Effectiveness of a bundled intervention of decolonization and prophylaxis to decrease Gram positive surgical site infections after cardiac or orthopedic surgery: systematic review and meta-analysis.


Objective To evaluate studies assessing the effectiveness of a bundle of nasal decolonization and glycopeptide prophylaxis for preventing surgical site infections caused by Gram positive bacteria among patients undergoing cardiac operations or total joint replacement procedures.

Design Systematic review and meta-analysis.

Data sources PubMed (1995 to 2011), the Cochrane database of systematic reviews, CINAHL, Embase, and clinicaltrials.gov were searched to identify relevant studies. Pertinent journals and conference abstracts were hand searched. Study authors were contacted if more data were needed.

Eligibility criteria Randomized controlled trials, quasi-experimental studies, and cohort studies that assessed nasal decolonization or glycopeptide prophylaxis, or both, for preventing Gram positive surgical site infections compared with standard care.

Participants Patients undergoing cardiac operations or total joint replacement procedures.

Data extraction and study appraisal Two authors independently extracted data from each paper and a random effects model was used to obtain summary estimates. Risk of bias was assessed using the Downs and Black or the Cochrane scales. Heterogeneity was assessed using the Cochran Q and I2 statistics.

Results 39 studies were included. Pooled effects of 17 studies showed that nasal decolonization had a significantly protective effect against surgical site infections associated with Staphylococcus aureus (pooled relative risk 0.39, 95% confidence interval 0.31 to 0.50) when all patients underwent decolonization (0.40, 0.29 to 0.55) and when only S aureus carriers underwent decolonization (0.36, 0.22 to 0.57). Pooled effects of 15 prophylaxis studies showed that glycopeptide prophylaxis was significantly protective against surgical site infections related to methicillin (meticillin) resistant S aureus (MRSA) compared with prophylaxis using β lactam antibiotics (0.40, 0.20 to 0.80), and a non-significant risk factor for methicillin susceptible S aureus infections (1.47, 0.91 to 2.38). Seven studies assessed a bundle including decolonization and glycopeptide prophylaxis for only patients colonized with MRSA and found a significantly protective effect against surgical site infections with Gram positive bacteria (0.41, 0.30 to 0.56).

Conclusions Surgical programs that implement a bundled intervention including both nasal decolonization and glycopeptide prophylaxis for MRSA carriers may decrease rates of surgical site infections caused by S aureus or other Gram positive bacteria.


Although multiple studies have assessed the efficacy of interventions to prevent surgical site infections caused by Gram positive bacteria, these interventions are not uniformly applied to surgical patients. Our results showed that nasal decolonization was associated with decreased rates of Gram positive surgical site infections andStaphylococcus aureus surgical site infections among patients undergoing cardiac or orthopedic surgical procedures. However, these results remained statistically significant for S aureus surgical site infections, though not all Gram positive surgical site infections, when the meta-analysis was limited to randomized controlled trials. Additionally, a bundle that included nasal decolonization and glycopeptide prophylaxis for patients who carried methicillin (meticillin) resistant S aureus (MRSA) was associated with significantly decreased rates of surgical site infections caused by Gram positive bacteria and by S aureus.

We also found that routine use of prophylactic glycopeptides protected against MRSA infections but not against all Gram positive surgical site infections. Additionally, dual prophylaxis with a glycopeptide and another antimicrobial agent seemed to be more protective against Gram positive surgical site infections than prophylaxis with glycopeptides alone. This finding is consistent with studies of methicillin susceptible S aureus (MSSA) bacteremia, which found that vancomycin is less effective than a β lactam antibiotic for treating MSSA infections.63 64 These results are similar to the conclusions of a recent review article, which stated that vancomycin is not recommended for preoperative prophylaxis but may be considered as a component of an MRSA bundle to prevent surgical site infections.65

Our meta-analyses were the first to assess a bundle that included nasal decolonization and targeted glycopeptide prophylaxis for MRSA carriers. Other meta-analyses have assessed nasal decolonization or glycopeptide prophylaxis alone,66 67 68 and our results confirm the findings of the previous studies and extend these by including the results of recent studies. Future meta-analyses should assess other outcomes associated with these interventions. These outcomes could include duration of hospital stay since one group of researchers found that the mean duration of hospital stay was significantly shorter in those randomized to mupirocin and chorhexidine gluconate rather than to placebo.27 Future meta-analyses should also confirm our preliminary findings that these interventions do not open a niche for pathogens other than S aureusto fill, and should also analyze other patient populations such as those requiring trauma surgery to determine if these findings are generalizable to other surgical specialties.

Nasal decolonization protected against S aureus surgical site infections when all patients were decolonized and when only S aureus carriers were decolonized. Routine nasal decolonization of all surgical patients may be easier to implement and more cost effective than using cultures or polymerase chain reaction testing to screen patients preoperatively.69 None the less, it may be prudent to reserve mupirocin decolonization for patients who carry S aureus to prevent widespread mupirocin resistance.70Similarly, it may be prudent to do further research on targeted prophylaxis with vancomycin before including this bundle in clinical practice. Of note, the pooled relative risks assessing Gram positive surgical site infections were identical for both the decolonization studies and the bundle studies. Thus high quality studies such as cluster randomized trials are still needed to determine whether adding glycopeptide prophylaxis to nasal decolonization will further decrease the incidence of Gram positive surgical site infections.

