, 95 percent of the infection

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SPECIAL REPORT: IMPROVING THE TREATMENT OF CHRONIC BONE INFECTIONS

What Can Go Wrong with Bones? John Hancock, Editor Whether it’s disease or a fracture, bones are vulnerable

ONE INFECTIONS are an increasing problem with treatment similarly on the rise. Many such infections can be treated with medical interventions although, as bacteria develop resistance to ever more antibiotic treatments (see further in this Report) that is becoming a less reliable therapy.

The Prevalence of Bone Infections The alternative to medical is surgical intervention and, in a survey3 published by the Royal College of Surgeons (RCS) in 2015, it was found that, “Two-thirds of patients… underwent an operation. “Across England, that added up to “250,000 bone operations including 60,000 hip replacements performed annually.” that’s according to NHS England4. A growing number of bone infections that require surgery are related to earlier prosthetic joint surgery; itself, to a growing extent, reflecting, “Increases in patient obesity [which] will raise further challenges to prevention efforts given the associated elevated risk of infection.” according to the ‘Journal of Antimicrobial Chemotherapy’5.

Bone Infections Different infections and related risk factors There is more than one type of bone infection, but it is the conditions involving infection of the bone that are most likely to require surgery, i.e. debridement of infected tissue and reconstruction of the bone. Oxford University Hospitals NHS Foundation Trust6 explains how a bone can become infected, “If a germ gets into a bone or joint it can cause an infection. This can happen through the bloodstream, but many infections arise because of injury, a skin ulcer or surgery.” Diabetes and a weakened immune system (HIV or chemotherapy for cancer) can cause infection as can using a prosthetic device, using street drugs, which are often contaminated, or being dependent on alcohol. A common infection is osteomyelitis that can often result from infection elsewhere in the body, surgery, an open fracture or even an injection near a bone. This might

well require surgery to remove the infection with debridement. Another bone condition, osteoporosis, is less likely to need surgery unless to deal with a bone fracture that is often the first time the condition is picked up. Other bone infections include septic arthritis and mycetoma. As with any disease, there are often people who are more at risk for a variety of reasons. With osteomyelitis, those risk factors include long term skin infections from which disease might spread down to the bone, also poorly controlled diabetes can be a risk factor as can arteriosclerosis, poor blood circulation. NHS choices offers a neat summation of risk factors7. Certainly, a bone infection is not something to take lightly. The first signs might be a high temperature (not always the case with very young children), bone pain, swelling and tenderness with impaired mobility. Left untreated, as Your MD8 explains, “If the infection is not treated and the immune system is unable to deal with the bacteria, a collection of dead white blood cells will build up inside the bone, forming a pocket of pus known as an abscess. In cases of chronic osteomyelitis, abscesses can block the blood supply to the bone, which will eventually cause the bone to die. Dead bone with no blood supply must be removed if infection is to be cleared.” That clearance might be debridement of the infected tissue or, in some cases, could mean amputation in order to have the best chance of removing the infection.

For global healthcare Smart Healing enables procedures that are more cost-effective and more sustainable. By aiming to help solve a global problem through improved patient care, Bonalive is committed to creating a better future for the healthcare ecosystem.

Bone Injuries A bone fracture is a condition in which bone continuity has been broken. Fractures are the main bone injuries that clinicians see although, particularly among older people, there will often be a link between fractures and one of the bone diseases mentioned above, osteoporosis. The loss of bone mass and structure that typifies osteoporosis weakens bones making them more liable to break and more difficult to repair. That said, what patterns there are for bone fractures are complicated by the large number of variables that come into play. WWW.HOSPITALREPORTS.EU| 7

SPECIAL REPORT: IMPROVING THE TREATMENT OF CHRONIC BONE INFECTIONS

If a germ gets into a bone or joint it can cause an infection. This can happen through the bloodstream, but many infections arise because of injury, a skin ulcer or surgery

