RxPG News : Antibiotics

Nanostructures lend cutting edge to antibiotics

Tue, 05 Apr 2011 15:25:22 PST

( from http://www.rxpgnews.com ) London, April 4 - Arming antibiotic drugs with nanostructures would make them much more effective in targeting infected cells.

These tiny particles would zoom in on infected cells but leave the healthy ones unharmed, according to a study by IBM Research.

James Hedrick, advanced organic materials scientist at IBM Research, said: 'The number of bacteria in the palm of a hand outnumbers the entire human population,' reports the journal Nature Chemistry.

'With this discovery, we've been able to leverage decades of materials development traditionally used for semiconductor technologies to create an entirely new delivery mechanism that could make drugs more specific and effective,' said Hedrick, according to the Telegraph.

'Using our novel nanostructures, we can offer a viable therapeutic solution for the treatment of MRSA - and other infectious diseases,' added Yiyan Yang, group leader at the Institute of Bioengineering and Nanotechnology in Singapore, who also worked on the project.

'This exciting discovery effectively integrates our capabilities in biomedical sciences and materials research to address key issues in conventional drug delivery,' Yang added.

The nanoparticles are physically attracted to infected cells like a magnet, which means they can eradicate bacteria without destroying healthy cells.

They also act in a different way to traditional antibiotics as they have been designed by the researchers to break through the membranes and walls in bacterial cells, which is hope will prevent the bacteria developing resistance to drugs.

Inhibition of protein HipA pevents cell dormancy and bacterial persistence

Thu, 15 Jan 2009 14:32:01 PST

( from http://www.rxpgnews.com ) Bacteria hunker down and survive antibiotic attack when a protein flips a chemical switch that throws them into a dormant state until treatment abates, researchers at The University of Texas M. D. Anderson Cancer Center report in the Jan.16 edition of Science.

"For antibiotics to work, bacteria have to be growing. Dormancy stops everything, allowing some bacteria to persist after treatment," said senior author Richard Brennan, Ph.D., professor in M. D. Anderson's Department of Biochemistry and Molecular Biology.

By demonstrating in detail how the HipA protein freezes bacterial activity, the researchers have opened the possibility of adding a new class of drugs to therapy against chronic and multidrug resistant bacterial infection.

Working in Escherichia coli, the team solved the structure of HipA and several of its protein complexes down to the atomic level, confirming that HipA is a protein kinase - an enzyme that works by transferring phosphate groups to its target molecules.

HipA is a type of protein kinase that is uncommon in bacteria, said lead author Maria Schumacher, Ph.D., associate professor of biochemistry and molecular biology. While other types of phosphorylation occur in bacteria, HipA phosphorylates proteins at their serine or threonine amino acids. This kinase activity is more commonly associated with eukaryotic cells, which make up animals, plants and fungi, and are generally thought to be more complex.

"These 'simple bacteria' are so complex. We're finding that life is sophisticated at all levels," Schumacher said. HipA is active in other types of gram-negative bacteria, which cause significant human bacterial infections.

Inhibitor could make persistent cells 'vanish'

A number of cancer drugs inhibit kinase activity in specific targets.

"If you stop HipA from working, there essentially is no persistence," Brennan said. "We need to see whether kinase inhibitors will bind to and block HipA's active site. If they work, persistent cells, which are already rare, would vanish." Persistent cells are a one-in-a-million-cells occurrence because HipA is normally kept in check by a protein called HipB.

Persistence is common in "biofilms," bacterial colonies that become attached to a surface in a supportive matrix. Drug-resistant biofilms cause about 60 percent of infections in the developed world, the researchers note.

Overexpression of HipA previously had been associated with cell dormancy and bacterial persistence. Evidence had pointed to kinase activity.

Schumacher, Brennan and colleagues demonstrated the molecular details of HipA's role in multidrug tolerance and HipB's role keeping HipA under wraps in a series of experiments:

Using X-ray crystallography to determine and then compare the structures of several HipA complexes, they showed that HipA has a serine/threonine protein kinase fold and that it binds tightly to adenosine triphosphate (ATP), a common characteristic of kinases. Phosphorylation occurs when an enzyme binds to both ATP and to its target protein.
Assays of candidate proteins to identify a target for HipA found that EF-Tu interacts strongly with HipA in the presence of ATP. EF-Tu is the most abundant protein in E.coli and plays an essential role in protein synthesis.
Subsequent experiments and structural analysis of a HipA/EF-Tu peptide complex indicated that HipA phosphorylates EF-Tu, freezing up the bacteria's protein-making machinery and inducing dormancy.
To analyze how HipB normally prevents HipA's function, the team solved the structure of the HipB/DNA/HipA complex. HipB tightly binds two HipA molecules in a sandwich-like structure.
HipB does not block HipA's active site, but inactivates it by forcing it into an "open" position. "Proteins move a lot to function, they open and close - think of a clam shell, for example," Brennan explains. To function, a protein must be able to close down on its target molecules - called substrates. The closed state is the active state.
HipB also might physically sequester HipA from EF-Tu because the HipA/HipB/DNA complex is located in E. coli's nucleoid, far from the bacteria's membrane where EF-Tu is mainly found.

HipA is free to cause trouble when its ties to HipB are broken; an infrequent occurrence which the authors note is likely caused by proteases tugging the smaller and structurally vulnerable HipB protein out of the complex.

Protein kinases often bind to more than one protein, so there are likely multiple targets for the protein in E. coli and other gram-negative bacteria, Schumacher and Brennan said.

Future research will focus on finding other HipA targets in E. coli, and kinase inhibitors will be examined for their ability to affect HipA function. If a promising inhibitor is found, its structure will be solved to clarify its binding mode and how it might be tweaked to bind HipA even better. "Structure-based drug design should provide the best chance at formulating highly specific and effective drugs against HipA," Schumacher said.

Study on spread of antibiotic resistance between bacteria

Sat, 10 Jan 2009 09:25:41 PST

( from http://www.rxpgnews.com ) Scientists have identified the structure of a key component of the bacteria behind such diseases as whooping cough, peptic stomach ulcers and Legionnaires' disease. The research, funded by the Wellcome Trust and the Biotechnology and Biological Sciences Research Council (BBSRC), sheds light on how antibiotic resistance genes spread from one bacterium to another. The research may help scientists develop novel treatments for these diseases and novel ways to curtail the spread of antibiotic resistance.

Antibiotic resistance spreads when genetic material is exchanged between two bacteria, one of which has mutated to be resistant to the drugs. This exchange is facilitated by a multi-component device known as a type IV secretion system, which acts to transport antibiotic resistance genes from within one cell, through its membrane and into a neighbouring cell.

Type IV secretion systems also play an essential role in transporting toxins or proteins from within bacteria into the cells of the body, causing diseases. Examples of Gram-negative bacterial pathogens using such a device are Helicobacter pylori (which causes peptic ulcers), Legionella pneumophila (which causes Legionnaires' disease), and Bordetella pertussis (which causes whooping cough).

Now, in a paper published in the journal Science, scientists from the Institute of Structural and Molecular Biology (ISMB) at Birkbeck, University of London, and UCL (University College London) describe the structure of the core complex of a type IV secretion system, viewed using cryoelectron microscopy (a form of electron microscopy where the sample is studied at very low temperatures).

"Type IV secretion systems play key roles in secreting toxins which give certain bacteria their disease-causing properties and, importantly, are also directly involved in the spread of antibiotic resistance," says Professor Gabriel Waksman, Director of the ISMB and lead author of the study. "This is why they have become obvious targets in the vast effort required to fight infectious diseases caused by bacteria."

Gram-negative bacteria have a double membrane. At the core of the type IV secretion system is a double-walled chamber which spans the two membranes and opens at one side. Dr Waksman believes this chamber may offer a new pathway for targeting these bacteria.

"If we can inhibit the secretion systems that mediate transfer of antibiotic resistance genes from one bacterial pathogen to another, we could potentially prevent the spread of antibiotic resistance genes," he says. "For those pathogens that use type IV secretion system for secretion of toxins, the system can be targeted directly for inhibition. In both cases, this would have a considerable impact on public health."

