Long-Term Antibiotics Reduce COPD Exacerbations, Raise Questions

Long-term use of a macrolide antibiotic may reduce the frequency of exacerbations in patients with moderate to severe chronic obstructive pulmonary disease (COPD) by as much as 35 percent, according to a London-based study.

“Our results show a significant effect of low-dose macrolide therapy, reducing exacerbation frequency and severity with moderate to severe COPD,” wrote lead author of the paper, Terence A. R. Seemungal, Ph.D., and Jadwiga Wedzicha, M.D., principle investigator.
The encouraging news comes on the heels of World COPD Day 2008 and a new report from the Centers for Disease Control and Prevention (CDC) that detailed the rising number of deaths related to COPD. More women than men now die of COPD, and while death rates for men have leveled, the rate is still increasing for women, according to the CDC.

The latest study is the first ever year-long randomized, double-blind, placebo-controlled study of the effects of erythromycin in COPD. The results were published in the first issue for December of the American Journal of Respiratory and Critical Care Medicine, which is published by the American Thoracic Society.

The researchers assessed and followed 109 patients with moderate to severe COPD for a year, after randomly assigning them to receive either a placebo or a twice daily 250 mg dose of erythromycin. The patients recorded their exacerbations and hospitalizations in a daily diary card, and they were assessed using spirometry, sputum testing and blood testing for lung function, bacterial infection and markers of inflammation.

The researchers found that not only did the patients randomized to receive erythromycin have fewer exacerbations, but among the patients studied, 60 percent of the exacerbations that occurred were within the placebo group. While the number of exacerbation-related hospitalizations was small, more than twice as many occurred among the placebo group-14 versus 6. The median duration of exacerbations from onset to resolution of symptoms was 9 days in the erythromycin group and 13 days in the placebo group.

“Our results did not allow us to determine a mechanism for these findings. However based on in-vitro studies we suspect that the mechanism is likely to involve the anti-inflammatory properties of erythromycin,” noted Dr. Seemungal.

While their findings are encouraging, Dr. Seemungal points out that they must be put in context with future findings. Furthermore, the threat of growing antibiotic resistance resulting from widespread prophylactic use of erythromycin is not a trivial concern. “In this scenario, substantial, widespread emergence of macrolide bacterial resistance is virtually foreordained, with attendant reduction in the antimicrobial usefulness of this drug class,” wrote Ken M. Kunisaki, M.D. and Denise E. Niewoehner, M.D., of the Veterans Affairs Medical Center in Minneapolis, in the accompanying editorial. “Balancing benefit against harm could pose a dilemma for which there might be no clear answers.”

Moreover, not all of the study patients were treated with guideline-recommended therapy, such as inhaled corticosteroids or inhaled long-acting bronchodilators, which have been shown to decrease exacerbation frequency. The degree of added benefit of erythromycin over and above standard therapy will require further study.

“Observations that any intervention might decrease the frequency and severity of acute exacerbations in COPD present considerable public health implications,” observed John Heffner, M.D., past president of the ATS. “Exacerbations occur about once a year among patients with moderate to severe COPD and account for more than $30 billion dollars in direct and indirect costs annually in the United States alone.”

“Many patients with advanced COPD receive highly potent, extended spectrum antibiotics during acute exacerbations,” commented Dr. Heffner. “The relative risks of breeding resistance with a long-term preventative use of erythromycin versus more frequent short-term dosing of highly potent antibiotics for acute exacerbations require careful analysis. If future studies demonstrate similar efficacy of prolonged erythromycin therapy, especially if patients are already receiving inhaled steroids and long-acting bronchodilators, the benefits likely will outweigh the risks.”