A complex epidemiology A wide-ranging survey to better understand the epidemiology of fractures in the United Kingdom between 1988 and 2012 considered factors such as sex, age, geography, ethnicity and socioeconomic status as well as seventeen types of bone trauma. The results were published in Bone9 in 2016 and are also available from NCBI10. While the detailed results are too lengthy to include in this article (they would fill an article on their own) there is a brief summation that concludes, “Fracture incidence rates by age and sex were comparable to those documented in previous studies and demonstrated a bimodal distribution. Substantial geographic heterogeneity in age- and sexadjusted fracture incidence was observed, with rates in Scotland almost 50% greater than those in London and South East England. Lowest rates of fracture were observed in black individuals of both sexes; rates of fragility fracture in white women were 4.7 times greater than in black women. Strong associations between deprivation and fracture risk were observed in hip fracture in men, with a relative risk of 1.3 (95% CI 1.21–1.41) in Index of Multiple Deprivation

category 5 (representing the most deprived) compared to category 1.” A similar survey by University of Southampton11 came up with similar results, “Ethnicity, socioeconomic status and place of residence in the UK all influence the risk of breaking a bone, a new Southampton study has shown.” As if that was not complex enough, there are also different types of bone fracture. Again, there isn’t space here to list them all, but Medical News Today12 itemises fifteen, each of which, of course, requires a slightly different treatment. And, finally, the same Medical News Today article explains that, “A significant percentage of bone fractures occur because of high force impact or stress. However, a fracture may also be the result of some medical conditions [pathological fracture] which weaken the bones, for example osteoporosis, some cancers, or osteogenesis imperfecta (also known as brittle bone diseases).” And we mustn’t omit that, to an increasing degree, bone surgery is also often about replacement joints or the longer-term consequences of replacement joints, and prosthetics following amputation. More of those topics will be covered in later articles.

Ethnicity, socioeconomic status and place of residence in the UK all influence the risk of breaking a bone, a new Southampton study has shown

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SPECIAL REPORT: IMPROVING THE TREATMENT OF CHRONIC BONE INFECTIONS

A Process with Risks Camilla Slade, Staff Writer From bone disease to treatment, there are many things to consider

O SURGERY is straightforward but treating infected bones includes the added challenge of dealing with an infection within the bone. Also, of course, bones are the structure supporting (literally) the body and so any intervention can have the potential to be life altering.

Challenges of Treating Bone Infections In the processes before bone surgery, a surgeon needs to be able to access the best information so that s/he can better address the challenge of judging the extent of infection in order to be able to calculate the correct amount of bone tissue to remove during debridement. Too little removed and there’s a very good chance that the infection will return; too much removed, and the integrity or strength of the remaining bone might not be sufficient to function properly or support any later reconstruction. As well as debridement to remove infection, where a fracture is slow in healing or where an exposed fracture has occurred, treating the fracture might become complicated by also having to treat an infection. Many of these challenges are set out in the Springer-Verlag paper, ‘Difficulties and challenges to diagnose and treat post-traumatic long bone osteomyelitis.’13 which offers some realism in, “In some cases, eradication of the infection may only be obtained by aggressive resection of a long bone or intra-articular segment, at the expense of patient’s functional outcome. On the other end of the spectrum, a return to baseline function may be acceptable with the requirement of long-term suppressive antibiotics and multiple procedures. As cost-effectiveness becomes more of a focus in today’s healthcare environment, the long-term expense of limb salvage versus amputation will need consideration...” For cost issues, see below. Clinical Microbiology Reviews explains the challenge of managing infection in stark terms14, “Staphylococcal infections are becoming an increasing global concern, partially due to the resistance mechanisms developed by staphylococci to evade the host immune system and antibiotic treatment. In addition to the ability of staphylococci to withstand treatment, surgical

intervention in an effort to remove necrotic and infected bone further exacerbates patient impairment. Despite the advances in current health care, osteomyelitis is now a major clinical challenge, with recurrent and persistent infections occurring in approximately 40% of patients.” For all the above reasons, clinicians recommend that treatment should be aggressive to minimise the risk of amputation. The outlook for bone infection is good if treated early. Later treatment can result in slower or no long-term healing. Most bone and joint infections follow a familiar treatment path of diagnosis, treatment with antibiotics and surgery, and rehabilitation where the surgery has impacted a patient’s mobility.