Type IV secretion systems were first discovered in Agrobacterium tumefaciens, which uses the system to transfer tumour-inducing DNA into plants, causing "crown gall", which can be devastating to crops such as grape vines, sugar beet and rhubarb. However, crop scientists have been able to successfully exploit this transfer system as a way of introducing new genes into industrial crops, conferring herbicide-resistance and resistance to pathogens.

Two-component lantibiotic with therapeutic potential discovered

Tue, 31 Oct 2006 16:13:00 PST

( from http://www.rxpgnews.com ) The discovery and preparation of a naturally occurring antibiotic could open the door to new therapeutic drugs for treating nasty infections.

The rapid spread of drug-resistant bacterial strains poses a persistent threat to human health, and requires new sources of antibiotics to treat infections. Researchers at the University of Illinois at Urbana-Champaign are tackling this problem by discovering and preparing natural antibiotics called lantibiotics.

Lantibiotics are a class of very potent antimicrobial compounds whose antimicrobial properties are attributed to their structure. They possess unusual sulfur bridged rings that provide structural rigidity for binding their cellular targets. Lantibiotics are commonly used in the food industry to inhibit the growth of microorganisms.

"Having the ability to make analogs of these naturally occurring antibiotics gives us the flexibility to look for improvements in properties such as toxicity, biostability and bioavailability," said Wilfred van der Donk, a William H. and Janet Lycan Professor of Chemistry at the U. of I. He is a corresponding author of a paper that will be posted online this week ahead of regular publication by the Proceedings of the National Academy of Sciences. In previous work, van der Donk first identified the molecular activity of an enzyme (LctM) responsible for naturally turning a small protein into a lantibiotic. That discovery, reported in the journal Science in 2004, involved lacticin 481, a lantibiotic produced by several strains of Lactococcus lactis, a bacterium used in cheese production.

In March 2006, van der Donk's team reported, again in Science, the synthesis of the lantibiotic nisin. The most studied lantibiotic, nisin has been used as a food preservative for more than 40 years without the development of significant antibiotic resistance.

Then, in the Oct. 26 issue of Chemistry and Biology, the team demonstrated that LctM could accept substrates vastly different from its natural substrate, in vitro.

"Normally, enzymes are very selective, and will work only on their natural substrate," said van der Donk, who is also an affiliate of the university's Institute for Genomic Biology. "We showed that our enzyme could modify many synthetic substrates, and produce sulfur bridged rings of different sizes and shapes. This offered us the opportunity to control and alter the structure of lantibiotics."

In their latest work, to be published in PNAS, van der Donk and his collaborators describe a new two-component lantibiotic. These lantibiotic systems utilize two peptides that are each post-translationally modified to an active form, and act in synergy to provide antibacterial activity.

"Given the synergy observed among two-component lantibiotics, which display similar or higher activity than the best single-component lantibiotic, nisin, the possibility of engineering new lantibiotics with therapeutic potential is even greater for these systems," van der Donk said.

Using bioinformatics, the researchers found genes annotated in the fully sequenced genome of the Gram-positive bacterium Bacillus halodurans C-125 as precursors of the lantibiotics mersacidin and cytolysin. This strain had not previously been reported to produce a lantibiotic.

The new two-component lantibiotic was named haloduracin by its discoverers. "The bacterium that produces haloduracin grows at pH 9 and above, suggesting that the lantibiotic it produces will be stable in the human body, unlike nisin, which is unstable at pH 7 and above," van der Donk said. Significantly, the researchers succeeded in expressing in the bacterium Escherichia coli the machinery to produce haloduracin, thereby creating the first in vitro biosynthesis of a two-component lantibiotic.

"The in vitro biosynthesis opens the door to new, intriguing possibilities involving antimicrobial peptide design and engineering," van der Donk said. "Now we can start applying all the lessons we learned with lacticin 481."

Antibiotic inhibits cancer gene activity

Mon, 02 Oct 2006 01:39:00 PST

( from http://www.rxpgnews.com ) A little-known antibiotic shows early promise as an anti-cancer agent, inhibiting a gene found at higher-than-normal levels in most human tumors, according to researchers at the University of Illinois at Chicago College of Medicine.

"We chose to target a gene believed to be over-expressed in cancer cells to screen for promising anti-cancer agents," said Andrei Gartel, assistant professor of medicine and of microbiology and immunology at UIC and principal investigator on the study.

The FoxM1 gene is responsible for turning on genes needed for cell proliferation and turning off genes that block proliferation. Uncontrolled proliferation is characteristic of cancer cells.

The researchers developed a new screening system, based on a naturally fluorescent protein called luciferase, to identify small molecules that inhibit proteins that turn genes on and off. Using this system, they identified an antibiotic, siomycin A, that specifically targets FoxM1 without affecting other cell functions.

In further experiments in tissue cultures, the researchers found that siomycin A induced cancer cells, but not normal cells, to commit suicide in a process called apoptosis.

The new screening technique, Gartel said, gives researchers a rapid way to find agents that target oncogenes -- genes believed to cause cancer. He said siomycin A, the first compound found with the method, "is particularly promising because we know that it is not toxic."

Siomycin A must now be tested against other cell lines in the laboratory and in preliminary animal experiments before human trials could be planned. Only a tiny fraction of promising candidate drugs enter clinical trials, and few of those are ever approved.

Gartel said the participation of the late Robert Costa, professor of biochemistry and molecular genetics at UIC and a leader in research on FoxM1, was critical for the success of the project thus far.

Senthil Radhakrishnan, a visiting bioinformatics expert at UIC, is first author of the paper. Uppoor Bhat, Douglas Hughes and I-Ching Wang also contributed to the study.

Rapamycin shown to inhibit angiogenesis

Tue, 15 Aug 2006 02:48:00 PST

( from http://www.rxpgnews.com ) Scientists have long known that the blood vessels of tumors differ markedly from normal blood vessels. Now, a research team led by scientists at Beth Israel Deaconess Medical Center (BIDMC) has identified a signaling pathway which, when activated, transforms otherwise healthy blood vessels into the leaky, misshapen vasculature that characterizes cancerous tumors.

The findings, published in the August 2006 issue of Cancer Cell, additionally demonstrate that rapamycin, a compound used for immunosuppression in transplant patients and currently under investigation as a cancer treatment, can successfully block this signaling pathway--known as the Akt pathway-- in blood vessels. This discovery further enhances the drug's promise as a cancer therapy.

"There are three major hallmarks associated with tumor blood vessels," explains the study's senior author Laura Benjamin, PhD, an investigator in BIDMC's Department of Pathology and Associate Professor of Pathology at Harvard Medical School.

"First, unlike healthy blood vessels which are uniform in structure, a tumor's blood vessels balloon and narrow, forming a highly irregular shape. Second, the layer of smooth muscle that you would expect to find covering the blood vessels is inadequate, often resulting in only intermittent coverage. And last, a tumor's blood vessels are overly permeable or leaky."

The hypothesis that blood vessel formation in tumors is essential for the growth and spread of cancer was first proposed in the early 1970's, and in 1983, it was shown that tumors secrete a factor called VEGF (vascular endothelial growth factor) that induces the permeability associated with blood vessels in cancer.

In this new study, Benjamin and first author Thuy Phung, MD, PhD, of BIDMC's Department of Pathology, hypothesized that the Akt pathway was mediating many of the functions of VEGF in tumors, including the stimulation of blood vessels with abnormal structure and excessive leak. Using a mouse model that enabled them to activate the Akt pathway in healthy blood vessel cells without the complicating influence of tumor cells they observed that Akt-induced blood vessels demonstrated the very same abnormalities that are seen in tumor blood vessels. Moreover, adds Benjamin, "We discovered that simply removing the activated Akt was sufficient to reverse these vasculature changes."

The scientists then went on to treat the animals with rapamycin. As predicted, the agent blocked the Akt-induced blood vessel changes. In subsequent experiments, rapamycin reduced tumor growth and vascular leak in a mouse tumor model.