Caution For Pregnant Women Taking Antibiotics

Two studies published early online and in an upcoming edition of The Lancet find that when antibiotics are given to pregnant women experiencing premature labor, even with intact membranes and no infection, there is an increase in risk of functional impairment and/or cerebral palsy. These unexpected findings are the results of a study of long-term follow-up data from the ORACLE Children’s Study, authored by Dr Sara Kenyon (University of Leicester, UK) and colleagues from the ORACLE study group.Completed in 2001, the original ORACLE I and II trials were designed to see if the antibiotics erythromycin and co-amoxiclav could halt underlying infections in women threatening to give birth prematurely, and therefore delay or prevent premature birth and possibly improve outcomes in the first four weeks of life. The experiment was structured as a factorial randomized design, where mothers received placebo and erythromycin, placebo and co-amoxiclav, both antibiotics, or double-placebo. The ORACLE Children Study I and II were designed to analyze the long-term effects of the antibiotics on the children at 7 years of age that were born to these mothers.

In the ORACLE Children Study II, researchers looked at mothers who had spontaneous premature labor with intact membranes surrounding the unborn children and no obvious infection signs. Seven years after birth, a structured parental questionnaire was used to gather follow-up data on the health status of the children of the 4,221 women who had completed the study. The researchers were able to recover data for 71% (3196) of eligible children. The study revealed that in children whose mothers received erythromycin, there was an increase in functional impairment compared to children of mothers who had not received erythromycin - 42·3% to 38.3%, respectively. This translates to an increase in relative risk of 18% for receiving erythromycin. The researchers found no effect on children whose mothers received Co-amoxiclav - with or without erythromycin - concerning functional impairment.

Further, the investigators discovered that children were more likely to develop cerebral palsy who were born to mothers who had received the antibiotics - an unexpected finding. Specifically, 3.3% of children with mothers who received erythromycin (with or without co-amoxiclav) and 1.7% of children with mothers who did not receive the antibiotic had cerebral palsy. Similar numbers were found for children of mothers given co-amoxiclav (with or without erythromycin) - 3.2% and 1.9% developed cerebral palsy, respectively. For children of mothers given both antibiotics, the risk of cerebral palsy was highest - 4.4% of children had the disease compared to 1.6% of children with mothers who received double placebo. This is a tripling of risk.

The researchers did not conclude that either antibiotic had an effect on the number of deaths, other medical conditions, behavioral patterns, or educational attainment. “The prescription of erythromycin for women in spontaneous preterm labour with intact membranes was associated with an increase in functional impairment among their children at seven years of age. The risk of cerebral palsy was increased by either antibiotic, although the overall risk of this condition was low,” conclude Dr Kenyon and colleagues.

In the ORACLE Children Study I, researchers followed up 4,148 eligible children whose mothers joined the trial with preterm rupture of the membranes without obvious infection signs. Erythromycin is currently the recommended treatment since the original trial found that this antibiotic resulted in reductions in short term neonatal death. Seventy-five percent of eligible children (3,298) were assessed in The Children Study, and the researchers found no differences in functional impairment, behavioral difficulties, medical conditions, or educational achievement with either antibiotic. The researchers conclude that: “The prescription of antibiotics for women with preterm rupture of the membranes seems to have little effect on the health of children at seven years of age.”

Professor Philip J Steer (Chelsea and Westminster Hospital, London, UK) and Dr Alison Bedford Russell (Warwick Medical School and Heart of England NHS Trust, UK) write in an accompanying editorial that: “The lessons to be learned seem clear; contrary to popular opinion (’might as well give them, they don’t do any harm’), antibiotics are not risk-free. There are good reasons not to give them in association with threatened preterm labour unless there is clear evidence of infection. It is vital the practice is not extended by stealth beyond that which is justified by the evidence, and interventions given in pregnancy should always be evaluated with proper long-term follow-up.”

Get Well Soon - Without Antibiotics, UK

Government launches campaign in fight against infections

The latest phase in a campaign to remind the public that antibiotics do not help to treat viral infections such as cough’s, colds and a sore throat was launched today by the Chief Medical Officer for England.