In our sensitivity analyses we found that nasal decolonization was associated with a 1% risk difference and the bundle was associated with a 0.5% risk difference in Gram positive surgical site infections. Although these differences seem small, they are clinically significant considering that cardiac and orthopedic operations are common and surgical site infections are associated with considerable morbidity. Each year, approximately 300 000 cardiac operations and approximately 900 000 total joint arthroplasties are done in the United States alone.71 Thus these interventions could prevent 6000 to 12 000 surgical site infections per year in the United States and even more worldwide.

Limitations of this study

Our study has some limitations. Firstly, meta-analyses are only as valid as the studies that contribute to the pooled risk ratio. We included many studies that were simple before and after quasi-experimental studies. Additionally, none of the included studies adjusted statistically for potential confounders, thus confounding may be problem, especially among the observational studies. To mitigate this limitation, we performed subset analyses on the results of only randomized controlled trials. Secondly, we did not include studies that did not report or could not provide specific data on Gram positive infections, thus we may have excluded important decolonization and prophylaxis studies. However, nine of 15 contacted investigators submitted additional data for inclusion in the analyses. Thirdly, studies of the association between interventions and Gram positive surgical site infections were heterogeneous, and thus some of the meta-analysis results should be interpreted with caution. Once these studies were stratified by potential sources of heterogeneity, the stratified subsets were homogeneous. For example, nasal decolonization aims to decrease the incidence of endogenous S aureus surgical site infections. The association between nasal decolonization and Gram positive surgical site infections may have been different for studies in which S aureus caused most Gram positive surgical site infections compared with studies in which surgical site infections due to other Gram positive pathogens were common. Thus we limited heterogeneity by doing subset analyses that separated studies focusing on S aureus surgical site infections from those focusing on all Gram positive surgical site infections.


Surgical site infections caused by Gram positive bacteria may be prevented by decolonizing patients who carry S aureus in their nares and potentially by adding a glycopeptide to the usual prophylaxis using β lactam antibiotics for MRSA carriers. High quality randomized controlled trials or cluster randomized trials should be performed to further assess this bundle.

What is already known on this topic

  • Surgical site infections (SSIs) are potentially preventable adverse events of cardiac and orthopedic operations
  • SSIs significantly increase hospital length of stay, readmission rates, healthcare costs, and mortality rates
  • Clinicians and researchers have debated whether nasal decolonization or glycopeptide antibiotic prophylaxis reduce SSIs caused by Gram positive bacteria
  • Among patients undergoing cardiac or orthopedic surgery:
  • Nasal decolonization with mupirocin ointment was protective against Gram positive SSIs
  • Preoperative prophylaxis with anti-methicillin (meticillin) resistant Staphylococcus aureus (MRSA) antibiotics when given to all patients was not protective against Gram positive SSIs
  • A bundle that included nasal decolonization and anti-MRSA prophylaxis for MRSA carriers was significantly protective against Gram positive SSIs

What this study adds


  • Among patients undergoing cardiac or orthopedic surgery:
  • Nasal decolonization with mupirocin ointment was protective against Gram positive SSIs
  • Preoperative prophylaxis with anti-methicillin (meticillin) resistant Staphylococcus aureus (MRSA) antibiotics when given to all patients was not protective against Gram positive SSIs
  • A bundle that included nasal decolonization and anti-MRSA prophylaxis for MRSA carriers was significantly protective against Gram positive SSIs

Source: BMJ



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Rapid Activation of Stat3 and ERK1/2 by Nicotine Modulates Cell Proliferation in Human Bladder Cancer Cells.

Cigarette smoke is a major risk factor for bladder cancer. The main component in cigarette smoke, nicotine, can be detected in the urine of smokers. Nicotine has been implicated as a cocarcinogen that promotes lung cancer development through prosurvival pathways. Although the mechanisms of nicotine-induced cell proliferation have been well studied in lung epithelial cells, the molecular mechanism of its action in bladder epithelial cells is still unclear. The aims of this study were to investigate whether there is nicotine-induced bladder epithelial cell proliferation and to identify the signaling transduction pathway regulated by nicotine. We found that nicotine simultaneously activates Stat3 and extracellular signal regulated kinase 1/2 (ERK1/2) in T24 cells. Stat3 activation via nicotinic acetylcholine receptor (nAChR)/protein kinase C signaling pathway was closely linked to Stat3 induction and nuclear factor-κB DNA binding activity, which is associated with Cyclin D1 expression and cell proliferation. ERK1/2 activation through nAChR and β-adrenoceptors plays a dual role in cell proliferation; it phosphorylates Stat3 at Ser727 and regulates cell proliferation. We conclude that through nAChR and β-adrenoceptors, nicotine activates ERK1/2 and Stat3 signaling pathways, leading to Cyclin D1 expression and cell proliferation. This is the first study to investigate signaling effects of nicotine in bladder cells. The current findings suggest that people exposed to nicotine could be at risk for potential deleterious effects, including bladder cancer development.




Should electronic cigarettes be as freely available as tobacco cigarettes? No.

