Prevention of Brain Injury by Daptomycin in Experimental Pneumococcal Meningitis.

Prevention of Brain Injury by the Non Bacteriolytic Antibiotic Daptomycin in Experimental Pneumococcal Meningitis.
Antimicrob Agents Chemother. 2007 Mar 19

Grandgirard D,
Schurch C,
Cottagnoud P,
Leib SL.
Institute for Infectious Diseases, University of Bern, Switzerland, Department of Internal Medicine; and Clinic for Infectious Diseases, University Hospital, Inselspital, Bern, Switzerland.

Background: Bacteriolytic antibiotics cause the release of bacterial components that augment the host inflammatory response which in turn contributes to the pathophysiology of brain injury in bacterial meningitis. In the present study in experimental pneumococcal meningitis, antibiotic therapy with non-bacteriolytic daptomycin vs. bacteriolytic ceftriaxone was evaluated for an effect on inflammation and brain injury.

Methods: Eleven day old rats were injected intracisternally with 1.3 +/- 0.5 x 10(4) colony forming units (cfu) of Streptococcus pneumoniae serotype 3 and randomized for therapy with ceftriaxone (100 mg/kg s.c., n=55) or daptomycin (50 mg/kg s.c., n=56) starting at 18 h after infection. Cerebrospinal fluid was assessed for bacterial count, matrix metalloprotease-9 and TNF-alpha at different time intervals after infection. Cortical brain damage was evaluated at 40 h after infection.

Results: Daptomycin vs. ceftriaxone cleared bacteria more efficiently from the CSF within two hours after initiation of therapy (log10 3.6+/-1.0 vs. log10 6.3+/-1.4 cfu/ml, P<0.02),>

Conclusion: Compared to ceftriaxone, daptomycin cleared bacteria more rapidly from the CSF and caused less CSF inflammation. This combined effect provides an explanation for the observation that daptomycin prevented the development of cortical brain injury in experimental pneumococcal meningitis.

Further research is needed to investigate whether non-bacteriolytic antibiotic therapy with Daptomycin represents an advantageous alternative over current bacteriolytic antibiotics for the therapy of pneumococcal meningitis.

PMID: 17371820 [PubMed - as supplied by publisher]

Amikacin-induced nephropathy: is there any protective way?

Amikacin-induced nephropathy: is there any protective way?
Ren Fail. 2007

Kaynar K,
Gul S,
Ersoz S,
Ozdemir F,
Ulusoy H,
Ulusoy S.
Department of Nephrology, School of Medicine, Karadeniz Technical University.

Amikacin is a commonly used antibacterial drug that can cause significant nephrotoxic effects in both humans and experimental animals. It has been reported that one mechanism of the toxic effects of aminoglycoside antibiotics are the result of oxidative reactions. The aim of this study is to examine the effects of N-acetylcysteine, a thiol-containing antioxidant, on renal function (serum creatinine) and morphology (renal tubular damage) in mice subjected to amikacin-induced nephrotoxicity. A total of 32 mice were equally divided into four groups that were injected with either saline, amikacin (1.2g/kg intraperitoneally), N-acetylcysteine (150mg/kg intraperitoneally for three days) plus amikacin (1.2 g/kg intraperitoneally on the third day as a single dose), or N-acetylcysteine (150mg/kg intraperitoneally).

Amikacin administration led to granulovacuolar tubular degeneration in light microscopic examination and myeloid bodies, mitochondrial electron-dense material deposition, and mitochondrial swelling in the proximal tubule epithelium in the electron microscopic evaluation. N-acetylcysteine administration before amikacin injection caused significant decreases in myeloid body and mitochondrial swelling and granulovacuolar tubular degeneration formation. Serum creatinine levels did not change as a result of any treatment.

The results show that N-acetylcysteine has a protective effect on nephrotoxicity induced by amikacin. Higher doses of amikacin should be tried to observe biochemical effects.

Meta Press

Gentamicin-loaded bioresorbable films for prevention of bacterial infections associated with orthopedic implants.

Gentamicin-loaded bioresorbable films for prevention of bacterial infections associated with orthopedic implants.
J Biomed Mater Res A. 2007 Mar 5

Aviv M,
Berdicevsky I,
Zilberman M.
Department of Biomedical Engineering, Tel-Aviv University, Tel-Aviv 69978, Israel.

Adhesion of bacteria to biomaterials and the ability of many microorganisms to form biofilms on foreign bodies are well-established as major contributors to the pathogenesis of implant-associated infections. Treatment of bone infection remains problematic, due to the difficulty of systemically administered antibiotics to locally penetrate bone. The current research addresses this issue by focusing on the development and study of novel gentamicin-loaded bioresorbable films designed to serve as "coatings" for fracture fixation devices and prevent implant-associated infections.

Poly(L-lactic acid) and poly (D,L-lactic-co-glycolic acid) films containing gentamicin were developed through solution processing. The effects of polymer type, drug content, and processing conditions on the drug release profile were studied with respect to film morphology. The examined films generally exhibited a burst effect followed by a moderate approximately constant rate of release. The drug contents in the surrounding medium exceeded the required minimal effective concentration.

Various gentamicin concentrations that were released from the films with time exhibited efficacy against bacterial species known to be involved in orthopedic infections. The developed systems can be applied on the surface of any metallic or polymeric fracture fixation device, and may therefore comprise a significant contribution to the field of orthopedic implants.

Keywords:
bioresorbable films • poly(lactic acid) • poly(D,L-lactic-co-glycolic acid) • gentamicin • controlled drug delivery

2007 Wiley Periodicals, Inc. J Biomed Mater Res 2007.

Clostridium difficile colitis that fails conventional metronidazole therapy: response to nitazoxanide.