For patient wellbeing To enable a faster recovery time, fewer surgeries and a higher quality of life for patients, Smart Healing solutions are comprised of natural biological compounds for use in both adult and pediatric patients.

Risks of Bone Disease and Treatment The risks alluded to above are a challenge whoever the patient might be, but with older people, the issue can be even more serious. Science Daily, ‘Fractures Can Lead to Premature Death in Older People’ suggests,15 “… certain fractures due to osteoporosis can cause premature death in people 45 and older… Health professionals have been aware for some time that having a hip fracture when you are older increases your risk of dying in one to two years after the fracture, but [they] have not been so aware that other fractures could increase this risk as well…” There can also be risks consequent on the treatment of bone infections. The traditional standard surgery has been a two-stage process where, in stage one, the surgeon removes infected tissue and a margin of ‘clean’ tissue in a process of debridement. Sometimes, following this process, the wound might be left open to make possible further treatment prior to a second operation. At that second operation, the void where the infected tissue has been removed will be filled with a suitable product before the operating site is closed. Apart from the risk when a surgical wound has to be left open, any additional surgery will pose the usual risks to the patient and those risks increase with a patient’s age, frailty or the presence of complex health issues. Another risk is that associated with WWW.HOSPITALREPORTS.EU| 9

SPECIAL REPORT: IMPROVING THE TREATMENT OF CHRONIC BONE INFECTIONS

Another risk is that associated with antibacterial resistance, a growing problem for healthcare systems today

antibacterial resistance, a growing problem for healthcare systems today.

The Costs of Bone Disease in Life Impact, Time and Money Any bone disease has the potential to impact a patient’s quality of life. Elsevier, ‘Bone and joint infections’16 reports that, “Osteomyelitis and infectious arthritis are serious health problems that affect a patient’s family, work, and social life... Patients typically are feverish, complain of pain, and have limited articular movement.” Even if a patient is able to control their pain with drugs, that might limit their ability to perform in anything but the most basic work and, in the event that the pain is accompanied by lack of mobility, then they will probably be unable to work at all. This brings with it all sorts of socioeconomic consequences, impacts on mental health and might also put strains on family and relationships. Looking from a monetary point of view, Dr Jan Geurts, Consultant Orthopaedic Surgeon explains, “Bone infection is a very expensive problem to treat because patients often stay

in hospital for a long time, also often have to undergo multiple surgeries, there is a need for follow-up and there is a rate of recurrence which means that the problem has not been treated definitively. It all adds up to a high burden on healthcare systems. For instance, looking at PJI, the cost of treating a prosthetic joint infection is roughly five or six times the cost of a primary joint replacement. So, if a primary joint replacement is in the order of e15,000, a prosthetic joint infection can cost up to e100,000. Moreover, the problem often affects young people who are economically active, making a bone or joint infection a wider socioeconomic issue.” The Journal of Bone & Joint Surgery17 certainly sees the burden in those terms, “[Bone infections] create an additional burden on total health-care expenditures, and can lead to functional impairment, long-lasting disability, or even permanent handicap, with the inevitable social and economic burdens.” calling for, “… the burden created by bone and joint infections to be included in… global health-care priorities.”

The cost of treating a prosthetic joint infection is roughly five or six times the cost of a primary joint replacement. So, if a primary joint replacement is in the order of e15,000, a prosthetic joint infection can cost up to e100,000

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SPECIAL REPORT: IMPROVING THE TREATMENT OF CHRONIC BONE INFECTIONS

Antibiotics and the End of Time Peter Dunwell, Medical Correspondent Mapping the decline of a champion and wondering what comes next

EVERAL TIMES in this Report we have already mentioned the topic of antibiotic resistance. This is a growing problem across the healthcare sector and especially so for a condition such as bone disease where antibiotics have been the treatment of choice for many decades.