The Medicines and Healthcare Products Regulatory Agency has decided to license electronic cigarettes as medicines from 2016. Simon Chapman agrees with regulation, seeing e-cigarettes as another way for big tobacco to try to make nicotine addiction socially acceptable again, but Jean-François Etter (doi:10.1136/bmj.f3845) says restrictions will result in more harm to smokers

Amid the feverish embrace of electronic cigarettes, come several statements by the tobacco industry that should cause public health proponents of such products to get a grip. For example, the chief executive of Reynolds America told shareholders in November 2012, just six months before entering the e-cigarette market, “We have a little mantra inside of the company . . . which we call the 80-90-90 . . . We spend about 80% of our resources in the combustible space. The combustible space is still 80%, 80+% of our operating income . . . [and] 90% of the organizational focus . . . And despite a lot of these new innovations that you see coming out, 90% of our R&D [research and development] budgets are actually directed at the combustible category . . . That is the category that’s still going to deliver a lot of growth into the future.”1


Big tobacco is not investing in e-cigarettes to wean itself off cigarette sales. Its recent

oleaginous rhetoric about them saving lives is utter duplicity. None of the big companies now in the e-cigarettes market have desisted from virulent opposition to policies that are known to reduce smoking. None has declared accelerated targets for reducing cigarette sales. As with other forms of smokeless tobacco, big tobacco wants smokers to use e-cigarettes as well as cigarettes, not instead of them. Its five goals are widespread dual use; retarding smoking cessation; resocialising public smoking back into fashion from its forlorn exile outside buildings; conveying to young, apprehensive would-be smokers that nicotine is a benign drug; and welcoming back lapsed smokers.

If big tobacco succeeds with any of these ambitions, e-cigarettes may cause a net increase in population harm. Urged on by myopic health professionals who seem to have lost any population health focus they might have had, this may become one of the biggest blunders of modern public health.

Public health enthusiasts for e-cigarettes see their promise as a way to get smokers to quit or reduce toxic exposure, but they seem blasé about the other possible effects described above. There are many impassioned, vocal testimonies that e-cigarettes have helped many thousands to quit or cut down smoking. But the first prospective study found that although smoking cessation and harm reduction motivated many e-cigarette users, there were no differences in smoking quit rates between e-cigarette users and non-users.2 And importantly, cutting down cigarettes rather than quitting confers little if any health benefit,3 so dual use may be as bad as continued smoking in terms of health outcomes.

Regulation is required

So how should we respond to e-cigarettes? The first step must be to move beyond anecdotal testimony and naive optimism and study large populations to build the evidence about whether e-cigarettes do accelerate quitting and to quantify behaviours indicative of the important industry goals above.

Tobacco use may kill a billion people this century,4 largely because of tobacco’s historic treatment as an unexceptional item of commerce and, later, decades of glacial action by governments failing to regulate this dangerous consumer product. But in the past 50 years, we have learnt much about how to reduce tobacco use—for example, only 15.7% of Australians aged 15 or over now smoke daily,5 and youth smoking has never been lower.6 We are finally pulling access to tobacco products back to where it should have started: expensive, highly regulated, non-advertised, plain packaged, and out of retail sight.

We should make none of the many disastrous mistakes made with cigarettes in the name of allowing e-cigarettes to compete better with cigarettes. We should start by not assuming they are benign items of commerce. Drug companies have long been able to sell nicotine in small doses as a quitting aid but have never tried to register high dose products. Their awareness of the role of nicotine in apoptosis, angiogenesis, inflammation, and cell proliferation7 8 9 has always put the brakes on any temptation to have regulatory agencies allow them to sell products with doses that genuinely compete with cigarettes. So why should e-cigarettes, for which users can create their own e-juice, escape such regulation?

Many smokers want to access e-cigarettes to quit or reduce risk, and they should not be denied this opportunity. But the needs of often desperate smokers must not become the tail that wags the dog of tobacco control policy, putting at risk the massive gains we have achieved. The advent of e-cigarettes provides a perfect pretext to introduce a form of user licence for nicotine products in the same way that access to potent drugs has long required a temporary licence (a prescription) for those who need them.10 This would balance the right to use e-cigarettes with all the constraints and disincentives that are now, and should be further, applied to cigarettes. For countries where e-cigarettes are virtually “off the leash” this will probably be impossible. But for most nations that have acted cautiously, e-cigarettes may in fact turn out to be a Trojan horse, stimulating regulators to take more seriously the regulation of all tobacco and nicotine products—not just pharmaceutical nicotine—regardless of the motive of the individual user or the stated and unstated motives of the manufacturer.


Cite this as: BMJ 2013;346:f3840


  • Competing interests: I have read and understood the BMJ Group policy on declaration of interests and have no relevant interests to declare.
  • Read Jean-François Etter’s side of the debate at doi:10.1136/bmj.f3845.
  • Provenance and peer review: Commissioned; not externally peer reviewed.


Moore M. Reynolds American’s CEO hosts investor day [transcript]. 2012. seekingalpha.com/article/1001691-reynolds-american-s-ceo-hosts-investor-day-transcript.

Adkison SE, O’Connor RJ, Bansal-Travers M, Hyland A, Borland R, Yong H-H, et al. Electronic nicotine delivery systems. International tobacco control four-country survey. Am J Prev Med2013;44:207–15.


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Proctor RN. Tobacco and the global lung cancer epidemic. Nature2001;1:82-7.

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Australian Bureau of Statistics. Australian health survey: first results, 2011-12.www.abs.gov.au/ausstats/abs@.nsf/Lookup/73963BA1EA6D6221CA257AA30014BE3E?opendocument.

Tobacco in Australia. Facts and issues. www.tobaccoinaustralia.org.au/chapter-1-prevalence/1-6-prevalence-of-smoking-secondary-students.

Zeidler R, Albermann K, Lang S. Nicotine and apoptosis. Apoptosis2007;12:1927-43.

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Chapman S. The case for a smoker’s license. PLoS Med2012;9:e1001342.



Source: BMJ



globalisation of unhealthy lifestyles.