Clostridium difficile colitis that fails conventional metronidazole therapy: response to nitazoxanide.

J Antimicrob Chemother. 2007 Mar 2;

Musher DM,
Logan N,
Mehendiratta V,
Melgarejo NA,
Garud S,
Hamill RJ.
Medical Service (Infectious Disease Section), Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA.

Objectives Clostridium difficile-associated disease has increased in incidence and severity. Recommended treatments include metronidazole and vancomycin. Recent investigations, however, document the failure of metronidazole to cure a substantial proportion of patients with Clostridium difficile colitis, but oral administration of vancomycin raises concerns over selection of antibiotic-resistant organisms in the hospital environment. We have recently shown that nitazoxanide is as effective as metronidazole in initial therapy for C. difficile colitis. We hypothesized that this drug might be effective in treating patients who fail therapy with metronidazole. Methods In the present study, we identified 35 patients who failed treatment with metronidazole for C. difficile colitis; failure was defined as either no improvement in symptoms or signs of disease (28 patients) after >/=14 days of treatment with metronidazole or prompt recurrence on at least two occasions after initially responding to such treatment (seven patients). These patients were ill with numerous co-morbidities. Nitazoxanide, 500 mg twice daily, was given for 10 days; results from all patients are included. Results Twenty-six (74%) of 35 patients responded to nitazoxanide, of whom seven later had recurrent disease, yielding a cure rate of 19 of 35 (54%) from initial therapy. Three who initially failed and one who had recurrent disease were re-treated with, and responded to, nitazoxanide. Thus, the aggregate cure with nitazoxanide in this difficult-to-treat population was 23 of 35 (66%). Conclusions Nitazoxanide appears to provide effective therapy for patients with C. difficile colitis who fail treatment with metronidazole.

PMID: 17337513 [PubMed - as supplied by publisher]

Pre- and probiotics

Pre- and probiotics
Ther Umsch. 2007 Mar

Meier R,
Lochs H.
Medizinische Universitatsklinik, Abteilung fur Gastroenterologie, Hepatologie und Ernahrung, Kantonsspital, Liestal.

Nowadays, the regular consumption of pre- and probiotics is recommended to provide various positive health benefits. The in vitro and in vivo demonstrated actions on the intestinal microflora, the mucosal barrier and the immunological system are very interesting to propose beneficial health effects, but the scientific proof in humans is not demonstrated yet. Pre- and probiotics are very active in the intestinal tract (mainly in the colon) by maintaining a healthy gut microflora and influencing metabolic, trophic and protective mechanism.

Prebiotics stimulates the growth of apathogen bacteria and increase the short chain fatty acid concentration by fermentation. Short chain fatty acids are necessary substrates for a healthy gut. Probiotics inhibit the growth of pathogen bacteria, reduce the translocation of bacteria and toxins and modulate the intestinal immune system. For some specific clinical diseases (ulcerative colitis, pouchitis, diarrhoea) a therapeutic and prophylactic effect with pre- and probiotics was shown.

In the near future more indications for pre- and probiotics (used as a single strain or as in a combination) will be added. Promising results are already shown in irritable bowel syndrome, prevention of antibiotic induced diarrhoea, in surgical and in intensive care patients.

Future studies should focus to determine the characteristics of a healthy gut and the evaluation of specific health benefits by well-designed, controlled human studies of adequate duration.

PMID: 17323288 [PubMed - in process]

Strategies in the treatment of infections with antibiotics in intensive care medicine.

Strategies in the treatment of infections with antibiotics in intensive care medicine.

Anasthesiol Intensivmed Notfallmed Schmerzther. 2007 Feb

Deja M,
Nachtigall I,
Halle E,
Kastrup M,
Guill MM,
Spies CD.

Abstract

The treatment of infections is one of the central elements in post-operative intensive care and contributes significantly to outcome. Measures of quality of antibiotic therapy include survival, duration of ICU or in-atient stay and rates of organ failure, antibiotic resistance or nosocomial infection. The pre-requisites for antibiotic prescribing in the intensive care unit are as follows: the treatment has to be started early, the antibiotic must be effective against probable causative organisms, the patient's risk factors for infection with multi-drug resistant organisms must be taken into account, local patterns of resistance must be known, an effective dosage must be used and the duration of therapy should be adjusted to the patient's risk factors and probable causative organisms. The multiplicity of factors which must be taken into account when determining timely empirical therapy and the fact that this must be possible at any time of the day, make local standard operating procedures for antibiotic prescribing imperative. These standards should reflect local resistance patterns and should be regularly reviewed. The aim of this educational article is to portray a selection of the pre-requisites and strategies available in the treatment of infections with antibiotics in intensive care medicine.

PMID: 17309018 [PubMed - as supplied by publisher]

New Rules for Usage of Ketek by FDA

FDA Curbs Use of Ketek - 2 of 3 Indications Taken Away, New Warning Added

By Todd Zwillich

WebMD Medical News

Reviewed By Louise Chang, MD on Monday, February 12, 2007

Feb. 12, 2007 -- Federal regulators Monday narrowed the approved uses of the controversial antibiotic Ketek, and said they will add new safety warnings for the drug.

The move is the latest in years of maneuvering over Ketek, which has been the subject of a pair of FDA reviews and a U.S. Senate investigation.

Agency officials said Ketek will no longer be approved to treat bacterial sinus infection and bacterial exacerbations of chronic bronchitis bronchitis, two generally safe upper respiratory tract infections.

