Antibiotics for Superbacteria

New antibiotics discovered that could beat back superbacteria

Researchers hope to stop virulent form of staph

By LEE BOWMANSCRIPPS HOWARD NEWS SERVICE

Researchers reported Friday they have found four promising antibiotics in chemical families never used before against germs through a novel testing tool that can screen dozens of compounds at once.

The four compounds appear to kill bacteria, at least in a lab dish. Because they probably attack bacteria in different ways, germs should take some time to develop resistant strains.
"These represent whole new classes of antibiotic agents," said Helen Blackwell, lead author of a University of Wisconsin-Madison report on the discoveries published in the journal Chemistry and Biology.

Also, while the most potent compounds were able to kill several dangerous strains of bacteria, the strongest activity was against a highly drug-resistant strain of staph infection (Staphylococcus aureus) that has been plaguing hospitals for years and has recently become common in community settings.

"Strains are emerging that are drug-resistant to all known antibiotics," Blackwell said. "This is not a problem that is going to go away, and actually it's going to get worse. There's a sense of urgency."

The best approach is to be able to hit bacteria with drugs they have not seen before. But finding a potentially useful drug against a broad spectrum of germs is not much different from finding a needle in a haystack.

Blackwell's team designed a way to sift through a lot of hay at once with a device it calls a small-molecule macroarray. The scientists synthesize molecules on a flexible, paperlike sheet, building a compound from the bottom up by adding ingredients to the sheet one at a time.

Each array has dozens of compounds arranged in grids of dots that are about the size of a pencil eraser.

They put each array up against a battery of germs, testing the potency of each compound against various bacterial strains.

The whole process of building and testing a batch of 50 to 300 compounds takes about two days.
Only about 2 percent of the compounds tested using the arrays show any potential against bacteria. And that's just a first step on a long path to drug development.

The next stage is to understand how the compounds work to kill bacteria. "What features of compounds are necessary for activity, and can we improve them?" Blackwell said.

Once the active elements and mechanism are understood, researchers can begin testing doses and evaluating the compounds for safety in animals and eventually humans, if trials go well.

The key is that with the new macroarray, Blackwell said it's possible to see which molecules are active fairly quickly, and "we can gather information on how to improve them fairly quickly."

Seattlepi

Hydrates and solid-state reactivity: A survey of beta-lactam antibiotics.

Hydrates and solid-state reactivity: A survey of beta-lactam antibiotics.

J Pharm Sci. 2007 Apr 23

Hickey MB,
Peterson ML,
Manas ES,
Alvarez J,
Haeffner F,
Almarsson O.

TransForm Pharmaceuticals, Inc., 29 Hartwell Avenue, Lexington, Massachusetts 02421.

Crystalline hydrates of hydrolytically susceptible pharmaceuticals are commonly encountered, and are particularly prevalent in the beta-lactam class of antibiotics. In order to rationalize how the apparent chemical incompatibility between water and beta-lactams is reduced through crystallization, a review of the published literature and available structural information on the solid state stability was undertaken. A search in the CSD yielded a total of 32 crystal structures of water-containing beta-lactams which were examined and classified in terms of hydrogen-bonded networks.

In most cases the waters of hydration in the single crystal structures were found to fulfill structural roles and were not sufficiently close in proximity to react with the beta-lactam ring. Published data for the solid-state of several hydrates were also considered. In general, the stability data indicate high thermal stability for the crystalline hydrates. Moreover, even when water molecules are in appropriate proximity and orientation with respect to the beta-lactam moiety for a reaction to occur, the crystalline solids remain stable.

The use of the crystal structure information along with computational modeling suggests that a combination of proximal relationships, steric and mechanistic arguments can explain the observed solid-state stability of crystalline beta-lactam hydrates.

(c) 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 1090-1099, 2007.