Press adverts and posters will appear in newspapers and magazines from today are aimed at patients and Clinicians and are intended to reduce unnecessary requests for antibiotics from patients. The campaign forms part of the Government’s strategy to tackle the increasing problem antibiotic resistance which could make treatment for common bacterial infections such as pneumonia much more difficult in the future.Chief Medical Officer for England, Sir Liam Donaldson said:
“Antibiotics don’t work on colds, most coughs or sore throats or even the flu. Using antibiotics when they are not necessary will increase resistance to them and make it difficult to treat serious bacterial infections in the future.

“If you are suffering with cold and flu symptoms or a sore throat you should rest, take plenty of fluids and speak to your pharmacist who will advise you on over the counter remedies that are available.”

Antibiotic resistance is a global public health issue in which we all have a part to play in order to keep antibiotics effective. Latest data from the Health Protection Agency shows that resistance to the antibiotic most often used to treat E.Coli increased by 10% between 2001 and 2007. Bacteria will always try to find ways to survive by evolving and developing resistance to antibiotics so we must stay one step ahead of the game.

Notes

– Patients with colds do not normally need medical advice but should consult their doctor if they are worried or if:

- a cough lasts more than three weeks,
- they have shortness of breath or chest pains develop,
- if they already have a chest complaint.

Nanotechnology Used To Probe Effectiveness Of Antibiotics

A group of researchers led by scientists from the London Centre for Nanotechnology, in collaboration with a University of Queensland researcher, have discovered a way of using tiny nano-probes to help understand how an antibiotic is effective against bacteria.

Bacteria such as MRSA (commonly known as Golden Staph) are becoming increasingly resistant to antibiotics, posing a major community health problem.

Professor Matt Cooper, the Australian in the team, has this week joined the Institute for Molecular Bioscience at UQ on a $4 million Australia Fellowship.

Through the fellowship, he will establish a research program in the development of antibiotics and antifungals that are active against drug-resistant pathogens, in particular those responsible for hospital-acquired infections.

“It order to attack this problem we need to understand not only the ways in which bacteria develop and exhibit resistance to antibiotics, but also how new antibiotics can work to kill or slow the growth of resistant bacteria,” Professor Cooper said.

To study antibiotic action, the London team made nano-probes coated with molecules found in bacterial cell walls from normal bacteria and bacteria resistant to antibiotics.

They then added doses of the “last resort” antibiotic, vancomycin, to the system and found that probes from normal bacteria were stressed and changed shape, whereas probes from resistant bacteria were only weakly affected. These bent probes could be detected with a laser, indicating that the antibiotic was applying a force to the surface.

This allowed the researchers to quickly assess the effectiveness of an antibiotic and propose new ways in which antibiotics may be acting to cause the bacteria to burst and die.

“This advance will help us to understand the mode of action of drugs targeted against resistant bacteria, and could also lead to rapid diagnostic tools and novel methods of investigating antibiotic action,” Dr Cooper said.

“There is only a tiny molecular difference between resistant and non-resistant bacteria. We now know that these probes can detect that difference, and can do so within minutes.”

The system was able to detect that it is 1,000 times harder for vancomycin to attach to resistant bacteria than to non-resistant bacteria.

The team are now screening other novel antibiotics with the goal of finding a drug that is able to bind strongly to resistant bacteria and cause substantial structural weaknesses to the cell wall.

University College London researcher Dr Rachel McKendry, who led the team, said the findings had implications for improving the response to the bacteria.

“Investigating both these binding and mechanical influences on the cells’ structure could lead to the development of more powerful and effective antibiotics in future,” Dr McKendry said.

The research was published late last year in the journal Nature Nanotechnology.