It will remain an option for the treatment of community-acquired pneumonia pneumonia of mild to moderate severity.

John Jenkins, MD, head of the FDA's office of new drugs, said the agency's decision was "the result of a comprehensive analysis of risks and benefits" of Ketek.

Those risks include liver toxicity, a side effect that has increasingly concerned FDA scientists and industry watchdogs since Ketek gained U.S. approval in April 2004.

An analysis commissioned by the agency late last year found 35 cases of severe injuries that analysts say were likely attributable to Ketek.

Doctors have written an estimated 6 million prescriptions for Ketek since its approval.
But scientists have worried that the risk of liver problems, while rare, may not be worth Ketek's limited benefits.

The drug was never shown to be better than other antibiotics at curing bacterial infections, but was approved under FDA regulations that seek to speed newer agents to market in an effort to combat drug resistance.

Ketek's label was changed in June 2006 to add the warning that it carries a risk of liver damage.

New Ketek Warning

Now, a new boxed warning in Ketek's labeling will warn doctors and consumers that the drug should not be used in patients with myasthenia gravismyasthenia gravis, a chronic condition that causes muscle to tire and weaken, the agency said.

Sanofi-Aventis, Ketek's manufacturer, said it will alert doctors to the changes and begin distributing patient information guides. Sanofi-Aventis is a WebMD sponsor.

In a statement, the France-based company said Ketek remains "an important option" for doctors.

Senate Scrutiny

The FDA has come under scrutiny from Congress over Ketek.

A U.S. Senate committee report in December 2006 concluded the agency had failed to inform expert advisors reviewing Ketek that a large safety study was flawed by researcher misconduct.
And the agency's handling of Ketek is likely to be a key focus of hearings on the agency's practices scheduled for Tuesday in the U.S. House of Representatives.

Jenkins referred to the 2006 episode Monday as "a learning experience for us." If the agency encounters a similar situation in the future, "it's possible we would take a different decision at that point," he said.

Sen. Charles E. Grassley (R-Iowa), whose staff issued the Senate report, said the FDA has been held accountable for its questionable approval of Ketek.

"Now the uses for Ketek are limited, and the public is safer and better informed," Grassley said.
Sanofi-Aventis posted $58.3 million in Ketek sales in the first nine months of 2006, company spokesman Melissa Feltmann tells WebMD.

"I think it's premature to speculate on the exact impact" of Monday's announcement, she says.
SOURCES: John Jenkins, MD, director, Office of New Drugs, FDA. News release, Sanofi-Aventis. Sen. Charles E. Grassley (R-Iowa). Melissa Feltmann, spokesman, Sanofi-Aventis.

Webb MD

Linezolid: a new antibiotic for newborns and children?

Linezolid: a new antibiotic for newborns and children?
J Chemother. 2006 Dec

Cuzzolin L,
Fanos V.

Department of Medicine & Public Health, University of Verona, Italy.

Staphylococcus aureus remains one of the most common and troublesome microorganisms causing disease in humans, despite the development of effective antibiotics. Linezolid is a member of a new class of synthetic antibiotics called oxazolidinones, introduced into therapy due to the increasing resistance of Gram-positive pathogens to traditional antibiotics. Information about the pharmacokinetics and tolerability profile of linezolid in the pediatric population mostly derive from adult studies and especially in the neonatal field relatively few data are available. Here we summarize linezolid's characteristics and report data available in the literature regarding linezolid use in newborns and children. For this purpose, a Medline search was performed between 1990 and 2006 involving the term "linezolid" combined with the terms "newborn", "infant", "child", "pediatrics". Additional information was obtained from Reactions Weekly.

PMID: 17267334 [PubMed - in process]

Related Article:

Use of linezolid in children: an overview of recent advances.

Expert Rev Anti Infect Ther. 2006 Dec

Velissariou IM.
P and A Kyriakou Children's Hospital, Amphitritis, Street 3, 17561, Palio Faliro, Athens, Greece. jane_vel@hotmail.com

Linezolid is the first member of a new generation of antibiotics, the synthetic oxazolidinones, to become available, with a broad spectrum of in vitro activity against gram-positive organisms, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecalis and vancomycin-resistant E. faecium. Linezolid is showing great promise currently for the treatment of multiresistant gram-positive bacterial infections, especially complicated skin infections, catheter-induced bacteremia or nosocomial pneumonia both in the community and in a hospital setting, in children and in adults. Although most recent reports are favorable and anticipatory of a more extensive use of linezolid in appropriately selected pediatric population groups in the near future, following treatment failure of conventional antimicrobial agents, more clinical trials are, however, required to investigate the safety profile and tolerability of this new antibiotic in the pediatric population.

Full Text Article

The antibiotic resistome: the nexus of chemical and genetic diversity.

The antibiotic resistome: the nexus of chemical and genetic diversity.

Nat Rev Microbiol. 2007 Feb 5;

Wright GD.
Antimicrobial Research Centre, Department of Biochemistry and Biomedical Sciences, DeGroote School of Medicine, McMaster University, 1200 Main Street West Hamilton, Ontario, L8N 3Z5, Canada. wrightge@mcmaster.ca.

Over the millennia, microorganisms have evolved evasion strategies to overcome a myriad of chemical and environmental challenges, including antimicrobial drugs. Even before the first clinical use of antibiotics more than 60 years ago, resistant organisms had been isolated. Moreover, the potential problem of the widespread distribution of antibiotic resistant bacteria was recognized by scientists and healthcare specialists from the initial use of these drugs. Why is resistance inevitable and where does it come from? Understanding the molecular diversity that underlies resistance will inform our use of these drugs and guide efforts to develop new efficacious antibiotics.