Sauli Ninistö, President of Finland, opened the conference stressing that health is important for achieving other goals, but also has value in its own right. He spoke of Finland’s huge improvements in health since the 1940s achieved through investing the fruits of economic development in social and health infrastructure.

Congratulations to Margaret Chan, director general of the World Health Organization, for her powerful opening speech saying corporate interests on health pose a daunting challenge for health. She noted health is shaped by the “globalisation of unhealthy lifestyles,” leading to an epidemic of NCDs which is blowing out health budgets—e.g. diabetes consumes 15% of health budgets. Previously, progress has meant diseases vanished, whereas now NCDs are flourishing along with urbanisation and economic growth.

Chan said public health has been used to fighting Big Tobacco, but now also have to fight “Big Alcohol,” “Big Food,” and “Big Soda.”  She cast industry involvement in policy making as dangerous and leading to distortions. She pointed to the many tactics industry uses to water down public health measures. These include: civil society “front groups;” promising that self-regulation will be effective; industry funded research, which confuses the evidence; positioning government action to promote health as curbs on individual liberty. Her speech defined the problem well. Solutions are needed now!

On the opening panel, Alireza Marandi talked of Iran’s success in designing an effective primary healthcare system, which included reform of medical education. The Secretary of the Finnish Ministry of Agriculture and Forestry, Jaana Husu-Kallio, called for the “borders between professions” to be demolished in the interests of health and noted the need for a whole of government approach to food policy covering food security, production, safety, and nutrition. Tarja Halonen, former President of Finland, said education and health are “the tools of wellbeing.” There was much discussion about how the lessons from the Framework Convention on Tobacco Control can be applied to other areas and agreement that legal instruments should be more widely used to protect public health.

The afternoon’s panel on political will for Health in All Polocies (HiAP) disappointingly has gave few clues about how to create the will. The best suggestion was from Abdellatif Mekki, minister of health of Tunisia, who suggested that ministers of health should be vice presidents to give them more power, which they can then use against, for example, trade ministers who promote unhealthy industries like sugar.

I ended the day in a session on agriculture policy, food, and health. Bibi Giyose, from the African Union, reminded us that women make up more than 75% of food producers in Africa.  Priorities for nutritional sensitive agriculture are female empowerment, ensuring product diversity, and that processing sees food retaining its nutritional value. Yet we heard that global food chains dominate, rather than local food for local consumption, and that free trade agreements encourage unhealthy food supply. Fast food and supermarkets have increased massively. How do we change our food supply away from ultra processed food? Eating it seems to be killing people around the world!

Source: BMJ



Why real name HIV testing won’t fly in China

Two interesting documents that came across my desk this week got me thinking about how different HIV-related human rights look depending on where you’re standing. The first was a press release from UNAIDS, UNDP, and the International Commission of Jurists about the first ever judicial dialogue about HIV, human rights, and the law. The second was a news story from the China Daily about legislation recently passed in Guangxi Zhuang autonomous region requiring real names to be used for HIV tests.

The authorities in Guangxi, including doctors charged with the task of treating people who are living with HIV, and keeping the epidemic under control, have sound reasons for wanting to use real name testing. They say it will reduce loss to follow-up and it will be easier to track people down and convince them to get treated. It will also contribute to better public health policymaking because the region will have a more accurate picture of its HIV epidemic.

No it won’t, AIDS NGOs say, because people won’t come forward for testing in the first place, never mind being lost to follow-up. Instead they will at best do home self-testing, which is not accurate, and could leave them with a positive test result and no clue what to do next.

It’s a typical example of how public health policy often serves the needs of the health system instead of the patients. One of the main reasons patients prefer anonymous testing is that they want to know their status but have no inclination to share that information. Once the information leaks out of the medical system, all too common in a society where individuals’ rights are routinely trampled on by the state, people living with HIV are subject to widespread stigma and discrimination.

2009 survey conducted by the China Stigma Index found that over 49% of people living with HIV interviewed had experienced discrimination related to their HIV status. Over three quarters said their family had suffered the same discrimination. Pregnant women living with HIV are routinely advised to terminate their pregnancies: 12% of the respondents reported being pressured into having an abortion. The children of 9% of respondents were forced to leave school regardless of their own HIV status. Discrimination by medical staff, teachers, and government officials was rampant.

So I think it’s great that eminent judges from the Asia Pacific region gathered to discuss what they can do to provide a supportive legal environment for people living with HIV and to protect those particularly vulnerable to being infected. The conversation has to start somewhere, and there were Mainland Chinese judges participating in this ground breaking event.

But for people on the receiving end of public policy about HIV, it will be a long while yet before the target of zero discrimination is reached. And until that time, the Guangxi authorities would do well to turn around in their minds the conundrum of how to combat HIV and look at it from the perspective of their patients. Until they can guarantee that those who test positive won’t feel the chill of stigma from the very same healthcare workers responsible for testing and treating them, and until their communities are educated out of shunning them, real name testing is still just a good idea in theory.

I declare that I have read and understood the BMJ Group policy on declaration of interests and I have no relevant interests to declare.

Jane Parry is a Hong Kong based public health and medical journalist and researcher.

Source: BMJ


How can governments globally get “Big Food” to change its addiction to sugar and fat?