Antibiotics Before looking at the issue of antibiotic resistance, it might be as well to briefly reprise antibiotics themselves. The Microbiology Society18 describes them as, “Any substance that inhibits the growth and replication of a bacterium or kills it outright can be called an antibiotic. Antibiotics are a type of antimicrobial designed to target bacterial infections within (or on) the body. This makes antibiotics subtly different from the other main kinds of antimicrobials widely used today…” So far, so good; but NHS choices19, citing a global study, reports that, “global antibiotic consumption had increased by 65% over the 15-year period studied. The consumption of antibiotics was greater in LMICs [low and middle income countries] compared with HICs [high income countries]. Of particular concern was the high use of the strongest ‘last resort’ antibiotics, which are normally used for the most severe infections.” The problem is that bacteria naturally evolve to find a way to resist antibiotics and so, the more they are used, the more opportunities there are for them to develop resistance. To put this in perspective, the same report states that, “Many commentators have argued that antibiotic resistance poses a similar, or even greater, threat than climate change to our long-term future.” And there’s a reason: another report from PNAS and reported in Time20 goes so far as to say that, “in the USA, a third of antibiotic prescribed are unnecessary.” And that’s probably true for all advanced economies.

Antibiotic Resistance How Stuff Works21 offers an excellent summation of how bacteria can become resistant to antibiotics, first explaining that, “Antibiotics stop or interfere with a number of everyday cellular

processes that bacteria rely on for growth and survival…” then adding, “Antibiotics stop working because bacteria come up with various ways of countering these actions…” The article includes a lot more detail than there is space for here. The Alliance for the prudent use of Antibiotics (APUA)22 further reports that, “… bacteria may also become resistant in two ways: 1) by a genetic mutation or 2) by acquiring resistance from another bacterium.” So serious is this issue now that even the BBC’s GCSE Bitesize23 notes for young students explain antibiotic resistance, “This is an example of natural selection. In a large population of bacteria, there may be some that are not affected by the antibiotic. These survive and reproduce, creating more bacteria that are not affected by the antibiotic.” The cost of antibiotic resistance With a couple of tragic stories to illustrate the point, The Telegraph24 reported in March 2018 , “Official figures suggest antimicrobial resistance (AMR) claims the lives of 5,000 people a year in the UK, though experts have argued the real figure is at least double that. Getting global figures on the problem is difficult but reliable estimates suggest 700,000 are already dying each year [worldwide] – one person a minute. If no action is taken, the death toll could rise to 10 million a year by 2050... This is more people than currently die of cancer.” In fact, some estimates are that antibacterial resistance is already responsible for more deaths than Breast Cancer. It is also the case that the notorious ‘superbugs’ such as MRSA are a product of this growing problem which, in extremis, might be considered an existential matter for the Human Race if it is not addressed. As long ago as April 2015, The Guardian25 was reporting that, “As many as 80,000 people could die if there was an outbreak of a drug-resistant infection in Britain, a government forecast has warned. According to the report, about 200,000 people could fall

Smart Healing

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SPECIAL REPORT: IMPROVING THE TREATMENT OF CHRONIC BONE INFECTIONS

Antibiotics are a type of antimicrobial designed to target bacterial infections within (or on) the body. This makes antibiotics subtly different from the other main kinds of antimicrobials widely used today

victim to a bacterial blood infection if there was a widespread outbreak that existing antibiotics could not tackle.” The article also highlights the risk to even routine operations were antibiotics not available and, at the other end of the scale, the impossibility of major transplant surgery and, of course, that again would include bone surgery.

Who is at Risk? While bone disease is no respecter of age or gender, there are certain groups of people who will be at greater risk of developing osteomyelitis. Healthline26 sets out some conditions that can increase risk. • Diabetic disorders that affect blood supply to the bones; • Intravenous drug use; • Haemodialysis, which is a treatment used for kidney conditions; • Trauma to the tissue surrounding the bone; • Artificial joints or hardware that have become infected; • Sickle cell disease; • Peripheral arterial disease (PAD); • Smoking. Given that many patients with these conditions will already have multiple and complex health issues, the extreme case projection cited above might not be far-fetched.