"This paper represents an impressive advance in our understanding of the mechanisms by which tumors generate the new blood vessels they need to survive and grow," says Harold Dvorak, MD, Director of the Vascular Biology Center at BIDMC and Mallinckrodt Professor of Pathology Emeritus at Harvard Medical School, in whose laboratory VEGF was first discovered 23 years ago. "This suggests an attractive new molecular target for cancer therapy."

Approved by the U.S. Food and Drug Administration (FDA) as an immunosuppressant agent, rapamycin is being tested in clinical trials as a cancer treatment.

"These new findings suggest that we should think about using rapamycin in regimens where anti-angiogenic therapy in cancer patients is desired," says Benjamin. "If human tumors respond in the same way that animal models have, rapamycin may normalize and diminish the tumor vasculature, and this is particularly exciting because these findings are clinically relevant today."

In addition to Benjamin and Phung, study coauthors include BIDMC investigators Donnette Dabydeen, BS, Godfred Eyiah-Mensah, BA, Marcela Riveros, MD, Carole Perruzzi, BA, Jingfang Sun, DVM, Rita Monahan-Earley, BA, Janice Nagy, PhD, Ann Dvorak, MD, and Harold F. Dvorak, MD; Keren Ziv, MS, and Michal Neeman, PhD, of the Weizmann Institute of Science in Israel; Ichiro Shiojima, MD, PhD, and Kenneth Walsh, PhD, of Boston University School of Medicine; Michelle Lin, PhD, and William Sessa PhD, of Yale University School of Medicine, New Haven, Connecticut; and David Briscoe, MD, of Children's Hospital, Boston.

Tigecycline, worlds first glycylcycline expanded broad-spectrum antibiotic, launched in UK

Sat, 22 Jul 2006 19:18:00 PST

( from http://www.rxpgnews.com ) Tygacil (tigecycline), a new, expanded broad-spectrum IV antibiotic for the treatment of a wide range of infections including those caused by antibiotic resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), 1 will be available in the UK from 20 June 2006. Availability of this new antibiotic comes at a time when the need for effective new treatments is greater than ever and clinicians are running out of options.

"Difficult to treat, antibiotic-resistant and often life-threatening infections are a growing problem in the UK, costing the NHS an estimated additional £1 billion annually," says Dr Robert Masterton, Executive Medical Director and Consultant Microbiologist, NHS Ayrshire & Arran, "Even more worrying has been the emergence of the organisms commonly called 'superbugs' those very worrying bacteria that have become resistant to a large number and in some cases all available antibiotics. Add to this the diminishing development of new antibiotics in the last 20 years and we could soon see a return to the Florence Nightingale era where infections caused more death than bullets because there were no effective drugs to treat these diseases. The introduction of tigecycline in the UK comes at absolutely the right time and will provide a vital new weapon in the fight against infection."

Tigecycline has been licensed for use in the UK as a treatment for a variety of complicated skin and soft tissue infections including infected wounds and complicated intra- abdominal infections such as complicated appendicitis.1 It is the world's first glycylcycline and has been developed by Wyeth to overcome two common mechanisms of resistance that have reduced the efficacy and limited the use of certain existing antibiotics.1

While MRSA has received wide media and government attention and concern in the UK, other infections like Escherichia Coli (E. Coli) and Klebsiella could pose an even greater risk to public health.4, 5 Tigecycline is one of a few new antibiotics with measured activity against these bacteria6 and there are few other antibiotics with a similar spectrum of activity expected this decade.6

"Until now, the lack of available antibiotic options for these more difficult to treat bacteria has necessitated the use of combination therapies two or more different antibiotics to fight the resistant bacteria," explains Dr Mark Palazzo, Chief of Service for Critical Care Medicine at Hammersmith Hospitals NHS Trust, "Combination treatment can contribute to increased drug costs, drug interactions, with potentially higher patient risk and further increased antibiotic resistance which complicates the treatment. It would be an advantage for patient care to have the option of a new single effective therapy" he concludes.

Serious infections treated in the hospital are a major cause of morbidity and death among hospitalised patients worldwide.7 In the UK alone, hospital-acquired infections (HAIs) account for a staggering 5,000 deaths per year.8 It is estimated that these infections affect just over 300,000 patients every year9 with about nine per cent of hospital patients having a HAI at any one time.8

Tigecycline was licensed by the European Commission for use in Europe on 24th April 2006 and is available in the UK today. Tigecycline is indicated for the treatment of complicated infections of the skin and soft tissue and complicated intra-abdominal infections.1 Tigecycline is supported by comprehensive global in vitro studies and an in vivo clinical trials programme.

The most common adverse events reported in clinical trials with tigecycline were nausea and vomiting. These occurred early in the treatment and were generally mild or moderate in severity.1

FDA Warns of Liver Failure With Telithromycin

Fri, 30 Jun 2006 13:13:00 PST

( from http://www.rxpgnews.com ) The Food and Drug Administration (FDA) today completed its safety assessment of Telithromycin and is advising health practitioners and patients to be aware of rare but potentially serious health risks. Ketek (telithromycin) is the first FDA-approved antibiotic of the ketolide class. It is indicated for the treatment of acute exacerbation of chronic bronchitis; acute bacterial sinusitis; and community acquired pneumonia of mild to moderate severity, including pneumonia caused by resistant strep infections. The drug has been associated with rare cases of serious liver injury and liver failure with four reported deaths and one liver transplant after the administration of the drug. The manufacturer is revising the drug labeling to address this safety concern.

Although it is difficult to determine the exact frequency of Ketek-associated adverse events on the basis of FDAs mandatory and voluntary reporting systems, the agency has concluded that the drugs benefit to patients for the approved indications outweighs its risk, including the rare risk of liver failure, and supports its continued availability.

We are advising both patients taking Ketek and their doctors to be on the alert for signs and symptoms of liver problems," said Dr. Steven Galson, Director for FDAs Center for Drug Evaluation and Research. "Patients experiencing such signs or symptoms should discontinue Ketek and seek medical evaluation, which may include tests for liver function." The signs and symptoms of liver failure include fatigue, malaise, loss of appetite, nausea, yellow skin and dark-colored urine.

The warning, which Keteks manufacturer is adding to the drugs labeling, results from FDAs vigilant monitoring of all drugs after their introduction to the market. When the agency approved the drug in 2004, based on data in the marketing application, the risk of liver injury with Ketek was similar to that of other marketed antibiotics. A safety evaluation conducted one year after approval was consistent with this. However, as the product entered into wider use, FDAs adverse event monitoring system received some reports of serious liver problems in patients taking Ketek, including some cases of acute liver failure leading to death or requiring liver transplantation.

Following receipt of these reports, FDA conducted a rigorous and thorough assessment of existing data, and continued to engage in U.S. and ex-U.S. monitoring of additional post market events. This work involved efforts by experts in the agencys Office of Surveillance and Epidemiology and the Office of New Drugs, as well as by recognized external liver disease experts. FDA tracked reports of adverse events associated with Ketek via MedWatch and also had the benefit of three case reports described in the February 06 issue of Annals of Internal Medicine. FDA has now completed its evaluation of this information and determined that additional warnings are required.

FDA will continue to evaluate Ketek-associated safety issues and take further actions if warranted. It is important to note that negative effects on liver function are a known and potential complication with some antibiotics, including Ketek, and as drug usage becomes more widespread, it is expected that rare adverse events may be detected or reported in greater numbers.

What is the optimal duration of antibiotic therapy?

Sat, 10 Jun 2006 17:48:00 PST

( from http://www.rxpgnews.com ) Taking antibiotics for three days is just as effective for community acquired pneumonia as continuing treatment for the recommended 7-10 days, finds a study in this weeks BMJ. Shorter treatment can also help contain growing resistance rates.

The study raises questions about the optimal duration of antibiotic therapy for common infections.

Community acquired pneumonia is one of the most important indications for antibiotic prescriptions in hospitals. But a lack of evidence to support short course therapy means it has become accepted practice to continue treatment for days after symptoms have improved.