It was good to hear Pekka Puska present Finland’s health promotion success which has resulted in an 80% reduction in cardiovascular disease over 30 years. He stressed that this has been a long term complex process. The Finns realised early on that victim blaming doesn’t work and that changing the environment is vital. So they regulated food supply so it was lower in fat and salt and worked with the food industry to encourage them to make food healthier. Subsidies for dairy products were reduced and dairy farmers were encouraged to change to berry farming. Finland’s experience raises the question of how governments globally can get “Big Food” to change its addiction to sugar and fat?

Ravi Narayan presented a civil society perspective and noted the rapidly increasing inequities occurring everywhere. He spoke of the importance of listening to people at the grassroots and hearing their concerns. He stressed the importance of solidarity to social movements and the crucial importance of involving civil society in all policy making. He documented the mechanism society uses including “watches” such as the People’s Health Movement Global Health Watch, health tribunals, health assemblies, and campaigns. He spoke of the importance of social vaccines that build active civil society movements to protect health. Ravi also stressed the importance of seeing people not just as patients and customers, but also as citizens who can help plan and shape the style of health and other services. He also spoke of his work training “activist health professionals.”

The next plenary was on capacity bullding. Viroj Tangcharoensathien described the sophisticated Thai approach to Health in All Policies (HiAP) which uses constitutional mandates, regulation, citizen engagement through the Thai National Health Assembly, and organisational capacity development. Thailand offers many lessons for progressive health policy. Ilona Kickbusch (described by the chair as “the mother of health promotion”) talked about health as an overall societal goal which needs whole of government commitment. She stressed speed and agility as crucial skills to navigate health promotion systems. She also noted that complexity science and political science are essential to understanding HiAP processes because policy processes are chaotic and political. She says HiAP is an ever moving target and its work is never done. Stakeholder and network analysis and management are also crucial skills for HiAP. Learning systems are required where people can experiment and make mistakes and so keep their courage for challenging the status quo. She also spoke of the need for both hard (law) and soft (incentives) governance. This session would have benefited from a sharper analysis of how power interacts within and outside organisations to restrict capacity for action.

Work is progressing on the Helsinki Declaration and participants are invited to comment on drafts in plenary sessions and by email. It will be hard to come up with as robust a document as the Ottawa Charter. The conference is flagged as a green conference, but I wonder about the excessive use of bottled water when Finnish tap water perfectly is fine to drink!

Fran Baum is a professor of public health. She is the director of the Southgate Institute of Health Society and Equity, Flinders University, Adelaide, Australia, and is a member of the Global Steering Committee, People’s Health Movement. She is an Australian Research Council Federation fellow.

Source: BMJ


Dua Layer: Previously undetected part of the eye spotted for first time

Has pancreatic damage from glucagon suppressing diabetes drugs been underplayed?.

Incretin mimetics have been called “the darlings of diabetes treatment” and they may soon also be licensed for treating obesity. But a BMJ investigation has found growing safety concerns linked to the drugs’ mechanism of action. Deborah Cohen asks why patients and doctors have not been told.

They’ve been touted as the “new darlings of diabetes treatment”—the biggest breakthrough since the discovery of insulin nearly a hundred years before. The so called incretin therapies—glucagon-like peptide-1 (GLP-1) agonists and dipeptidylpeptidase-4 (DPP-4) inhibitors—looked as if they might change the face of type 2 diabetes. Their dual action of switching on insulin and suppressing glucagon to help control blood glucose was the ultimate in diabetes care.

The promise of a Nobel prize for the investigators loomed large. Scientists had discovered a treatment that could potentially modify disease progression. Studies in experimental animals showed that GLP-1 caused a proliferation in new insulin producing β cells. The hope was that these new cells might be able to replace those that died off in the course of human diabetes.

Nor did the promise end there. GLP-1 acts on the brain to makes people feel less hungry and the more powerful drugs aid weight loss—rather than weight gain like many antidiabetic drugs before them.

It’s an effect companies are seeking to market in its own right. Spurred on by the US Food and Drug Administration’s willingness to license new obesity treatment, Novo Nordisk’s chief science officer Mads Krogsgaard Thomsen said last year that the “political establishment in the US now knows that behaviour change alone is not enough.”1

His company’s drug, liraglutide, is in the process of late stage clinical tests, which Thomsen says show promising results.

But an investigation by the BMJ suggests Thomsen’s confidence might be optimistic. Concerns held by some specialists about the potential side effects of GLP-1 drugs have emerged into the mainstream after both the FDA and the European Medicines Agency announced in March that they would launch a review into whether the drugs may cause or contribute to the development of pancreatic cancer.

As yet neither agency has reached any conclusions, but they are meeting to discuss the matter later this month. And, as this investigation has found, for the regulators it is not a new concern. Over the years, drug assessors have become increasingly concerned that the incretin drugs have the potential for unwanted proliferative effects.

Expert concerns

Concerns long held by some experts about the potential side effects of incretin mimetics have gathered momentum with three publications this year. An independent analysis of health insurance data published in February found that people taking exenatide and sitagliptin were at twice the risk of hospital admission for acute pancreatitis compared with people taking other antidiabetic drugs2—the absolute risk 0.6%. And in April an analysis of data from the US Food and Drug Administration’s adverse event reporting system showed an increase in reports for pancreatitis and pancreatic cancer in people taking incretin mimetics compared with those taking other antidiabetic drugs.3

The FDA and EMA have both confirmed to the BMJ that their own analyses also show increased reporting or signals of pancreatic cancer with incretin mimetics. But they emphasise that this does not mean the relation is causal.