PMID: 17277795 [PubMed - as supplied by publisher]

Making Antibiotics More Effective

Making Antibiotics More Effective

Boost to Antibiotics Effectiveness

Source: scenta

Washington, Jan. 29 (ANI): Health experts say that a new approach based on bacteriophages may reduce the requirement of antibiotics while treating various diseases by up to 50 per cent.

It is possible because of the ability of certain bacteriophages to boost the effectiveness of antibiotics gentamicin, gramacidin or tetracycline, says Steven Hagens, previously at the University of Vienna.

He told Chemistry and Industry, the magazine of the SCI, that phages' have the ability to channel through bacterial cell membranes that boosts antibiotic effectiveness.

Hagen explained the working of phages with an example of 'pseudomonas bacteria, known for causing pneumonia and hospital-acquired infections.

These bacteria are particularly multi-resistant to antibiotics because they have efflux pump mechanisms that enable them to throw out antibiotics, but Hagen said that a pore in the cell wall could cancel the efflux effect.

Experiments in mice revealed that 75 per cent of those infected with a lethal dose of Pseudomonas survived if the antibiotic gentamicin was administered in the presence of bacteriophages, while none survived without the phages.

Hagen said that the bacteriophage approach would particularly be useful for treating cases of food poisoning, as the lower doses of antibiotic needed would not disrupt the friendly bacteria in the gut.Jim Spencer, a lecturer in microbial pathogenesis at the University of Bristol, welcomed the new approach, as the overuse of antibiotics since the 1940s had slowly created a host of infections that are resistant to antibiotics. '

The prospect of using such treatments to prolong the life of existing agents and delay the onset of widespread resistance is to be welcomed,' said Spencer. (ANI)

DailyIndia

Antibiotics in the Human Food Chain

Antibiotics in the Human Food Chain
Antibiotic resistancy remains issue in EU and US

31 jan 2007

Despite declines of in-feed antibiotics, totally in the EU and partly in the US, resistancy issues are still a problem, according to scientists and livestock industry members.

The 2005 DANMAP report from the Danish government's programme for surveillance of European antimicrobial resistance, the most recent statistics available, says: "Antimicrobial consumption in food animals is still low compared to the total consumption before the cessation of growth promoter use." A chart in the report also says antimicrobial use in animals levelled in 2004 and 2005. At the same time, the use of antibiotics in humans has held about steady from 1997 through 2005, the DANMAP report showed.

US cuts back on antibiotics

The US Food and Drug Administration (FDA) says about 70% of infection-causing bacteria are resistant to at least one of the drugs most commonly used to treat infections in humans. The FDA site does not say where these bacteria acquired their resistance, but says use of antibiotics in animal feed can cause microbes to become resistant to drugs used to treat human illness.

In the US, sub-therapeutic antibiotic use, or below the level required to cure a sick animal, in livestock and poultry feed has declined in the last three years, according to Ron Phillips, vice president of legislative and public affairs for the Animal Health Institute. Antibiotics are being removed from animal feeds because consumers want them removed. In July 2005, the FDA removed its approval for Baytril for use in chicken feed because of its similarity to human antibiotics and concerns about resistant diseases. "These trends correspond to an increase in therapeutic use to treat a higher numbers of sick animals or birds. It "is precisely what is taking place in Europe," Philips added.

Farmers and veterinarian response

A Western Kansas veterinarian with a large cattle feedlot practice said many of his clients continue to use low-dose antibiotics as growth promoters because they work and because there are no comparable human drugs in use. In essence, it wouldn't matter if the animal's bacteria developed resistance to these drugs, because the bacteria still would be susceptible to human drugs, he said.

An Iowa veterinarian also said there is talk among pig producers of cutting back on antibiotics in feed, but "it's a necessary part of production." They are fed not only as a growth promoter but to prevent pneumonia and scours, or diarrhoea, he said. As if to underscore this need, the FDA recently approved another antibiotic for feed use in pigs, although it is to be done by "veterinary directive" only, the Iowa veterinarian said.

The biggest issues in the cattle industry are whether or not cattle feeders will be allowed to continue to feed tylosin phosphate (to prevent liver abscesses) and/or monesin (to prevent coccidiosis, an intestinal disease in cattle)," said Gary Smith, Colorado State University professor of meat sciences.

The answer: Few and effectiveAccording to Michael Hansen, senior scientist at the Consumers Union, which publishes Consumer Reports, the ideal rule-of-thumb is to keep livestock away from antibiotics unless they are needed, and then to treat as few as possible with an effective dose. External links:FDAConsumers Union

All About Feed

Sanitation Beats Antibiotics, Vaccines on Greatest Medical Advances List

Sanitation Beats Antibiotics, Vaccines on Greatest Medical Advances List

Monday, January 22, 2007
By Miranda Hitti
WebMD

Sanitation is the greatest medical advance since 1840, according to voters in a poll on the medical journal BMJ's web site.

The runners-up: antibiotics and anesthesia, says BMJ (formerly the British Medical Journal).
Last year, BMJ invited readers to submit nominations for the top medical breakthrough since 1840, the year the journal was launched.

BMJ then posted 15 nominations and invited people to vote on its web site between Jan. 5 and Jan. 14, 2007.

Votes poured in from more than 11,000 people (mainly doctors) in countries including Australia, Bulgaria, Canada, Germany, India, Italy, Spain, U.K., and the U.S.