Why No New Antibiotics? Readers might wonder why no new antibiotics are coming on to the markets – only two new antibiotic classes have been introduced in the past 40 years. The answer, I’m afraid is largely economic. Antibiotic research UK27 reports, “Many of the large pharmaceutical companies have closed down their antibiotic research divisions because they cannot see how they can make money from antibiotics (they answer to shareholders after all!). Drugs like those used to treat cancer are often given for life and so provide a sufficient income stream to pharmaceutical companies to warrant research investment. Antibiotics are given for just a short course of treatment and so sales are very limited. In addition, governments hold down the price of antibiotics, leaving little financial incentive for pharmaceutical companies to invest in research.” As well as that economic issue, there is also the reality that, now we know how bacteria are able to develop resistance to our currently best weapon, antibiotics, the likelihood is that, whatever future versions are developed, they will only last for a short while before the bacteria find a way around them. Hence, there is now an effort to develop alternative means to treat bacterial contamination, as we will see in the next article.

This is an example of natural selection. In a large population of bacteria, there may be some that are not affected by the antibiotic. These survive and reproduce, creating more bacteria that are not affected by the antibiotic 12 |WWW.HOSPITALREPORTS.EU

SPECIAL REPORT: IMPROVING THE TREATMENT OF CHRONIC BONE INFECTIONS

The Way Things Are Now and Looking to the Future John Hancock, Editor Treating bone trauma and disease cannot stand still

S WITH any surgical discipline, there is a wealth of material available covering guidelines for orthopaedic surgery.

Processes to Treat Bone Trauma and Infection The ‘National Model of Care for Trauma and Orthopaedic Surgery’28 published by the Health Service Executive in Eire in 2015 provides a good summary in one document of a modern model for clinical best practice in the field. NHS England, as part of its bone and joint infection service specification offers a useful Clinical Pathway29 which clearly sets out the process for clinicians to follow from the initial circumstances and condition that bring a patient into the process right through to the post treatment regime (see chart on page 14). For a summary of the treatment process, NHS Direct Wales30 explains, “If diagnosed early, osteomyelitis can be treated with antibiotics for at least four to six weeks… In severe or chronic cases… surgery may be used in combination with antibiotics. Surgery is most often used to remove damaged bone and drain pus from wounds.”

Symptoms, Tests and Diagnosis Before any treatment programme can be initiated, it will first be necessary for the clinician to understand what has to be dealt with. Bone trauma and fracture are usually either the result of an event, such as a fall or traffic accident, or of the failure of an implant, but osteomyelitis is a condition that patients might all-too-often ignore as ‘part of getting older’ or from exercise. There are some symptoms for which clinicians need to be aware, as Your MD31 explains: • A sudden high temperature (fever) of 38°C (100.4°F) or above, although this symptom is often absent in children under one year old; • Bone pain, which can often be severe; • Swelling, redness and warmth at the site of the infection; • A general sense of feeling unwell; • The affected body part is tender to touch; • The range of movement in the affected body part is restricted;

• Lymph nodes (glands) near the affected body part may be swollen. Experiencing a new limp or a stiff back could be added to the list. There are several means by which a clinician might test for and diagnose bone disease. As always, the first will be to carry out a physical examination, in this case to check for swelling, pain and discolouration. It will also be useful to know about the patient’s recent medical history such as illness, injury, surgery or a previous infection. A blood test might be used to check for infection and the nature of bacteria causing the infection as well as throat swabs, a urine test and a stool analysis. Where an infection has spread to the skin, a sample of any discharge can be taken plus a sample might also be taken of fluid on an infected joint. It could also be necessary for a patient to have an X-ray or a bone scan to test for cellular and metabolic activity; or even an MRI scan, or a bone biopsy.