Both agencies announced in March that they will review data from a study just published showing pre-cancerous and dysplastic changes to the pancreas in organ donors exposed to incretin mimetics.4

The evidence is fiercely contested, with manufacturers stoutly defending the safety of their products. Merck, for example, told the BMJ that independent observational studies and a meta-analysis of clinical trials involving 33 881 patients found no association between DPP-4 inhibitors and pancreatic cancer. Bristol-Myers Squibb says that “post-marketing data does not confirm a causal relationship between saxagliptin or exenatide and pancreatitis and/or pancreatic cancer” (see bmj.com for full questions and answers with manufacturers).

But a “Dear Doctor” letter from Bristol-Myers Squibb and AstraZeneca on the UK Medicine and Healthcare Products Regulatory Agency’s website says: “A review of reports of pancreatitis from post-marketing experience revealed that signs of pancreatitis occurred after the start of saxaglitpin treatment and resolved after discontinuation, which is suggestive of a causal relationship. Moreover, pancreatitis has been recognized as an adverse event for other DPP-4 inhibitors.”5 A spokeswoman for Boehringer Ingelheim told the BMJ: “Pancreatitis has been reported in clinical trials and spontaneous post marketing sources. Guidelines for the use of linagliptin in patients with suspected pancreatitis are included in the prescribing information of the treatment.”

The increasingly fractious debate among scientists and doctors was played out last month in the specialty journal Diabetes Care.

Experienced GLP-1 investigator, Professor Michael Nauck, head of the Diabeteszentrum in Bad Lauterberg, Germany, and a consultant to many of the manufacturers, argued that the published evidence against the drugs is weak. “The potential harms and risks typically refer to rare events and are discussed in a controversial manner,” he wrote.6 But a team of four academics from the US and UK (one an expert witness in litigation against one of the manufacturers) suggested that neither the safety nor the effectiveness of the class can be assumed. “The story is familiar. A new class of antidiabetic agents is rushed to market and widely promoted in the absence of any evidence of long-term beneficial outcomes. Evidence of harm accumulates, but is vigorously discounted,” they wrote in their response. 7

In the course of this investigation, the BMJ has reviewed thousands of pages of regulatory documents obtained under freedom of information and found unpublished data pointing to unwanted proliferative or inflammatory pancreatic effects.

The BMJ has also found that, despite published reports that indicated safety concerns, companies have not done critical safety studies; nor have regulators requested them. And access to raw data that would have helped resolve doubts about the safety of these drugs has been denied.

On their own, the individual pieces of unpublished evidence may seem inconclusive — increases in size and abnormal changes in animal pancreases, raised pancreatic enzyme concentrations in humans, reports of thyroid neoplasms, and pancreatitis in early clinical trials.

But when considered alongside other emerging and long standing evidence—such as concerns about the effect of GLP-1agonists on α cells first published in 19998; the presence of the GLP-1 receptor on cells other than the target pancreatic β cell; and increasing signals from regulatory databases2 9—a more coherent and worrying picture emerges, posing serious questions about the safety of this class of drug.

What’s going on in the pancreas?

In a world where the prevalence of type 2 diabetes is increasing rapidly, finding new targets for therapy is a high priority for drug companies. The discovery by scientists in the 1970s and the then publication in 1993 by Michael Nauck of the double action of GLP-1 (glucagon-like peptide-1) provided just such a target.

GLP-1 is a hormone-like peptide released by the intestine in response to a meal; its functions include regulating insulin and blood glucose and slowing gastric emptying. In his study, Nauck found that GLP-1 both increased the insulin made in the pancreas and, by inhibiting the secretion of glucagon, reduced the glucose released by the liver. Excessive glucose release by the liver underpins the high circulating glucose that defines type 2 diabetes. Following secretion, GLP-1 is quickly inactivated by an enzyme, dipeptidyl peptidase-4 (DPP-4). The GLP-1 drugs are either analogues that are not inactivated by DPP-4, taken by injection (exenatide, liraglutide) or oral drugs that inhibit DPP-4 (sitagliptin, saxagliptin, and linagliptin).

The saliva of the desert dwelling Gila monster was the source for the first GLP-1 analogue on the market, exenatide. A heavy slow moving lizard, it eats once or twice a year, and uses the secretion of its salivary hormone exendin-4—which displays similar properties to GLP-1—to induce proliferation of its pancreas and gut to assimilate a meal. Some say this should have provided a valuable clue to the unwanted effects of raised circulating levels of a hormone that usually lasts for only minutes before it is broken down.

But now that most of the other treatments for type 2 diabetes are off patent, these are valuable drugs. Merck’s market leading drug sitagliptin generated about $4.1bn (£2.6bn; €3bn) in sales in 2012 with liraglutide’s 2012 sales of $1.7bn coming in behind. The profit margins mean there is much at stake for the companies and the organisations and doctors who depend on their support.

However, serious doubts about the wisdom of basing treatments on GLP-1 agonists have existed since the beginning. And the companies and regulators have, on reflection, had in their hands ample warning signs—and chance to resolve some of the emerging controversies.

In 2005, the New England Journal of Medicine published a study that showed pancreatic changes in patients who had a type of gastric bypass surgery called Roux-en-Y. The authors noted hypertrophy and hyperplasia of the islet cells, also affecting the cells in the pancreatic ducts. They thought this might be due to raised levels of the hormone GLP-1, which were known to occur after this type of procedure.21 (A later study on this type of surgery also showed a “pronounced” increase in α cell mass22).