Here, in order, are the results:

1. Sanitation: 1,795 votes.The importance of clean drinking water and waste disposal was recognized in the late 1800s, as diseases began to be linked to impure water. However, the World Health Organization says there is still a long way to go. More than 1.1 billion people now lack access to drinking water from an improved source; 2.6 billion do not have basic sanitation.

2. Antibiotics: 1,642 votes.Alexander Fleming, a British bacteriologist, discovered penicillin in 1928 by accident when he sloppily left a Petri dish of bacteria unwashed in his lab. He found a substance (later named penicillin) growing on it that killed the bugs, and modern-day antibiotics got its start. Fleming shared the Nobel Prize in 1945 for the discovery.

3. Anesthesia: 1,574 votes.In 1846, a Boston dentist used ether during surgery, putting an end to much of the pain of operations. Since then, general anesthesia has become a mainstay.

4. Vaccines: 1,337 votes.Vaccines have helped prevent a variety of diseases -- including polio, whooping cough, and measles. The first was Edward Jenner's smallpox vaccine, in 1796.

5. Discovery of DNA structure: 1,000 votes.Scientists James Watson and Francis Crick presented the structure of the DNA helix, the molecule responsible for carrying genetic information from one generation to the next, in 1953. It earned them the Nobel Prize in 1962.

6. Germ theory: 843 votes.In the late 1800s, Louis Pasteur was the first to suggest that disease is caused by exposure to microorganisms. Others furthered the theory, showing that specific diseases are caused by specific "bugs."

7. Oral contraceptive pill: 842 votes. The pill arrived on the U.S. market in 1960. For women who use it correctly, oral contraception can be up to 99% effective at preventing pregnancy.

8. Evidence-based medicine: 636 votes.As the name suggests, evidence-based medicine involves making use of the current best evidence (such as research), combined with a patient's values and a doctor's clinical experience, to make decisions about patient care. The term was coined in the early '90s and the concept has been evolving ever since.

9. Medical imaging: 471 votes.The X-ray was accidentally discovered in 1895. Since then, the field has expanded, giving us computed tomography (CT scans), positron emission (PET scans), magnetic resonance imaging (MRIs), and ultrasound.

10. Computers: 405 votes. From medical records to insurance, to making sure your new medication isn't going to clash with an existing one, computers are now considered as important as their stethoscopes by some doctors. They've been in use in medicine since the early 1960s. Doctors can access information on new drugs and interactions, new medical studies, and clinical trials, and keep patient records stored at their fingertips.

11. Oral rehydration therapy: 308 votes.This therapy involves giving fluids by mouth to replace losses by the body. It was first reported in 1964; now it's a mainstay of treatment in patients with cholera, acute diarrhea, and other conditions.

12. Risks of smoking: 183 votes.The first report of the connection between smoking and lung cancer was published in BMJ in 1950. Even so, tobacco use still kills an estimated 440,000 Americans each year.

13. Immunology: 182 votes.The history of immunology is traced to 1798, when Edward Jenner found that people could be immunized against the disease smallpox. Numerous other immunology discoveries followed, leading to a greater understanding of such things as allergies and antibodies.

14. Chlorpromazine: 73 votes.Discovered in 1952, chlorpromazine (Thorazine) was the first antipsychotic medication. It was used to treat psychotic disorders and their symptoms, such as hallucinations, hostility, and delusions. Its development brought new understanding of the biological basis for mental illness, and some say it provided more humane management.

15. Tissue culture: 50 votes.Tissue culture (keeping tissue alive and growing it in a culture medium for research or other purposes) was "discovered" in 1907; but it took until the 1950s for it to become an important tool for clinical investigation.

By Miranda Hitti, reviewed by Louise Chang, MD

SOURCES: News release, BMJ. WebMD Medical News: "What's the Greatest Medical Advance?"

Article

Antibiotic efflux pumps in Gram-negative bacteria: the inhibitor response strategy.

Antibiotic efflux pumps in Gram-negative bacteria: the inhibitor response strategy.

J Antimicrob Chemother. 2007 Jan 17
Mahamoud A,
Chevalier J,
Alibert-Franco S,
Kern WV,
Pages JM.

UMR-MD-1, Facultes de Medecine et de Pharmacie, Universite de la Mediterranee, 27 Boulevard Jean Moulin, F-13385 Marseille Cedex 05, France.

* Corresponding author. Tel.: +33-4-91-32-45-87; Fax: +33-4-91-32-46-06; E-mail: Jean-Marie.PAGES@medecine.univ-mrs.fr

After several decades of continuously successful antibiotic therapy against bacterial infections, we are now facing a worrying prospect: the accelerated evolution of antibiotic resistance to important human pathogens and the scarcity of new anti-infective drug families under development. Efflux is a general mechanism responsible for bacterial resistance to antibiotics. This active drug transport is involved in low intrinsic susceptibility, cross-resistance to chemically unrelated classes of molecules, and selection/acquisition of additional mechanisms of resistance.

Thus, inhibition of bacterial efflux mechanisms appears to be a promising target in order to (i) increase the intracellular concentration of antibiotics that are expelled by efflux pumps, (ii) restore the drug susceptibility of resistant clinical strains, and (iii) reduce the capability for acquired additional resistance. Structurally unrelated classes of efflux pump inhibitors (EPIs) have been described and tested in the last decade, including some analogues of antibiotic substrates and new chemical molecules. Among the current collection of EPIs, only a few compounds have been studied taking into account the structure-activity relationships and the spectrum of activity in terms of antibiotics, pumps and bacteria. While large efforts have characterized an increasing number of bacterial efflux pumps and generated several potentially active EPIs, they have not elucidated the molecular basis of efflux transport and inhibition.