Treatment We’ve covered a lot of the treatment options throughout this Report but Lifespan32 precedes any explanation of treatment options with some of the factors that might influence what is best for an individual patient. These include: • Age; • Overall health and past health; • How sick the patient is; • How well they can handle specific medicines, procedures, or therapies; • How long the condition is expected to last; • The patient’s opinion or preference. The list might also have added the type of osteomyelitis from which the patient is suffering (acute, sub-acute or chronic) which is well set out in Medical News Today ‘What is osteomyelitis?’33 Because there are so many factors to take into account, the length of time for any treatment programme cannot be generalised. It might vary from a short course of antibiotics to admission to hospital for two-stage surgery and time for recovery after that. docdoc34 adds that, “After the procedure, the wound is typically left open

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SPECIAL REPORT: IMPROVING THE TREATMENT OF CHRONIC BONE INFECTIONS

Bonalive® granules

to allow tissues to heal on their own. A splint is also attached to minimise movement of the affected limb.” And that might be expected to add time to the treatment process. The advent of materials that offer the potential for a one-stage debridement and fill surgery will greatly help to reduce treatment time. In light of concerns about antibiotic resistance, clinicians are endeavouring to minimise the time for which antibiotics are used. In that context, any material that can combat bacteria without supporting its resistance to antibiotics will be a good thing. On the issue of bacteria developing antibiotic resistance, there are several strands of attack being tried, including, as Healthline35 reports, “… peptide-conjugated phosphorodiamidate morpholino oligomer, or PPMO. These lab-synthesized forms of DNA or RNA can silence specific genetic targets… without the risk of bacteria becoming resistant...” Other alternatives include luminescent vibriosis in aquaculture. Also, clinicians are exploring the restriction of stronger antibiotics for use by patients whose need is greatest and a process

of alternating the antibiotics used to disrupt the process whereby a bacteria gains resistance. Bone surgery is subject to the same pressures as any clinical procedure inasmuch as hospitals will wish to be able to discharge a patient to homecare as soon as is feasible. That will minimise exposure to hospital-related infections, improve the patient’s mental state (most people prefer to be treated at home) and, of course, reduce the costs to the healthcare system.

Looking Ahead As in any area of healthcare, new and better ways of dealing with bone trauma and bone disease are being investigated and/or tried. Research is always underway to develop new treatment compounds and improved imaging technologies as identified in Infection Control Today36 in 2013. Hyperbaric Oxygen Therapy (HBOT) is a further addition to the clinician’s armoury and the development of bacteria-resistant or combatting material to fill voids after debridement is adding enormously to the range of options available in the treatment of bone trauma and disease.

After the procedure, the wound is typically left open to allow tissues to heal on their own. A splint is also attached to minimise movement of the affected limb

A unique bone regeneration technology that naturally inhibits bacterial growth and stimulates bone formation.

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•

Bone cavity filling Bone cavity filling in the treatment of chronic osteomyelitis Mastoid cavity obliteration

Product properties • •

Inhibition of bacterial growth Osteoconductive, osteostimulative* *non-osteoinductive

Composition • • • •

53% SiO2 23% Na2O 20% CaO 4% P2O5

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SPECIAL REPORT: IMPROVING THE TREATMENT OF CHRONIC BONE INFECTIONS

References: 1

In vitro antibiofilm activity of bioactive glass S53P4 www.ncbi.nlm.nih.gov/pubmed/24957087

Antibacterial Bioactive Glass, S53P4, for Chronic Bone Infections - A Multinational Study www.ncbi.nlm.nih.gov/pubmed/28050878

Annals of The Royal College of Surgeons of England publishing.rcseng.ac.uk/doi/full/10.1308/rcsann.2015.0050

NHS England www.england.nhs.uk/wp-content/uploads/2017/04/b07-bone-joint-infec.pdf

Oxford Academic Journal of Antimicrobial Chemotherapy academic.oup.com/jac/article/69/suppl_1/i5/772200

Oxford University Hospitals NHS Foundation Trust www.ouh.nhs.uk/boneinfection/information/bone-joint-infections.aspx#what