Researchers in the Netherlands compared the effectiveness of discontinuing treatment with amoxicillin after three days or eight days in adults admitted to hospital with mild to moderate-severe community acquired pneumonia.

119 patients who substantially improved after the conventional three days treatment with intravenous amoxicillin were randomly assigned to oral amoxicillin (63 patients) or placebo (56 patients) three times daily for five days. Patients were assessed at days 7, 10 (two days after treatment ended), 14, and 28.

In the three day and eight day treatment groups, the clinical success rate at day 10 was 93% for both, and at day 28 was 90% compared with 88%. Both groups had similar resolution of symptoms, x-ray results, and length of hospital stay.

These findings show that discontinuing amoxicillin treatment after three days is not inferior to discontinuing it after eight days in adults with mild to moderate-severe community acquired pneumonia who have substantially improved after an initial three days treatment, say the authors.

A shorter duration of treatment can also help to reduce overall antibiotic consumption and resistance rates for respiratory infections, they conclude.

This study suggests that current guidelines recommending 7-10 days should be revised, says Dr John Paul from the Royal Sussex County Hospital, in an accompanying commentary.

Not only does the study yield strong evidence in favour of short course therapy for a subset of patients with community acquired pneumonia, but also shows how centres can cooperate to tackle longstanding areas of uncertainty in clinical microbiology and infectious diseases, he writes. Many other common clinical situations would repay the efforts of comparable approaches.

Should children with suspected meningitis be given antibiotics before transfer to hospital?

Fri, 02 Jun 2006 23:05:00 PST

( from http://www.rxpgnews.com ) Several European countries advise doctors in primary care to do this, but the evidence is conflicting, with some studies suggesting benefit and others suggesting harm. Two papers in this weeks BMJ add to this uncertainty.

One shows that children who are given antibiotics before admission to hospital are more likely to die on reaching hospital. The other a review of all the current evidence cannot conclude whether or not pre-hospital antibiotics improve survival.

In the first study, UK researchers analysed 158 children diagnosed with suspected meningococcal disease by a general practitioner before admission to hospital. Two thirds were given parenteral (injected) penicillin, in accordance with national guidelines.

The children who were given penicillin were more likely to die than those who were not given penicillin.

However, the children who received penicillin also had more severe disease on reaching hospital. So, although a harmful effect of penicillin cannot be excluded, a more likely explanation for the higher mortality is that there is a strong bias towards giving penicillin to the most severely ill children, conclude the authors.

In the second paper, an international group of researchers reviewed evidence from 14 studies and found that oral antibiotics given before hospital admission were associated with reduced mortality. Results for parenteral antibiotics were inconsistent, though the data suggest that they might have a beneficial effect when a substantial proportion of patients is treated.

Once again, it is suggested that bias linked to illness severity may explain these results. For example, doctors are likely to prescribe oral antibiotics only in patients with milder disease.

We cannot conclude from this review whether or not antibiotics given before admission have an effect on case fatality, though the data are consistent with benefit when a substantial proportion of cases are treated, they write.

So, should doctors change their practice in light of these findings? Probably not, says Duncan Keeley, a general practitioner in an accompanying editorial. But frontline practitioners will be keen to hear a view from the Meningitis Research Foundation once it has considered their implications.

Meanwhile, further analysis of the data is crucial, and we should also remember the contributions general practitioners can make, including educating parents, early diagnosis, and rapid transfer to hospital with optimum supportive care, he writes. These measures may be more important for improving survival than administering parenteral penicillin in the community.

Production Practices Effect Antimicrobial Resistance in Poultry

Mon, 15 May 2006 17:27:00 PST

( from http://www.rxpgnews.com ) The use of conventional versus organic production practices can significantly affect the prevalence of antibiotic resistant to bacteria in poultry say researchers from Maryland and Ohio. Their findings appear in the May 2006 issue of the journal Applied and Environmental Microbiology.

Campylobacter is one of the leading causes of food-borne illnesses worldwide, causing more than 2 million cases of bacterial diarrhea each year in the U.S. alone. Although most Campylobacter infections in humans are attributed to ingestion of contaminated foods, consumption of undercooked poultry or foods cross-contaminated with raw poultry meat also pose a major risk of campylobacteriosis. With incidences of food-borne illness on the rise, experts are also seeing an increase in antimicrobial resistance among the Campylobacter species. Currently, 19 to 40% of Campylobacter strains isolated in humans are resistant to ciproflaxin and this is attributed in part to the widespread use of antimicrobial agents in humans and animals.

In the study, researchers compared Campylobacter from the intestinal tracts of broilers and turkeys from conventional farms where antibiotics were routinely used and organic farms where antibiotics had never been used. A total of 694 Campylobacter isolates were tested for resistance to nine antibiotic agents. Researchers found that although Campylobacter species were dominant in both poultry operations, there was a significant difference in antibiotic resistance with a rate of less than 2% from organically raised poultry and 46 to 67% resistance from conventionally raised broilers and turkeys.

"This study revealed significant differences in antibiotic-resistant Campylobacter isolates between conventional poultry operations and organic poultry operations," say the researchers. "These results suggest that the practice of antibiotic usage in conventional poultry production systems influence the prevalence of antibiotic-resistant Campylobacter organisms in conventionally raised broilers and turkeys."

Aspirin Protects Against Aminoglycoside Induced Hearing Loss

Thu, 27 Apr 2006 13:45:00 PST

( from http://www.rxpgnews.com ) Around the world, inexpensive antibiotics known as aminoglycosides have been used for the past 60 years in the battles against acute infections and tuberculosis as antibacterial prophylaxis in cystic fibrosis patients and in other conditions. But for all of the good they do, the drugs also have been widely linked to irreversible hearing loss.

Now, researchers at the University of Michigan's Kresge Hearing Research Institute and their Chinese colleagues, working under the leadership of Jochen Schacht, Ph.D., and Su-Hua Sha, M.D., have found that the hearing loss can be prevented in many people with the use of another inexpensive, widely available medication: aspirin. The results appear in the April 27 issue of the New England Journal of Medicine.

The researchers studied 195 patients in China who received 80 to 160 milligrams of gentamicin (a type of aminoglycoside) intravenously twice daily, typically for five to seven days. Of those, 89 patients were given aspirin along with the antibiotic, and 106 were given placebos along with the antibiotic. The results were dramatic: The incidence of hearing loss in the group that was given placebos was 13 percent, while in the aspirin group it was just 3 percent, or 75 percent lower.

"We would like to see the word get around to the medical community around the world that you can take some precautions to minimize the risk to your patients. Aspirin is available everywhere, and it's cheap," says senior author Schacht, professor of biological chemistry in otolaryngology at the University of Michigan Medical School and director of the U-M Health System's Kresge Hearing Research Institute. Gentamicin is not commonly used in the United States.

He notes that this research builds on earlier U-M studies that showed promise in combating drug-induced hearing loss in the laboratory. "Previously we found that such a treatment works well in mice, but I am very excited that this worked so well in humans," says Schacht. "Translating animal studies into clinical practice is not an easy thing to do. We were fortunate that our extrapolation from mice to men and women worked in the first trial."

The research is exciting, says lead author Sha, because hearing loss caused by these antibiotics is so prevalent. The incidence of aminoglycoside-induced hearing loss averages 8 percent but the numbers may be higher in developing countries, she notes, where aminoglycosides are frequently the only affordable antibiotics and are sold over the counter. No therapy currently exists to prevent ototoxicity.

This research began in 1999 with a collaboration with Chinese hospitals. Working with Schacht, Sha associate laboratory director of U-M's Kresge Hearing Research Institute's Biochemistry Laboratory got in touch with her colleagues in China. The two traveled to China and presented their ideas, and ultimately began a partnership with the Fourth Military Medical University in Xi'an, China. The third author on the paper, Jian-Hua Qiu, M.D., represents the colleagues of the Fourth Military Medical University.