The University of Queensland, Brisbane Australia

Researchers Develop Novel Antibiotics That Don’t Trigger Resistance

Bacterial resistance to antibiotics is one of medicine’s most vexing challenges. In a study described in Nature Chemical Biology, researchers from Albert Einstein College of Medicine of Yeshiva University are developing a new generation of antibiotic compounds that do not provoke bacterial resistance. The compounds work against two notorious microbes: Vibrio cholerae, which causes cholera; and E. coli 0157:H7, the food contaminant that each year in the U.S. causes approximately 110,000 illnesses and 50 deaths.

Most antibiotics initially work extremely well, killing more than 99.9% of microbes they target. But through mutation and the selection pressure exerted by the antibiotic, a few bacterial cells inevitably manage to survive, repopulate the bacterial community, and flourish as antibiotic-resistant strains.

Vern L. Schramm, Ph.D., professor and Ruth Merns Chair of Biochemistry at Einstein and senior author of the paper, hypothesized that antibiotics that could reduce the infective functions of bacteria, but not kill them, would minimize the risk that resistance would later develop.

Dr. Schramm’s collaborators at Industrial Research Ltd. earlier reported transition state analogues of an enzyme that interferes with “quorum sensing” the process by which bacteria communicate with each other by producing and detecting signaling molecules known as autoinducers. These autoinducers coordinate bacterial gene expression and regulate processes including virulence that benefit the microbial community. Previous studies had shown that bacterial strains defective in quorum sensing cause less-serious infections.

Rather than killing Vibrio cholerae and E. coli 0157:H7, the researchers aimed to disrupt their ability to communicate via quorum sensing. Their target: A bacterial enzyme, MTAN, that is directly involved in synthesizing the autoinducers crucial to quorum sensing. Their plan: Design a substrate to which MTAN would bind much more tightly than to its natural substrate so tightly, in fact, that the substrate analog permanently “locks up” MTAN and inhibits it from fueling quorum sensing.

To design such a compound, the Schramm lab first formed a picture of an enzyme’s transition state the brief (one-tenth of one-trillionth of a second) period in which a substrate is converted to a different chemical at an enzyme’s catalytic site. (Dr. Schramm has pioneered efforts to synthesize transition state analogs that lock up enzymes of interest. One of these compounds, Forodesine, blocks an enzyme that triggers T-cell malignancies and is currently in a phase IIb pivitol clinical study treating cutaneous T-cell leukemia.)

In the Nature Chemical Biology study, Dr. Schramm and his colleagues tested three transition state analogs against the quorum sensing pathway. All three compounds were highly potent in disrupting quorum sensing in both V. cholerae and E. coli 0157:H7. To see whether the microbes would develop resistance, the researchers tested the analogs on 26 successive generations of both bacterial species. The 26th generations were as sensitive to the antibiotics as the first.

“In our lab, we call these agents everlasting antibiotics,” said Dr. Schramm. He notes that many other aggressive bacterial pathogens S. pneumoniae, N. meningitides, Klebsiella pneumoniae, and Staphylococcus aureus express MTAN and therefore would probably also be susceptible to these inhibitors.

While this study involves three compounds, Dr. Schramm says that his team has now developed more than 20 potent MTAN inhibitors, all of which are expected to be safe for human use: Since MTAN is a bacterial enzyme, blocking it will have no effect on human metabolism.

Other Einstein researchers involved in the study were Jemy Gutierrez, the lead author, Tamara Crowder, Agnes Rinaldo-Matthis, M. C. (Joseph) Ho and Steven C. Almo. The powerful inhibitors were reported in an earlier publication in collaboration with the Carbohydrate Chemistry Team of Industrial Research Ltd., in New Zealand.

The study, “Transition State Analogs of 5′ Methylthioadenosine Nucleosidase Disrupt Quorum Sensing” by Vern L. Schramm et al., appears in the March 8, 2009 online edition of Nature Chemical Biology.

The compounds in this paper have been licensed to Pico Pharmaceuticals, which plans to develop and initiate clinical trials of transition-state analogues. Dr. Schramm is a Pico Pharmaceuticals co-founder and chairman of its scientific advisory board.