Recent studies of pump-substrate complexes, the 3D resolution of the efflux pumps, the synthesis of novel compounds and molecular dynamic studies may generate new clues to decipher and select novel targets inside the efflux mechanisms and, finally, may result in a clinically useful molecule.

Key Words: antibiotic resistance , drug efflux pumps , efflux pump inhibitors

Oxford Journals

Modes and Modulations of Antibiotic Resistance Gene Expression.

Modes and Modulations of Antibiotic Resistance Gene Expression.

Clin Microbiol Rev. 2007 Jan;20

Depardieu F,
Podglajen I,
Leclercq R,
Collatz E,
Courvalin P.

Unite des Agents Antibacteriens, Institut Pasteur, 75724 Paris Cedex 15, France. pcourval@pasteur.fr.

Since antibiotic resistance usually affords a gain of function, there is an associated biological cost resulting in a loss of fitness of the bacterial host. Considering that antibiotic resistance is most often only transiently advantageous to bacteria, an efficient and elegant way for them to escape the lethal action of drugs is the alteration of resistance gene expression. It appears that expression of bacterial resistance to antibiotics is frequently regulated, which indicates that modulation of gene expression probably reflects a good compromise between energy saving and adjustment to a rapidly evolving environment.

Modulation of gene expression can occur at the transcriptional or translational level following mutations or the movement of mobile genetic elements and may involve induction by the antibiotic. In the latter case, the antibiotic can have a triple activity: as an antibacterial agent, as an inducer of resistance to itself, and as an inducer of the dissemination of resistance determinants. We will review certain mechanisms, all reversible, that bacteria have elaborated to achieve antibiotic resistance by the fine-tuning of the expression of genetic information.

PMID: 17223624 [PubMed - as supplied by publisher]

Related Article:

Genetic linkage and horizontal gene transfer, the roots of the antibiotic multi-resistance problem.

Anim Biotechnol. 2006

Summers AO.

Department of Microbiology, University of Georgia, Athens, Georgia 30602, USA. summers@uga.edu

Bacteria carrying resistance genes for many antibiotics are moving beyond the clinic into the community, infecting otherwise healthy people with untreatable and frequently fatal infections. This state of affairs makes it increasingly important that we understand the sources of this problem in terms of bacterial biology and ecology and also that we find some new targets for drugs that will help control this growing epidemic.

This brief and eclectic review takes the perspective that we have too long thought about the problem in terms of treatment with or resistance to a single antibiotic at a time, assuming that dissemination of the resistance gene was affected by simple vertical inheritance. In reality antibiotic resistance genes are readily transferred horizontally, even to and from distantly related bacteria.

The common agents of bacterial gene transfer are described and also one of the processes whereby nonantibiotic chemicals, specifically toxic metals, in the environment can select for and enrich bacteria with antibiotic multiresistance. Lastly, some speculation is offered on broadening our perspective on this problem to include drugs directed at compromising the ability of the mobile elements themselves to replicate, transfer, and recombine, that is, the three "infrastructure" processes central to the movement of genes among bacteria.

Keywords:

Bacteriophage, Evolution, Integron, Plasmid, Toxic metal resistance, Transposon

Article

Bronchitis and Antibiotics

Bronchitis and Antibiotics

Antibiotics Are Useless for Most Cases of BronchitisBut doctors keep prescribing them, contributing to bacterial resistance, study says

Healthday

Most people who go to a doctor with the raspy breathing problem called bronchitis get an antibiotic. Most of them shouldn't, a new study contends.

Two physicians at the Virginia Commonwealth University School of Medicine surveyed the world literature on bronchitis -- research studies, clinical trials and anything related to bronchitis and its treatment.

"Physicians should be encouraged to avoid antibiotics in most cases," said Dr. Richard P. Wenzel, chairman of the department of internal medicine at Virginia Commonwealth and one of the authors of the report.

The findings are published in the Nov. 16 issue of the New England Journal of Medicine.
The primary reason for over-prescription of antibiotics is that most cases of bronchitis, which is inflammation of the tiny airways of the lungs, "are caused by agents for which we have no therapy yet," meaning viruses, Wenzel said. Only a small percentage of acute bronchitis cases are caused by bacteria that doctors can treat, such as whooping cough, he said.

Yet doctors keep prescribing antibiotics, he said. He estimated that 70 percent to 80 percent of bronchitis patients are given a course of antibiotics lasting five to 10 days.

That's a lot of antibiotics. One of every 20 American adults will get bronchitis in a given year, Wenzel said. A first reason for them not taking antibiotics is that the drugs cost money, in an era when the mounting cost of health care is a major concern, he said.

"And all antibiotics have side effects, such as rash, diarrhea and abdominal pain," Wenzel said. Side effects are acceptable only when a medication helps the patient, he said.

"The third reason for not prescribing antibiotics is the impressive pressure it puts on organisms to select more resistant strains, so that the ones we use will no longer be effective," Wenzel said. While economists worry about medical costs, physicians worry about antibiotic-resistant strains of bacteria.

With all those arguments against the practice, why do doctors still write those prescriptions?
One reason is convenience, Wenzel said. "Think of all the patients we have to move through the office," he said. "I could take 15 minutes to explain why an antibiotic is not needed or write a prescription in 30 seconds."

And bronchitis tends to be overlooked as a subject of medical interest, Wenzel said. "It isn't considered very jazzy," he said. "It doesn't get highlights in medical journals or educational conferences. I can't remember in the past 10 years hearing a speaker discuss bronchitis at a medical meeting."