After receiving approvals from institutional review boards at U-M and the Fourth Military Medical University, the otolaryngology department in Xi'an conducted the prospective, randomized, double-blind trial at Xijing Hospital and Airforce Chengdu Hospital from 1999 to 2003. All of the participants were ages 18 to 65, and were inpatients who were scheduled for treatment with gentamicin. Hearing damage, or ototoxicity, was defined as a shift from a person's baseline hearing by at least 15 decibels at both the 6 and 8 kHz frequencies, which are the first affected by the drugs. The effectiveness of the gentamicin as an antibiotic did not lessen when it was paired with aspirin.

Schacht notes that even though gentamicin has been linked widely with hearing loss, and its use has been declining in industrial countries, it is not practical to think that it will be replaced in the near future by other antibiotics because it has specific applications and is so inexpensive and available, especially in poor countries. While aspirin shows promise, and he hopes that health care providers pair it with gentamicin, he also notes it is not yet the perfect solution because of the potential side effects of aspirin, including gastric bleeding. And he notes that this is an off-label use of aspirin, which may inhibit some practitioners from giving it to patients in such instances.

He hopes that further studies will lead to the development of new and safer antibiotics, or another drug that can be paired with gentamicin that has fewer side effects than aspirin. He and Sha are exploring partnerships with other countries to conduct future research.

Avelox (Moxifloxacin) is as effective as Levofloxacin combination therapy for severe community-acquired pneumonia

Sun, 09 Apr 2006 12:44:00 PST

( from http://www.rxpgnews.com ) AVELOX (moxifloxacin HCl) monotherapy at 400 mg once daily is as effective as the high-dose combination of levofloxacin (500 mg twice daily) plus ceftriaxone (2 g once daily) in treating patients with severe community-acquired pneumonia (CAP) requiring hospitalization, according to results of a new clinical study presented at the 16th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) in Nice, France.

Known as the MOTIV (Moxifloxacin Treatment Intravenous) study, the head-to-head comparison of once-daily AVELOX monotherapy to a combination of high-dose levofloxacin plus high-dose ceftriaxone showed no significant difference in clinical cure rates (4-14 days after the last dose), the primary efficacy endpoint for the two per protocol treatment groups (86.9 percent vs. 89.9 percent, respectively), including CAP patients with the most severe pneumonia.

The per protocol population consisted of 569 patients. A total of 748 patients were enrolled in the study, of which 738 patients were randomized. Both treatments were well tolerated in the study, with similar adverse event profiles.

"The results of the MOTIV study are important because community-acquired pneumonia is a particular concern for people with chronic illnesses or impaired immune systems, and is a common cause of hospitalization worldwide," said Antoni Torres, M.D., professor of pulmonology at the University of Barcelona in Spain.

"CAP can critically affect older patients who may be struggling with existing conditions such as heart disease and diabetes," he added. "These results provide additional evidence that AVELOX is a safe and effective treatment for patients with CAP."

CAP affects approximately 5.6 million adults in the United States each year, with elderly patients (age 65 and above) 60 percent more likely than the general population to develop the infection.

Rapamycin (sirolimus) also effective in ADPKD

Wed, 22 Mar 2006 08:26:00 PST

( from http://www.rxpgnews.com ) A widely available drug may be effective in treating kidney disease, report scientists at the University of California, Santa Barbara. They describe the discovery in the online edition of the Proceedings of the National Academies of Science published the week of March 20.

The drug is rapamycin, also called sirolimus, and is currently used as an immunosuppressant, to help prevent rejection of a new, transplanted kidney.

Over 600,000 people in the U.S., and 12 million worldwide, are affected by the inherited kidney disease known as ADPKD, short for autosomal-dominant polycystic kidney disease. In the U.S., the number of individuals affected by ADPKD is greater than the number affected by cystic fibrosis, muscular dystrophy, hemophilia, Down's syndrome, and sickle cell anemia combined. The disease is characterized by the proliferation of cysts that eventually debilitate the kidney, causing kidney failure in half of all patients by the time they reach age 50.

Currently no treatment exists to prevent or slow cyst formation, and most ADPKD patients require kidney transplants or life-long dialysis for survival, explained Thomas Weimbs, director of the laboratory where the discovery was made. Weimbs is assistant professor in the Department of Molecular, Cellular and Developmental Biology at UCSB.

The scientists studied the effects of rapamycin on mice. "When we administered rapamycin to mice with PKD and looked at their kidneys afterwards, we were absolutely amazed," said Weimbs. "The kidneys were smaller, had smaller cysts and had retained their function."

"We have known the genetic mutations that cause PKD for over a decade," explained Weimbs. "The genetic mutations are located in the gene for the polycystin-1 protein. Unfortunately, the function of polycystin-1 has remained poorly understood, which has made it difficult to devise a treatment strategy for this disease."

Weimbs and his research team found that polycystin-1 controls an important regulatory protein called mTOR. A defect in polycystin-1 leads to over-activation of mTOR. This, in turn, causes excess growth and proliferation of kidney cells, which results in the formation of thousands of cysts that eventually destroy the kidney.

Fortunately, a highly effective inhibitor of mTOR is well known. This drug, rapamycin, was originally discovered in the 1970s in soil from Easter Island. It is used for immunosuppression in kidney transplant patients to prevent rejection of the new kidney.

Weimbs and his colleagues wondered about treating kidney patients with rapamycin. Most kidney transplant patients keep their diseased kidneys in place and the transplanted kidney is an additional, third kidney. So his colleagues, David A. Goldfarb and Andrew Novick, at the Cleveland Clinic in Ohio, suggested studying transplant patients who had received rapamycin to help their bodies accept the new kidney.

The research team identified a group of four rapamycin-treated patients and found that their polycystic kidneys shrank in size by 25% over two years. The polycystic kidneys in a control group showed no change.

"Even though we only had a very small number of patients, this result is highly encouraging because it points in the right direction," said Weimbs.

It shows, for the first time, a connection between polycystin-1 and mTOR, and strongly suggests that rapamycin may be a promising drug for treating PKD, explained Weimbs. "The fact that rapamycin is already clinically approved for other uses will facilitate future clinical trials of the drug."

Study of antibiotic resistance in the soil help predict future clinical emergence

Fri, 20 Jan 2006 15:40:00 PST

( from http://www.rxpgnews.com ) Dirt may be a key to how bacteria that infect humans develop a resistance to antibiotic drugs.

In an article in the January 20 issue of the journal Science, McMaster University researchers say that study of bacteria found in dirt may be the key in identifying how and why antibiotic resistance happens in bacteria that infect people, predicting future clinical problems, and testing new antibiotics.

Antibiotic resistance has become an increasing public health concern because the organisms that cause infections in humans and animals are becoming less receptive to the healing aspect of antibiotic drugs.

The team led by professor Gerry Wright, chair of Biochemistry and Biomedical Sciences of the Michael G. DeGroote School of Medicine, found that the numerous ways soil-dwelling bacteria become resistant to antibiotics are identical to the resistance patterns seen in patients.

These soil-dwelling bacteria also play a central role in the treatment of infectious diseases. Approximately two-thirds of all known antibiotics are produced by bacteria called actinomycetes, commonly found in soils, compost, and other environmental sources.

"By evolving in an environment of antibiotic production, incredibly resilient bacteria must develop diverse ways to survive or resist the toxic antimicrobial compounds produced by their neighbors," said Wright. "Their coping tactics may be able to give us a glimpse into the future of clinical resistance to antibiotics."

"This research suggests that not only can the study of resistance in the soil help predict future clinical emergence, but it can also guide the development of therapies to counteract this resistance."

Researchers screened 480 strains of soil bacteria isolated from diverse locations for resistance to 21 clinically relevant antibiotics. At high drug concentrations, the soil-dwelling bacteria displayed a stunning level of resistance. Not only were the bacteria resistant to an average of seven to eight antibiotics, but every strain was found to be multi-drug resistant.

The bacteria showed resistance to all major classes of antibiotics, regardless of whether the compounds were naturally produced, semi-synthetic, or completely synthetic.

Researchers also found that the way bacteria was resistant to vancomycin, one of the most commonly prescribed antibiotics for drug resistant staphylococcal infections, was identical to resistance found in clinics.