About Albert Einstein College of Medicine of Yeshiva University

Albert Einstein College of Medicine of Yeshiva University is one of the nation’s premier centers for research, medical education and clinical investigation. It is the home to some 2,000 faculty members, 750 M.D. students, 350 Ph.D. students (including 125 in combined M.D./Ph.D. programs) and 380 postdoctoral investigators. Last year, Einstein received more than $130 million in support from the NIH. This includes the funding of major research centers at Einstein in diabetes, cancer, liver disease, and AIDS. Other areas where the College of Medicine is concentrating its efforts include developmental brain research, neuroscience, cardiac disease, and initiatives to reduce and eliminate ethnic and racial health disparities. Through its extensive affiliation network involving five hospital centers in the Bronx, Manhattan and Long Island which includes Montefiore Medical Center, The University Hospital and Academic Medical Center for Einstein the College runs one of the largest post-graduate medical training program in the United States, offering approximately 150 residency programs to more than 2,500 physicians in training. For more information, please visit http://www.aecom.yu.edu.

New Research Strives To Understand How Antidepressants May Be Associated With Suicidality

The National Institute of Mental Health (NIMH), part of the National Institutes of Health, is funding five new research projects that will shed light on antidepressant medications, notably selective serotonin reuptake inhibitors (SSRIs), and their association with suicidal thoughts and actions (suicidality).
Studies have shown that most individuals suffering from moderate and severe depression, even those with suicidal thoughts, can substantially benefit from antidepressant medication treatment. However, use of SSRIs in children and adolescents has become controversial. In 2005, the U.S. Food and Drug Administration (FDA) adopted a “black box” warning–the most serious type of warning in prescription drug labeling–for all SSRIs. The notice alerts doctors and patients of the potential for SSRIs to prompt suicidal thinking in children and adolescents, and urges diligent clinical monitoring of individuals of all ages taking the medications. This can be particularly challenging because it is difficult for patients, their family members and practitioners to determine whether suicidal thoughts may be related to the depression, the medication, or both.

“These new, multi-year projects will clarify the connection between SSRI use and suicidality,” said NIMH Director Thomas Insel, M.D. “They will help determine why and how SSRIs may trigger suicidal thinking and behavior in some people but not others, and may lead to new tools that will help us screen for those who are most vulnerable,” he added.

The projects are listed below.

* Kelly Kelleher, M.D., of Columbus Children’s Hospital and the Ohio State University, and Joel Greenhouse, PhD, of Carnegie Mellon University, will build on data initially collected by the FDA to analyze antidepressant medication use and suicidal behavior among youth, adults and older adults. Dr. Kelleher will use new and more sensitive statistical approaches to integrate data from numerous other studies–both randomized and non-experimental–to paint a more complete picture of the relationship between antidepressant medication use and suicidal thoughts or actions.

* Marcia Valenstein, M.D., of the University of Michigan, will examine the records of 994,000 individuals from the U.S. Department of Veterans Affairs National Registry for Depression, Medicare records and the National Death Index to determine what relationships exist between the use of antidepressants and suicide attempts and/or deaths, and use of any concurrent medications or treatments. The study will help determine the relative effectiveness of different depression treatments in reducing suicidal thoughts and actions.

* Wayne Goodman, M.D., of the University of Florida, will investigate if and how SSRIs may induce in some young people an “activation syndrome”–a set of symptoms such as irritability, agitation and mood swings that may lead to suicidal thoughts or actions. He will study this potential syndrome among pediatric patients diagnosed with obsessive compulsive disorder. By focusing on patients with a disorder that is less likely to be associated with suicidality, he will be able to better assess whether SSRIs are related to an actual activation syndrome, and whether suicidality is a component of the syndrome. The study will improve recognition and understanding of the syndrome, and help identify interventions that will reduce the risk of suicide.