The information on bronchitis is there for any doctor who cares to look. The American Academy of Family Physicians notes that "because acute bronchitis is usually caused by viruses, antibiotics... usually do not help." The academy recommends getting lots of rest, drinking lots of non-caffeinated fluids, keeping the indoor humidity high and waiting for the condition to go away "after a few days or a week." If coughing and other symptoms persist, it could be a sign of a more serious condition, such as asthma or pneumonia.

One big reason for antibiotic prescriptions is patient demand, said Dr. Jeffrey Chapman, director of interstitial lung disease at the Cleveland Clinic.

"But patients are getting more savvy," he said. "They understand that a lot of infections are viral and that giving them an antibiotic places them at risk."

People with the bothersome symptoms of bronchitis shouldn't insist on a prescription, Chapman said. They should understand that "it may be the best course of treatment not to give an antibiotic."

"The message is getting out, a little bit at a time," he said. "There is a better understanding than there was, say, 10 years ago, that sometimes an antibiotic is not the better treatment."

HealthDay

Sinusitis and Antibiotics

Sinusitis and Antibiotics

Antibiotics Mostly Useless for SinusitisStudy only shows benefit with bacterial infections, which are minority of cases

(HealthDay News) -- If you develop a mild sinus infection this winter -- or even a moderately severe one -- antibiotics won't necessarily speed your recovery, new research shows.

"In the vast majority of cases, rhinosinusitis is a self-limiting disease," said Dr. An De Sutter, of Ghent University Hospital in Belgium. "It can last 10 days or longer, but antibiotics do not influence the course of the disease."

So, if you don't have signs of complications or severe infection, such as a high fever or extreme pain, your best bet is to forgo antibiotics, rely on symptomatic treatments and wait for a natural recovery, De Sutter said.

De Sutter estimates that 50 percent to 70 percent of sinusitis patients are prescribed antibiotics. Although the drugs can effectively treat patients who develop bacterial sinusitis, they are ineffective against viral sinusitis, which represents the majority of cases.

In the study, De Sutter and her colleagues looked at 300 patients with mild to moderately severe sinusitis, 218 of whom received sinus X-rays. They randomly assigned patients to receive either amoxicillin or a placebo, asked them to keep a symptom diary and observed them for 15 days.

The researchers found that neither typical sinusitis signs and symptoms nor abnormal X-rays had any value in predicting the course of the disease. They also found that the disease lasted as long in patients taking amoxicillin as it did in patients taking a placebo, and that 247 of the patients recovered within 15 days.

Only two subjective complaints -- a general feeling of illness and reduced productivity -- predicted a slower recovery from sinusitis. "In patients who feel ill or who do not feel able to work, recovery will take a few days longer," De Sutter said. "But antibiotic treatment does not speed recovery in these patients."

"We don't know for sure why antibiotic treatment seemed to have no effect on the duration of the illness," De Sutter said. "But there two possible explanations: Either the illness and X-ray abnormalities were not caused by a bacterial infection, or if they were, the patients' immune systems were able to overcome the infection just as quickly without antibiotics."

The results of the study are published in the November/December issue of the Annals of Family Medicine.

"We advise antibiotic treatment only when patients have severe symptoms such as high fever and bad pain or if they have impaired immune function," De Sutter said. "This is a very small minority of patients. For all others, we advise 'watchful waiting.' "

Instead of prescribing antibiotics, doctors should focus on symptom relief: paracetamol for pain relief and intranasal decongestants in case of a blocked nose, De Sutter suggested. "Some patients experience subjective relief by inhaling hot steam," she added.

In a similar study in the same journal, researchers found the desire for pain relief was one of the main reasons why sore-throat patients demand antibiotics. They concluded that it may be preferable to treat such patients with pain medications instead of antibiotics.

In most sinusitis cases, De Sutter believes that doctors should resist patient demand for antibiotics. "Doctors should explain to patients that antibiotics do not make a difference in the speed of recovery and can cause side effects," De Sutter said. "In our trial, diarrhea was more frequent with antibiotics. Other known side effects include nausea, oral or vaginal mold or yeast infection, allergic reactions and colitis."

The over-prescription of antibiotics, especially in children, also can cause the upper respiratory tract to become colonized with antibiotic-resistant bacteria such as S. pneumoniae, De Sutter said. "These resistant bacteria may cause infections that are more difficult to treat and may be passed on to other people."

"This is an interesting study because it looked at a large population of people with acute sinusitis," said Dr. David Sherris, chairman of otolaryngology at the University at Buffalo in New York.

"Most people do not need antibiotic therapy unless symptoms persist for more than seven to 10 days," Sherris said. "Plain X-rays of the sinuses add little or nothing to the diagnosis and treatment of acute sinusitis."

But that doesn't mean that imaging is of no value in sinusitis cases, he added. With prolonged or recurrent sinusitis or complications, computed tomography (CT) is the test of choice and works well, he noted.

"Early referral to an otolaryngologist is indicated in the most severe cases or where symptoms are out of proportion with findings," Sherris said. "The specialist can perform nasal endoscopy and accurately assess the most subtle CT scan findings."

Although the new study confirms some observations that Sherris has made during years of clinical practice, it would have been stronger if it had used the symptom system from the American Academy of Otolaryngology Head and Neck Surgery, Sherris said. "It is more complete than the one presented in this article, and though not infallible, is better to diagnose acute sinusitis."

Sherris also faulted the researchers' choice of antibiotics. "Amoxicillin, unless used in very high doses, is not a good first line antibiotic in acute sinusitis," he said. "Amoxicillin-clavulanate [augmentin] is a better choice, and is now generic in the United States. If there is an allergy to penicillin, physicians should consider azithromycin or a respiratory quinolone."