Senior executives from Amylin and Lilly wrote to the New England Journal to distance their drug from the paper and to stress the lack of evidence of a pathological effect on the islets in animal studies. “A study of nine months’ duration in healthy cynomolgus monkeys at doses of more than 400 times those used in humans showed minimal-to-mild islet hypercellularity with no increase in islet size (data on file, Amylin Pharmaceuticals),” they said.

The suppression of glucagon by incretin mimetics was highlighted by companies in their drug licensing applications and was noted by regulators. Billions of dollars of sales later, after concerns have been raised about the safety of glucagon suppression and its effect on glucagon producing α cells, the extent to which they do this is being contested.

Butler and colleagues’ finding of α cell hyperplasia in humans taking GLP1 based drugs4 was not the first. In 1999 GLP-1 researcher Joel Habener and a team at Harvard found that exendin-4 (exenatide) induced an increase in α cells in rats.8

But evidence of α cell hyperplasia has come from multiple models and sources—including the companies themselves. Whether this is applicable to GLP-1 based treatments is subject to fierce debate.

Only last October, Professor Dan Drucker, a long standing consultant to many of the companies, gave a keynote lecture at European Association for the Study of Diabetes conference. “The therapeutic window for reduction of glucagon action to manifest beneficial effects for glucose control while avoiding enhancement of hepatic lipid storage, dyslipidemia, hepatocyte injury, and α-cell proliferation in diabetic subjects is unclear,” the official conference journal reported.23

Others in industry have previously highlighted the important role of glucagon suppression in the control of diabetes. In 2005 at a session entitled “GLP-1s: the new darlings of diabetes treatment” Jens Holst, scientific director of the Novo Nordisk Foundation for Metabolic Research at Copenhagen University and a long standing consultant to the company, told the American Diabetes Association annual conference that GLP-1 agonists were a powerful inhibitor of glucagon secretion, adding that he thought this would be “a very important action to diabetes patients.”

A spokesperson for Novo Nordisk acknowledged an effect on α cells but only from full not partial glucagon suppression. She told the BMJ: “Complete removal or blocking of the glucagon receptor, or important signalling components, have caused α cell hyperplasia. This is separate from the relatively modest lowering of glucagon secretion induced by GLP-1.”

The BMJ asked Drucker about this. In response he sent a copy of an article he had written in Cell Metabolism, but this did not describe α cell effects.24 Yet the BMJhas found that the companies were aware of the unwanted effects of the full and partial suppression of glucagon before the incretin mimetics came onto the market.

At the turn of the century, Holst, working with scientists from Novo Nordisk, reported that glucagon suppression in mice resulted in massive enlargement of the pancreas and the proliferation of α cells (α cell hyperplasia).25 They concluded that α cells appear not just in the islets but in the pancreatic ductal epithelium—something that Butler and colleagues found. Importantly, this effect did not require complete blocking of glucagon receptors or the stopping of glucagon production. Even a partial reduction in the hormone signalling resulted in α cell hyperplasia, as shown by Eli Lilly in 2004.26 The Lilly team acknowledged that they hadn’t seen any neoplasia; the studies up until that point had been short—only four months long. They suggested that both glucagon and its receptor must be functional in order to maintain a feedback loop that restrains α cell growth “but the exact nature of this feedback loop is unclear.”26

Over the years, evidence of the effects of modifying glucagon signalling has mounted. In 2009 Run Yu, codirector of the carcinoid and neuroendocrine tumour programme at Cedars Sinai Hospital in Los Angeles, published a report in patients with a rare condition causing deficiencies in glucagon signalling.27 He found α cell hyperplasia and neuroendocrine tumours.

“In type 2 diabetes glucagon plays a role but there is a price to pay with reducing it,” he told the BMJ.

Yu said that he had shared his view with certain companies after the study came out. Because of agreements with the companies, he was unable to say which they were.

He then did a study in mice with decreased glucagon signalling that was far longer than any conducted by the companies. He found that neuroendocrine tumours invariably developed after formation of α cell hyperplasia and eventually led to death. Yu concluded that glucagon suppression was not a safe way to treat diabetes.28But whether this applies to GLP-1based therapies is still uncertain.

In the course of this investigation, the BMJ has looked at thousands of pages of regulatory documents from both the FDA and the EMA. There seems to be little discussion about the potential adverse effects of interfering with glucagon signalling on the α cell, even though the manufacturers spelt out —and the regulators noted—that glucagon suppression was one of the effects of the drugs. Michael Elashoff, a former FDA reviewer who has analysed the safety of the drugs, believes the regulators should have been more cautious in approving them.

“If some of the side effects can be anticipated in advance, then it seems incumbent upon the FDA to really force the companies to do real significant investigation of these potential side effects before the drug goes on the market and not leave it to experiment with actual patients taking the drug,” he said.

The FDA maintains that: “Long-term studies of incretin mimetics in rodents, dogs, and monkeys failed to demonstrate adverse pancreatic pathology or other toxicology reflective of a glucagon deficit that could be interpreted as a clear risk to human subjects.”

The BMJ asked the five companies who market incretin mimetics if they have ever studied the effects of glucagon suppression on the proliferation of α cells. Only Novo Nordisk responded to the question. It stressed that it had never seen α cell hyperplasia in any of its studies.29 30 31 “Alpha-cell hyperplasia is not mediated by the GLP-1 receptor,” a spokeswoman said. Behind the scenes, concerns also started to emerge about the potential inflammatory effects on the pancreas. Effects on pancreatic enzymes: Internal industry documents show that in 2005, one industry key opinion leader reported “extremely high” lipase levels in a patient taking exenatide. He was concerned that the company had missed signs of potential inflammation in its clinical trials.