* Sebastian Schneeweiss, M.D., of Brigham and Women’s Hospital, will assess critical issues surrounding the safety of antidepressant medication use by comparing several large datasets of SSRI users. He will measure rates of suicidality; identify social and demographic factors that may be associated with SSRI use and suicidality; and examine the impact of FDA actions on use of SSRIs. The study aims to develop and better target prescribing and risk management strategies.

* Prudence Winslow Fisher, PhD., of the New York State Psychiatric Institute, will develop better and more reliable ways of monitoring for adverse reactions to the use of antidepressant medication. The study’s long-term goal is to construct a standardized computer tool for adolescents and parents that could be used to screen for suicidality associated with the use of antidepressant medications.

Antidepressants Associated With Increased Risk For Suicide Attempts, Decreased Risk For Death

Suicidal individuals taking antidepressant medications appear to have an increased risk of additional suicide attempts, but a reduced risk of dying from suicide or any other cause, according to a large Finnish study reported in the December issue of Archives of General Psychiatry, one of the JAMA/Archives journals.Major depression is one of the most important risk factors for suicidal behavior, according to background information in the article. However, medications used to treat depression have also been linked to suicidal attempts and behavior, especially among children and adolescents taking a type of antidepressant known as selective serotonin reuptake inhibitors (SSRIs). The issue is difficult to study because the number of completed suicides is relatively low; an effective study would have to include tens of thousands of patients and last for several years. “Because previous suicide attempts are the most important risk factor for predicting suicide, a large cohort of suicidal patients would be an obvious choice to investigate the association between antidepressant treatment and the risk of suicide,” the authors write.

Jari Tiihonen, M.D., Ph.D., University of Kuopio and Niuvanniemi Hospital, Kuopio, Finland, and colleagues analyzed data from all individuals hospitalized in Finland for suicide attempts between 1997 and 2003. Information about 15,390 hospitalized individuals - including age, sex, location, dates of admission and discharge, number of previous hospitalizations for attempted suicide and antidepressant prescriptions - was gathered through Finnish national registries and databases. The patients were followed for an average of 3.4 years to see if they attempted suicide again, completed suicide or died from another cause.

Among the 7,466 males and 7,924 females in the study, 602 suicides, 7,136 suicide attempts leading to hospitalization and 1,583 deaths were recorded during follow-up. The risk of completed suicide was 9 percent lower among those taking any antidepressants than among those not taking antidepressants. However, the association varied by antidepressant-individuals taking an SSRI known as fluoxetine had a 48 percent lower risk of suicide (6.7 deaths per 1,000 total years that individuals took the drug) compared with those not taking medication (11 deaths per 1,000 years), while those taking venlafaxine hydrochloride, another SSRI, had a 61 percent increased risk (22.5 suicide deaths per 1,000 total years of medication use). The risk of death from any cause was 31 percent to 41 percent lower among those taking antidepressants. Those taking SSRIs had a 61 percent reduced risk of death compared with those taking no antidepressants, a fact that could be attributed to a reduction in deaths related to cardiovascular disease and stroke.

Patients taking any kind of antidepressant had a 36 percent increased risk of a subsequent suicide attempt leading to hospitalization (204.7 per 1,000 total years of taking medications) compared with those taking no antidepressants (106.2 per 1,000 years); a slightly greater increase in risk was observed among those age 10 to 19 years (132.7 per 1,000 years for those taking antidepressants vs. 82.9 for those not taking antidepressants).

Among those who had ever taken antidepressants, current antidepressant use was associated with a 39 percent increase in risk of attempted suicide but a 32 percent decrease in risk of completed suicide and a 49 percent reduced risk of death from any cause. “This opposite type of effect on fatal vs. nonfatal suicidal behavior may be explained by an increased risk of intoxication because of easy availability of means (antidepressant medication), resulting in an increase in nonfatal suicidal behavior, and by a decrease in the incidence of violent and more fatal methods of suicide attempts, such as hanging and shooting,” the authors write.