Furthermore, the researchers' uncovered bacteria that produced enzymes capable of breaking down or modifying or rendering inactive two recently U.S. FDA-approved antibiotics, a situation which has yet to emerge clinically for these drugs.

"The link between clinical and soil-associated resistance to vancomycin illustrates the value of studying resistance in the soil to rationally anticipate future clinical resistance," said Wright. "It suggests that the soil serves as an under-recognized source of resistance, resistance that has the potential to reach clinics.

"This work could prove to be extremely valuable to the drug development process, complementing traditional laboratory studies of clinical situations. By screening newly developed drugs for resistance in soil bacteria, not only can pharmaceutical companies can gain a better understanding of what may emerge in the future as clinical problems, but sufficient warning can be given to hospital microbiology laboratories, physicians and the drug discovery sector to allow for the development of diagnostic techniques and alternative therapies.

Sporulating soil isolates. Top Left: Soil Isolate PP#15, inactivates daptomycin Top Right: Soil Isolate Cu#22 Bottom Left: Soil Isolate WMB#19 Bottom Right: Trimethoprim Resistant Soil Isolates

"Furthermore, studying enzymes that inactivate antibiotics can serve as a foundation for the development of new combination therapies for resistant bacterial strains. Studying antibiotic resistance from an evolutionary perspective is one way that researchers are attempting to stay one step ahead of resistant bacteria."

Antibiotic resistant bacteria have become a major health threat and have limited our ability to treat even common infections with antibiotics," said Dr. Bhagirath Singh, Scientific Director of the Canadian Institutes of Health Research Institute of Infection and Immunity. "Dr. Wright's exciting discovery points to the fact that in nature, bugs in the soil survive in a very hostile environment. They do this by developing resistance to the antibiotics produced by other soil bacteria. Understanding this process opens up a new avenue for finding new therapies to prevent and treat antibiotic resistance in a clinical setting.

New peptide antibiotic - American Oyster Defensin (AOD)

Thu, 01 Dec 2005 05:46:00 PST

( from http://www.rxpgnews.com ) North Carolina Sea Grant researchers have isolated a new peptide antibiotic from the American oyster that may have implications for managing many diseases in oysters.

The new antimicrobial peptide "American oyster defensin" (AOD) may protect against bacteria in Crassostrea virginica, a species that is native to North Carolina and important economically to Atlantic and Gulf Coast fisheries.

"This peptide may be helpful in selecting disease-resistant oysters for aquaculture and fisheries and may also allow for the development of a test to monitor oyster health," says Ed Noga, professor at the North Carolina State University College of Veterinary Medicine. "In recent years, a number of pathogens, especially bacteria and parasites, have devastated American oyster populations."

The research findings appear in the new (Dec. 30) issue of Biochemical and Biophysical Research Communications.

Pathogens such as dermo (Perkinsus marinus) have caused major decreases in oyster productivity -- bacterial pathogens -- such as Vibrio vulnificus that can cause a food-borne illness are a human health concern, according to Noga.

This is the first time that researchers have isolated an antimicrobial peptide from any oyster species, he says.

NC State veterinary medicine postdoctoral research associate Jung-Kil Seo, as well as scientists J. Myron Crawford and Kathryn L. Stone of Yale University's Keck Biotechnology Resource Laboratory, collaborated with Noga on the study. "The results may be used to better understand the innate immune system of American oysters and to enhance research to protect it from important microbial infections," according to Noga. "Further studies are needed to identify sites of synthesis and storage of AOD and determine mechanisms affecting its regulation."

Reducing Antibiotic Use Lowers Rates of Drug-Resistant Bacteria

Sun, 04 Sep 2005 08:03:00 PST

( from http://www.rxpgnews.com ) Fewer antibiotic prescriptions leads to fewer superbugs. Thats the take-home message behind a new study in the Oct. 15 issue of Clinical Infectious Diseases, now available online. The study found that reducing antibiotic use for pediatric respiratory tract infections resulted in lower rates of carriage of drug-resistant bacteria.

Drug-resistant bacteria, commonly called superbugs, are fast becoming a problem due to overuse and inappropriate prescribing of antibiotics. Streptococcus pneumoniae bacteria, also called pneumococci, are commonly found in childrens noses and throats, and can result in ear infections, sinusitis, pneumonia and even meningitis. Many pneumococcal infections are treated with penicillin, but resistance to the drug is making the microbes more difficult to control.

Researchers in France tested two intervention methods intended to reduce the rate of carriage of penicillin-resistant pneumococci in kindergarteners. The prescription-reduction method involved not prescribing antibiotics for respiratory tract infections that were thought to be viral, since antibiotics work against bacteria, not viruses. The dose/duration method involved using only recommended doses of antibiotics for no longer than 5 days. The researchers also targeted physicians, pharmacists, parents, and children in the groups receiving both interventions with an information campaign about antibiotic resistance and appropriate antibiotic use. A control group of children and their doctors received no specific information about antibiotic use.

The study was conducted from January through May of 2000. By the end of the study, antibiotic use had declined by more than 15 percent in both intervention groups, compared to less than 4 percent in the control group. Although colonization by regular pneumococci was higher in the intervention groups than in the control group, colonization by penicillin-resistant pneumococci was lower in the intervention groups than in the control group. The prescription-reduction group saw the greatest decline in penicillin-resistant colonization (from 53 percent to 35 percent), and the dose/duration group dropped from 55 percent to 44 percent. The control group remained nearly unchanged. This suggests that reduced antibiotic pressure allows drug-susceptible bacteria to re-establish themselves as dominant colonizers of the respiratory tract.

Implementing intervention programs that are focused on populations most exposed to antibiotics--that is, children--is the first step in reining in superbugs, said lead author Didier Guillemot, MD, PhD, of Institut Pasteur.

Intervention methods such as reducing the number of prescriptions and, when ordered, the dose and duration of antibiotics, can induce significant and rapid reductions of penicillin-resistant pneumococcal colonization in areas that have high rates of drug-resistant bacteria, according to the study. In essence, doctors can make their own jobs easier by prescribing antibiotics more judiciously, thus slowing the spread of superbugs.

FDA Approves Tigecycline, a Novel Antibiotic with Broad Spectrum of Antimicrobial Activity

Fri, 17 Jun 2005 20:59:00 PST

( from http://www.rxpgnews.com ) The U.S. Food and Drug Administration (FDA) today approved Tygacilä (tigecycline), a novel I.V. antibiotic with a broad spectrum of antimicrobial activity, including activity against the drug-resistant bacteria methicillin-resistant Staphylococcus aureus (MRSA).

TYGACIL is indicated for the treatment of complicated intra-abdominal infections (cIAI) and complicated skin and skin structure infections (cSSSI) in adults. Approval of this first-in-class product comes at a time when the need for new antibiotic options to combat serious, resistant infections is increasing.

Life threatening infections are a growing concern globally, says Dr. Joseph Camardo, Senior Vice President, Global Medical Affairs, Wyeth Pharmaceuticals. Bacterial infections are becoming more difficult to treat, with resistant strains on the increase. The approval of TYGACIL will provide physicians with an important option for patients with complicated skin, skin structure, and intra-abdominal infections.

TYGACIL can be used as an empiric monotherapy to treat a variety of cIAI and cSSSI, both hospital- and community-acquired, including complicated appendicitis, infected burns, intra-abdominal abscesses, deep soft tissue infections, and infected ulcers. TYGACIL provides clinicians with a novel, broad-spectrum option that can be used at the onset of treatment when the specific bacteria present are not yet known. In addition, TYGACIL does not require dosage adjustment in patients with impaired renal function, and is conveniently dosed every 12 hours.

A Clinical Challenge

The U.S. Centers for Disease Control and Prevention (CDC) states that persons infected with drug-resistant organisms are more likely to have longer hospital stays and require treatment with multiple drugs. The increasing prevalence of resistant bacteria often necessitates the use of combinations of antibiotics to fight infections. Antibiotic resistance costs U.S. society between $4 billion and $5 billion annually. According to the CDC, antibiotic resistance has become so widespread that many significant bacterial infections in the world are becoming resistant to commonly used antibiotics.