NHS choices www.nhs.uk/conditions/osteomyelitis/

Your MD www.your.md/condition/osteomyelitis/#chapter-introduction

Europe PMC www.ncbi.nlm.nih.gov/pmc/articles/PMC4890652/

Bone www.ncbi.nlm.nih.gov/pmc/articles/PMC4890652/

University of Southampton www.southampton.ac.uk/news/2016/04/broken-bone-nos.page

Medical News Today www.medicalnewstoday.com/articles/173312.php

Springer-Verlag France link.springer.com/content/pdf/10.1007/s00590-014-1576-z.pdf

Clinical Microbiology Reviews cmr.asm.org/content/31/2/e00084-17.abstract

Science Daily www.sciencedaily.com/releases/2015/11/151108084919.htm

Elsevier www.sciencedirect.com/science/article/pii/S0011393X9680097X

The Journal of Bone and Joint Surgery journals.lww.com/jbjsjournal/Abstract/2017/03010/Global_Forum___The_Burden_of_Bone_and_Joint.14.aspx

Microbiology Society

microbiologysociety.org/education-outreach/antibiotics-unearthed/antibiotics-and-antibiotic-resistance/what-are-antibiotics-and-how-do-they-work.html

NHS choices www.nhs.uk/news/medication/global-antibiotic-use-has-increased-sparking-fears-worldwide-resistance/

Time time.com/5215398/antibiotics-rates-worldwide/

How Stuff Works science.howstuffworks.com/environmental/life/cellular-microscopic/question561.htm

APUA emerald.tufts.edu/med/apua/about_issue/about_antibioticres.shtml

BBC ‘GCSE Bitesize’ www.bbc.co.uk/schools/gcsebitesize/science/edexcel/problems_in_environment/infectiousdiseaserev6.shtml

The Telegraph www.telegraph.co.uk/news/2018/03/26/almost-died-true-cost-antibiotic-resistance-britain-around-world/

The Guardian www.theguardian.com/science/2015/apr/06/drug-resistant-disease-could-kill-80000-single-uk-outbreak-report-warns

Healthline www.healthline.com/health/osteomyelitis

Antibiotic Research UK, ‘About antibiotic resistance’ www.antibioticresearch.org.uk/about-antibiotic-resistance/

Health Service Executive, Eire

www.hse.ie/eng/services/publications/clinical-strategy-and-programmes/national-model-of-care-for-trauma-and-orthopaedic-surgery-2015.pdf 29

NHS England www.england.nhs.uk/wp-content/uploads/2017/04/b07-bone-joint-infec.pdf Page 11

NHS Direct Wales www.nhsdirect.wales.nhs.uk/encyclopaedia/o/article/osteomyelitis/

Your MD www.your.md/condition/osteomyelitis/#chapter-introduction

Lifespan www.lifespan.org/conditions-treatments/diseases-and-conditions/osteomyelitis

Medical News Today www.medicalnewstoday.com/articles/178819.php

docdoc www.docdoc.com/info/procedure/bone-debridement/

Healthline www.healthline.com/health-news/tech-two-new-techniques-to-fight-bacteria-without-antibiotics-101813#1

Infection Control Today

www.infectioncontroltoday.com/infectious-diseases-conditions/scientists-develop-new-model-and-possible-treatment-osteomyelitis

**Advertisement References: Antibacterial effect of bioactive glasses on clinically important anaerobic bacteria in vitro. https://www.ncbi.nlm.nih.gov/pubmed/17619981 In vitro antibiofilm activity of bioactive glass S53P4. https://www.ncbi.nlm.nih.gov/pubmed/24957087 Antimicrobial activity and resistance selection of different bioglass S53P4 formulations against multidrug resistant strains. https://www.ncbi.nlm.nih.gov/pubmed/26228640 Bactericidal effects of bioactive glasses on clinically important aerobic bacteria. https://www.ncbi.nlm.nih.gov/pubmed/17569007 Efficacy of antibacterial bioactive glass S53P4 against S. aureus biofilms grown on titanium discs in vitro. https://www.ncbi.nlm.nih.gov/pubmed/24108602

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