HealthDay

The danger of not taking all of your prescribed antibiotics

The danger of not taking all of your prescribed antibiotics

By Dr. Tom Gross Marin Independent Journal (California)Copyright 2007 Marin Independent Journal, a MediaNews Group publicationAll Rights Reserved Editor's note: Dr. Tom Gross is the emergency medical services director for the Novato Fire Protection District. His column appears every Monday.

I answered a telephone call the other day from a neighbor, who told me that she had a sinus infection. She wanted to know if it was OK for her to take some antibiotics. I asked her, "What antibiotics?"

She said, "Oh, I don't know, just something I have left over from my last infection." She described to me her symptoms, which included a sore throat, nasal congestion and sneezing; in other words, a common cold and not a sinus infection. She told me that whenever she gets those symptoms, she takes some leftover antibiotics from her medicine cabinet for a few days, but just until she feels better. Even though her cold would have resolved on its own, she thinks that the antibiotics are curing her illness.

There has been some doomsday press recently about strains of bacteria that are resistant to antibiotics. It is not difficult to create your own strain of antibiotic resistant bacteria. You can do it yourself at home. In fact, most people do.

Here is an experiment that you can try. All you need is some dishes of culture medium, easily available from any biological supply house, some cotton swabs, and your own vial of leftover antibiotics from the last time that you did not take your medication as prescribed.

First, take the cotton swab, wipe it along the back of your throat and rub it on a culture medium. Put the culture dish in a warm, dark place, like at the bottom of a laundry hamper and wait.

After a few days, the culture medium will be teeming with little white mounds of bacteria that look like cookie dough and smell like a laundry hamper.

Take another swab and transfer some of the bacteria to a new culture dish. Grind up a few of your leftover antibiotics and sprinkle them in the dish, close the lid and put it back in the bottom of the laundry hamper.

After a few days, examine your experiment again. The areas in the dish nearest to the antibiotic powder will be relatively free of bacterial culture; that is, no cookie dough.

However, the bacteria that have grown will have survived despite the presence of antibiotics. You will have just created your own strain of antibiotic-resistant bacteria, and you may now consider yourself to be a world-class WMD bioweapons manufacturer. You can go one step further, by repeating the experiment with another antibiotic, and you can make a bacterial culture that has multidrug resistance.

This type of experiment is known as "in vitro"; that is, your experiment was carried out "in glass." You can also perform this experiment "in vivo"; that is, in a living organism. In vivo experiments carry more scientific validity than in vitro experiments because their results are shown to be valid in actual patients rather than merely in a glass jar.

People who take their antibiotics for less than the prescribed period of time are performing in vivo experiments on themselves.

By taking antibiotics for only a few days, they are killing off the bacteria that are most susceptible, and leaving the most resistant behind to survive. They have participated in a living experiment that has demonstrated the validity of Darwin's theory of natural selection.

By exposing bacteria to intermittent small doses of antibiotics, they have killed off the bacteria that are most susceptible and have selected for those that are antibiotic resistant.

Having grown in their throats an antibiotic resistant strain of bacteria, then their next sinus infection will be truly resistant to antibiotics. These resistant bacteria can also spread to other people.

You may read in the paper about deadly strains of antibiotic resistant bacteria, such as MRSA (methicillin resistant staph aureus) or VRE (vancomycin resistant enterococcus). You may read about strains of tuberculosis bacillus that are resistant to all five antibiotics used to treat this disease.

This is no joke. This threat is real. The next time that you read about strains of antibiotic resistant bacteria, ask yourself if maybe you have been a part of this great experiment. Do you have antibiotics at home in your medicine cabinet left over from the last time that you did not take them as prescribed?

Please don't ask for stronger antibiotics. They have not been invented yet.

Article

Elective penicillin skin testing in a pediatric outpatient setting.

Elective penicillin skin testing in a pediatric outpatient setting.
Dec 2006

Jost BC,
Wedner HJ,
Bloomberg GR.
Division of Allergy and Immunology, Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA.

BACKGROUND: Adverse reactions associated with penicillin-type antibiotics are common in pediatric practice, leading to the subsequent unnecessary use of alternative antibiotics. IgE-mediated penicillin allergy represents only a fraction of these adverse reactions.

OBJECTIVES: To examine (1) the trend of penicillin skin test reactivity during a recent 10-year interval, (2) the relative distribution of specific reagents related to a positive skin test result, and (3) skin test reactivity as a function of reaction history.

METHODS: Penicillin testing using 3 reagents--benzylpenicilloyl polylysine, penicillin G, and sodium penicilloate (penicillin A)--was conducted in a prospective study of 359 consecutive patients referred to an outpatient pediatric allergy clinic between January 1, 1993, and May 31, 2003. We also retrospectively reviewed penicillin skin test results for 562 children previously tested between January 1, 1979, and December 31, 1992.

RESULTS: Between 1993 and 2003, the prevalence of penicillin skin test sensitivity markedly declined. Of all the positive skin test results between 1979 and 2002, either penicillin G or sodium penicilloate or both identified 34%, with sodium penicilloate alone responsible for 8.5%. The rate of positive skin test reactions was not significantly different between patients with vs without a history of suggestive IgE-mediated reactions.

CONCLUSIONS: A marked decline in penicillin skin test sensitivity in the pediatric age group is identified. The minor determinant reagents penicillin G and sodium penicilloate are both necessary for determining potential penicillin allergy. Relating history alone to potential penicillin sensitivity is unreliable in predicting the presence or absence of a positive skin test result.

PubMed