Dennis Kim, then executive director at Amylin, wrote in an email that the doctor’s report was a “bit concerning” and confirmed that pancreatic amylase and lipase were not measured systematically in the company’s clinical trials.

The BMJ has found that companies have measured these enzymes for “safety issues,” but in many cases the data have not been reported in the published studies.

For example, in one Lilly funded trial comparing weekly exenatide with sitagliptin and two other diabetes treatments—insulin and pioglitazone—enzyme levels increased in a higher percentage of people taking incretin mimetics after 26 weeks of treatment.

Regulatory documents show the mean (SD) lipase concentration in the exenatide group increased from 42.0 (23.77) U/L on day 1 to 60.8 (38.39) U/L at week 26. Sitagliptin also increased lipase from 40.3 (21.3) U/L to 48.7 (30.7) U/L. The levels in the pioglitazone control dropped. However, when the trial was published in theLancet, these data did not make the final cut.32 The company did not say why when the BMJ put it to them. Neither did lead author, Richard Bergenstahl, answer theBMJ’s queries.

Earlier this year, the Lancet published another study funded by Eli Lilly and Amylin in which enzyme levels were measured but not reported.33 “Routinely measured concentrations of pancreatic lipase and total amylase varied in both groups and were not predictive of gastrointestinal symptoms,” the paper said.

The FDA says that the clinical value of routine amylase and lipase monitoring in asymptomatic patients is not clear. But pancreatologists, have told the BMJ that reporting enzyme levels is important because they may reflect a subclinical effect of the drug.

“Many large phase III trials report findings of significant biochemical abnormalities, even though the clinical significance may be uncertain at the time, and in this case where the drug is known to exert effects on the pancreas, I would find such information of value,” Thor Halfdanarson, a pancreatic surgeon, at the Mayo Clinic in Arizona said.

Indeed, writing in support of incretin mimetics in Diabetes Care last month, Michael Nauck said that the effect on pancreatic enzymes may be important.6 “Effects of GLP-1 receptor stimulation on pancreatic enzyme synthesis, potential leakage into the circulation rather than direct secretion into pancreatic digestive juice, and a potential induction if a chronic inflammatory response need to be studied,” he said.


Source: BMJ



Antibiotic prophylaxis for urinary tract infections after removal of urinary catheter: meta-analysis.


Objective To determine whether antibiotic prophylaxis at the time of removal of a urinary catheter reduces the risk of subsequent symptomatic urinary tract infection.

Design Systematic review and meta-analysis of studies published before November 2012 identified through PubMed, Embase, Scopus, and the Cochrane Library; conference abstracts for 2006-12 were also reviewed.

Inclusion criteria Studies were included if they examined antibiotic prophylaxis administered to prevent symptomatic urinary tract infection after removal of a short term (≤14 days) urinary catheter.

Results Seven controlled studies had symptomatic urinary tract infection after catheter removal as an endpoint; six were randomized controlled trials (five published; one in abstract form) and one was a non-randomized controlled intervention study. Five of these seven studies were in surgical patients. Studies were heterogeneous in the type and duration of antimicrobial prophylaxis and the period of observation. Overall, antibiotic prophylaxis was associated with benefit to the patient, with an absolute reduction in risk of urinary tract infection of 5.8% between intervention and control groups. The risk ratio was 0.45 (95% confidence interval 0.28 to 0.72). The number needed to treat to prevent one urinary tract infection was 17 (12 to 30).

Conclusions Patients admitted to hospital who undergo short term urinary catheterization might benefit from antimicrobial prophylaxis when the catheter is removed as they experience fewer subsequent urinary tract infections. Potential disadvantages of more widespread antimicrobial prophylaxis (side effects and cost of antibiotics, development of antimicrobial resistance) might be mitigated by the identification of which patients are most likely to benefit from this approach.


This meta-analysis of available data indicates an overall benefit of antibiotic prophylaxis at the time of removal of a urinary catheter to prevent subsequent urinary tract infections. The number needed to treat indicates that 17 patients would need to receive prophylaxis to prevent one symptomatic urinary tract infection. We know little, however, about the potential negative consequences of implementing antibiotic prophylaxis in this setting in a wider frame or indeed which types of patients would be most likely to benefit. Increasing antimicrobial resistance, healthcare costs for antibiotics, and the potential for side effects of antibiotic administration are disadvantages that merit careful review. From a public health standpoint, we should be careful not to encourage antibiotic use when it might not be necessary. The healthcare provider of a catheterized patient, however, might consider antibiotic prophylaxis before catheter removal, after taking individual risk factors into account. Future studies should better characterize who is at risk of developing symptomatic urinary tract infection after catheter removal (whether bacteriuric or not) and then examine antibiotic prophylaxis in those at greatest risk.

What is already known on this topic

  • Catheterization of the urinary tract is associated with an increased risk of bacteriuria and symptomatic urinary tract infection
  • Antibiotic administration at the time of removal of a urinary catheter might effectively reduce urinary tract infections, but guidelines for catheter associated infections note insufficient evidence to support this practice
  • Antibiotic prophylaxis at the time of urinary catheter removal in general surgery, prostatectomy, and medical patients effectively reduced the incidence of symptomatic urinary tract infections with a number needed to treat of 17
  • The effect size of antibiotic prophylaxis in this meta-analysis was stable to sensitivity analyses with exclusion of non-randomized trials and two studies in non-surgical patients

What this study adds.


Source: BMJ