Additionally, few broad-spectrum antibiotic agents are currently in development. Antibiotic development has slowed to the point that FDA has had few opportunities to approve new agents. In fact, development and approvals of new antibacterial agents have decreased by 56 percent over the past 20 years (1998-2002 vs. 1983-1987). New classes of antibiotics are needed to address increasing antibiotic resistance among common pathogens.

About TYGACIL

TYGACIL, the first antibiotic approved in a new class called glycylcyclines, was developed by Wyeth to overcome key mechanisms of resistance that have affected antibiotic use.

TYGACIL is approved for adults with complicated skin and skin structure infections (cSSSI) caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates only), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus agalactiae, Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Streptococcus pyogenes, and Bacteroides fragilis.

TYGACIL is also approved for adults with complicated intra-abdominal infections (cIAI) caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible isolates only), Staphylococcus aureus (methicillin-susceptible isolates only), Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros.

The TYGACIL New Drug Application (NDA) submission included data from four pivotal phase III studies examining the safety and efficacy of TYGACIL for the treatment of cIAI and cSSSI. The submission also included in vitro data showing activity against both gram-negative and gram-positive bacteria, anaerobes, and certain drug-resistant pathogens.

In clinical trials, empiric monotherapy with TYGACIL provided comparable clinical cures rates in cSSSI to vancomycin and aztreonam, a combination treatment. Empiric monotherapy with TYGACIL also provided clinical cure rates comparable to imipenem/cilastatin, an empiric treatment for cIAI. The overall discontinuation rate for TYGACIL (5.0 percent) was comparable to vancomycin and aztreonam (5.3 percent) and imipenem/cilastatin (4.4 percent).

Wyeth now awaits decisions on approval of TYGACIL from other regulatory bodies around the world. TYGACIL was accepted by the European Medicines Agency (EMEA) for review, and Wyeth has filed for approval in other countries, including Brazil, Canada, Colombia, Mexico, Switzerland, Taiwan, and Venezuela. The Australian Therapeutic Goods Administration and the South African Medicines Control Council (MCC) granted priority evaluation to TYGACIL. Wyeth anticipates that TYGACIL will be available to hospitals in the U.S. in the near future.

Important Safety Information

TYGACIL is contraindicated in patients with known hypersensitivity to tigecycline. TYGACIL should be administered with caution in patients with known hypersensitivity to, and may have adverse effects similar to, tetracycline class antibiotics. In clinical trials, the most common treatment-emergent adverse events in patients treated with TYGACIL were nausea (29.5 percent) and vomiting (19.7 percent).

TYGACIL may cause fetal harm when administered to a pregnant woman. The safety and effectiveness of TYGACIL in patients below age 18 and lactating women have not been established. Use of TYGACIL during tooth development may cause permanent discoloration of the teeth. Pseudomembranous colitis has been reported with nearly all antibacterial agents and may range from mild to life threatening. Monotherapy should be used with caution in patients with clinically apparent intestinal perforation.

Research to Study Effects of Antibiotics on Intestinal Microbes

Sun, 10 Apr 2005 09:25:00 PST

( from http://www.rxpgnews.com ) The tiny organisms that live inside of us play a huge role in our health, yet we dont know much about them. In sheer numbers, the bacteria in our body outnumber our own cells tenfold. They perform tasks that are beneficial (processing nutrients, helping store fat and providing protection against invading pathogens) and harmful (being a potential source of infection, creating carcinogens and triggering chronic illnesses).

We have co-evolved with the organisms and communities inside of us, certainly for the hundreds of millions of years that animals have had guts, said Les Dethlefsen, PhD, a postdoctoral scholar in microbiology and immunology at the Stanford University School of Medicine. We have this phenomenally complex ecosystem inside of us, yet we know so little about how we interact with these internal inhabitants.

Dethlefsen is starting a yearlong study to track the stability of the microbial community in the large intestine and how that community is affected by an antibiotic. He is currently seeking volunteers for the study. Participants will provide stool samples, monthly for most of the year with more frequent sampling surrounding two periods of antibiotic use.

To survey the hundreds of types of bacteria living in the colon, Dethlefsen will sequence a gene that all bacteria share in common. Minor differences in the gene sequence allow individual identification of the bacteria in the sample.

Two months into the study, and again six months later, volunteers will take a five-day course of the antibiotic Cipro (generically known as ciprofloxacin) that will kill off some types of bacteria, but which is not lethal to most of the microbes in the intestine. The researchers are interested in seeing Cipros effects on the whole community of bacteria living in the colon, not just the ones directly sensitive to the drug.

Our study really takes the form of a classical ecological perturbation study, said Dethlefsen. As an example, he compared their work to that of a field ecologist who puts two fence enclosures around an area of a meadow; one enclosure would be sealed and the other open on one end to allow animals through. The scientist could then compare what happens to plant species with and without grazing. In that example, Dethlefsen said, there are both direct and indirect effects that ripple through the ecosystem.

We are looking at Cipro as a perturbation of the intestinal ecosystem and, if we see any effects, it will likely be those that are rippling through the ecosystem rather than the direct effects of drug, he said.

Previous studies of bacteria in culture indicate that the effects of antibiotics, even those much more potent than Cipro, are no longer seen after two to six weeks, and the microbial environment returns to normal. Or at least it appears to be normal, said Dethlefsen. He outlined several scenarios in which a second dose of an antibiotic might elicit a response that could indicate some memory of an earlier antibiotic exposure. He designed his study to have the participants take Cipro twice to see if he can observe any such residual effect.

Dethlefsen works with David Relman, MD, associate professor of medicine (infectious diseases and geographic medicine) and of microbiology and immunology. Relman emphasized that Cipro poses minimal risk to study participants.

The studys findings might have ramifications for general widespread antibiotic use. It may be that in the not-too-distant future, we look at the indiscriminate use of antibiotics much like we look back at the indiscriminate use of pesticides in agriculture, Dethlefsen said. It may be that we open the door to further problems down the road, even as we solve an immediate problem.

He added, Thats why its worth knowing about the ecosystem of the gut, so we can use the knowledge to our advantage.

Volunteers will be compensated $200 for their time in the study, which is funded by the Ellison Medical Foundation. Call Dethlefsen at (650) 493-5000, ext. 63193, for more information or to volunteer. Relmans lab is located at the Veteran Affairs Palo Alto Heath Care System.

NADH Dehydrogenase Inhibitors suggested to be new Anti-Tubercular Antibiotics

Fri, 11 Mar 2005 17:22:00 PST

( from http://www.rxpgnews.com ) A worldwide health problem, tuberculosis kills more people than any other bacterial infection. The World Health Organization estimates that two billion people are infected with TB, and that two million people die each year from the disease.

However, due to multi-drug resistance and a protracted medication regimen, it is extremely difficult to treat. Hence, there is still a great deal of interest in developing new anti-tubercular drugs. Researchers at the University of Pennsylvania School of Medicine have identified a biochemical target that could lead to a new class of antibiotics to fight TB. They report their findings in this week's online edition of the Proceedings of the National Academy of Sciences.

In a proof-of-principle study, Harvey Rubin, MD, PhD, Professor of Medicine, Division of Infectious Diseases, and colleagues were able to stop the bacteria from multiplying by inhibiting the first step in a common biochemical pathway. This pathway is responsible for making the energy molecules all cells need to survive. First author Edward Weinstein, an MD/PhD student, Rubin, and colleagues characterized the pathway and showed that an important enzyme in it is a key target for anti-TB agents.

The pathway, explains Rubin, is like a series of links in a chain, with enzymes facilitating reactions along the way. "We discovered that if you inhibit the very first enzyme in the chain, you inhibit everything else downstream and eventually the bacteria die," he explains.

The research group tested phenothiazine, a drug used in the past to treat schizophrenia, in cultures of Mycobacterium tuberculosis, the bacterium that causes TB. They found that phenothiazines killed the bacterium in culture and suppressed its growth in mice with acute TB infection.

While the effect on the growth of TB in mice was small, it suggested that a valid target was identified. The research group went on to show that the enzyme disabled by the phenothiazines is called type II NADH dehydrogenase and is a unique and important antimicrobial target.

"What we have now is a new target in TB," says Rubin. "We've been able to find at least the beginnings of a class of compounds that we can start working with and that we know is biochemically active against the TB bacteria in culture and in small animals."

Is it a new drug for tuberculosis? Not yet, cautions Rubin. It's premature to say that this class of drugs will cure TB, but it does represent the start of basic research towards that, he concludes. Next steps include more investigations on inhibitors of the NADH biochemical pathway in TB, and the development of high-throughput screens to find better and safer inhibitors of type II NADH dehydrogenase.

A Microdialysis Technique will Help to Design and Test New Antibiotics

Sat, 05 Mar 2005 07:00:00 PST

( from http://www.rxpgnews.com ) Call it a chemical crystal ball. A new approach to predict whether a drug in development is likely to work and which dose is best could get antibiotics to market faster and more cheaply, say University of Florida researchers.

In recent years, scientists worldwide have sounded the alarm:
There simply aren't enough drugs to combat bad bugs. Bacteria are increasingly adept at outwitting the traditional antibiotic arsenal.

Yet designing and testing new antibiotics can be a maddeningly slow and costly process if pharmaceutical companies even bother, says Hartmut Derendorf, Ph.D., chairman of the department of pharmaceutics at the University of Florida College of Pharmacy.

Many would rather invest in compounds aimed at patients with chronic conditions such as high cholesterol or diabetes, not in drugs designed to be used for a week or two and then stopped once an infection clears, he said.

Now UF researchers have devised a patent-pending method that combines testing of various drug concentrations at the site of infection with a series of laboratory analyses and mathematical models designed to streamline drug development.

The method helps better determine which drugs are worth studying in people and at which dose, avoiding the typically lengthy and expensive trial-and-error approach that can take years.

About one new antibiotic a year is approved, said Derendorf, who will discuss the technique Saturday (March 5) at the annual meeting of the American Society for Clinical Pharmacology and Therapeutics in Orlando.

That's certainly not enough. Even more worrisome, there are very few in the pipeline right now. Meanwhile, the requirements are getting longer and longer, and this is a huge dilemma with the recent discussion about Vioxx. That's created some doubt in the approval procedure. I think we have to come to a reasonable expectation here in terms of the balance between benefits and potential harm. The worries I have right now are because of these unrealistic expectations, the requirements are going to be even higher and it's going to be harder and even more expensive to bring a new drug to market.

About 70 percent of bacteria found in hospitals resist at least one of the drugs commonly used to treat the infections they cause, according to the Food and Drug Administration.

The agency warns that unless problems are detected early and swift action taken to find substitute drugs, previously treatable diseases could again emerge in more virulent forms. Public health officials cite antibiotic resistance as a growing problem for a host of diseases, from childhood ear infections to malaria.

Last year, the FDA published a report calling attention to inefficiencies in the drug and medical product development process, urging changes to make the process more predictable and less costly. The latest estimates put the cost of bringing a new product to market at $1.6 billion to $1.8 billion.

UF researchers are working on an approach known as PK/PD, which combines principles of pharmacokinetics, or an analysis of drug concentrations in the body, and pharmacodynamics, their effect on bacteria or how a drug kills bacteria.

In the past, blood samples were taken and the serum concentration of the drug was measured and that number was used to make dosing decisions, said Derendorf, whose work is primarily funded by the pharmaceutical companies Pfizer and Sankyo. That may not always be the right place to look. Most infections are not in the blood but in other sites of the body. Some of the recommendations we have may not be the optimal doses.

UF researchers have developed a patent-pending technique called microdialysis that uses a small needle probe to measure how much of a drug actually ends up in the fluid surrounding the bacteria at sites of infection and are among the first in the country to test the method in people. These concentrations can differ widely from those found in the bloodstream, said Derendorf, who has published results from studies that evaluated the technique in people and animals with various infections.

In the past, microbiologists would expose bacteria to certain concentrations of an antibiotic and then determine the minimum concentration that prevents bacterial growth. That number was taken and compared with concentrations of the drug in the blood, and from those two numbers a dosing decision is made.

We feel that's not the optimal way go, he said. It doesn't give you the full story it doesn't tell you, for example, how quickly the bacteria are killed.

So UF scientists developed a system of pumps they can use to expose bacteria to changing concentrations of an antibiotic, mimicking the concentration profile present in a patient at the actual site of an infection. They then measure how quickly the bacteria are killed or see if they regrow, and use mathematical modeling to estimate the optimal dose.

Based on the results in the lab, then you can do a clinical study of what you think is going to work best, Derendorf said, and you'd find the best dose much faster than just by going by trial and error or by using some of the traditional ways.

Consider one recent example:
Derendorf led a series of laboratory experiments designed to evaluate an investigational, sustained-release form of a cephalosporin antibiotic. Ultimately the PK/PD approach showed that the difference in drug concentrations in the tissues arising from the standard form of the drug versus the sustained-release variety was so minimal, development of the new formulation was not warranted.

The company that was interested in that decided not to continue that project any more and made that decision much sooner probably than they would have in earlier days, said Derendorf, who published the findings in the Journal of Clinical Pharmacology. Using the information early on to make a no-go' decision for a product so you don't do a lot of other experiments to study a compound that later will be dropped that alone saves a lot of money.

UF researchers say they will continue to apply the screening approach to other drugs in various situations and also will seek to develop better ways of determining how frequently and at what dose a drug should be given to minimize the development of resistance.

They recently collaborated, for example, with NASA to analyze blood and tissue concentrations of an antibiotic in people living for a few days in a simulated zero-gravity atmosphere.

This approach is not just limited to anti-infectives, Derendorf added. We can expand it to other classes of drugs. It may be useful to answer many, many different questions.

The PK/PD approach aims to ensure that doses tested in clinical trials are adequate and likely to yield good results, said William Craig, M.D., a professor of medicine at the University of Wisconsin, adding that until now, many, many antibiotics that initially came out have either had their dosages changed because they were excessive or had them increased because they weren't enough.

Peptide Deformylase Inhibitors : A Novel Class of Antibiotics for Resistant Bacteria

Sat, 05 Mar 2005 06:50:00 PST

( from http://www.rxpgnews.com ) Vicuron Pharmaceuticals Inc. announced today that the company has received another milestone payment from Novartis Pharma AG in recognition of follow-up lead product candidates identified for Novartis' development from its ongoing research collaboration focused on peptide deformylase inhibitors, a novel class of antibiotics.

The company also announced that Novartis has suspended Phase 1 development of the first lead product candidate from the outpatient respiratory tract program in favor of developing a second lead compound, which is expected to enter the clinic by the end of the year.

"The identification of a second lead candidate further validates our mechanism-based drug design and demonstrates the speed and efficiency with which this prolific collaboration has brought multiple optimized drug candidates from concept toward the clinic," said Zhengyu Yuan, Ph.D., Senior Vice President of Research. "With the preclinical studies started and an aggressive development timeline established, we expect this candidate to move from preclinical studies into the clinic in a timely manner."

Peptide deformylase inhibitors constitute one of the most promising new antibiotic classes and hold the potential to treat large markets of community bacterial infections. The peptide deformylase inhibitor class of antibiotics targets a novel protein that is essential for bacterial growth and provides the basis for selective activity toward a wide range of bacterial pathogens. This new class has already demonstrated promising in vitro and in vivo activities against a broad spectrum of bacteria, including those resistant to widely used penicillin, cephalosporin, macrolide, and quinolone antibiotics.

Peptide deformylase is a new target for antibacterial drug discovery. Vicuron scientists have combined their expertise in bacterial genomics and mechanism based drug design, with skills in microbiology and pharmacology, in collaboration with expert scientists at Novartis, to identify a family of promising molecules from which a lead compound was chosen which demonstrates selective inhibition of peptide deformylase and exhibits potent broad spectrum activity against key bacterial pathogens both in vitro and in several in vivo models.