PMID: 17455335 [PubMed - as supplied by publisher]

Sequential Therapy Beats Standard Therapy For Helicobacter Pylori

Sequential Therapy Beats Standard Therapy For Helicobacter Pylori

Four antibiotics versus three

Main Category: GastroIntestinal / Gastroentorology News

Article Date: 19 Apr 2007 - 21:00 PDT

In a clinical trial testing two different ways to treat Helicobacter pylori infection (a common cause of stomach ulcers), researchers found that four antibiotics given sequentially cured the infection more often than standard treatment with three antibiotics taken together for 10 days (Article, p. 556). The cure rate for the sequential treatment was 91 percent compared to 71 percent for the standard treatment. The sequential regimen was also more effective than conventional therapy for patients with certain antibiotic-resistant H. pylori bacteria. (The article and editorial are published online. They will be available in the May 1, 2007, print edition of Annals of Internal Medicine.) Note: Annals of Internal Medicine is published by the American College of Physicians.

Dental Work and Antibiotics

Guidelines: Only Some Need Dental Antibiotics

Risks May Outweigh Benefits

POSTED: 9:46 am EDT April 20, 2007

Taking antibiotics before visiting the dentist may do more harm than good, the American Heart Association says.

Some dentists prescribe antibiotics before routine cleanings or extractions to prevent infective endocarditis, an infection of the heart's inner lining or valves. But the AHA now says that is only needed for people at high risk, such as those with artificial valves, a history of endocarditis or serious heart problems.

The doctor who led the work, Walter Wilson, said there is no evidence that the antibiotics prevent infection, and they may increase resistance of bacteria when infections do occur.

A news release said that everyday tooth brushing causes 154,000 times the risk of exposure to bacteria that could cause problems than having a tooth pulled.

Original Post

Methicillin-Sensitive and Methicillin-Resistant Staphylococcus aureus: Management Principles and Selection of Antibiotic Therapy.

Methicillin-Sensitive and Methicillin-Resistant Staphylococcus aureus: Management Principles and Selection of Antibiotic Therapy.
Dermatol Clin. 2007 Apr

Elston DM.
Department of Dermatology, Geisinger Medical Center, 100 North Academy Ave., Danville, PA 17822, USA; Department of Pathology, Geisinger Medical Center, 100 North Academy Ave., Danville, PA 17822, USA.

Strains of community-acquired Methicillin-resistant Staphylococcus aureus (CA-MRSA) have emerged as an important group of pathogens. Most infections present as cutaneous abscess and most of these may respond to drainage alone. Sulfonamide and tetracycline antibiotics remain valuable agents for most CA-MRSA infections, but inducible resistance to clindamycin is problematic in some areas. Linezolid, and the newer parenteral antibiotics should be reserved for serious infections.

PMID: 17430753 [PubMed - as supplied by publisher]

Antibiotic-containing collagen for the treatment of bone defects

Antibiotic-containing collagen for the treatment of bone defects
J Biomed Mater Res B Appl Biomater. 2007 Apr 5

Rupprecht S,
Petrovic L,
Burchhardt B,
Wiltfang J,
Neukam FW,
Schlegel KA.
Oral and Maxillofacial Surgery, Friedrich Alexander University Erlangen-Nuremberg, Germany.

Recent studies have explored the use of biodegradable implants that incorporate antibiotics for the treatment of bone infections. In this study, a biodegradable composite containing bovine collagen and teicoplanin (Targobone(R)) was used for the treatment of mandibular nonunion defects. Patients with mandibular nonunion defects subsequent to osteosynthesis were treated with Targobone(R) (n = 9) or with autologous bone grafts (n = 12). Clinical and radiological evaluations were performed preoperatively, immediately postoperatively, and 4 and 24 weeks postoperatively. Bone regeneration was defined relative to the original defect area in the panoramic radiograph by using image analysis software. In the Targobone(R) group, the defect area decreased to 78% (SD +/- 21.8%) of the preoperative area within 4 weeks and to 21% (SD +/- 9.7%) of the preoperative area within 24 weeks. In the autologous bone graft group, the defect area decreased to 69% (SD +/- 32.4%) of the preoperative area within 4 weeks and to 4.7% (SD +/- 5.6%) of the preoperative area within 24 weeks. Thus, Targobone(R) is a promising option for the treatment of bone defects.

2007 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2007.

PMID: 17415766 [PubMed - as supplied by publisher]

Parental knowledge about antibiotic use: results of a cluster-randomized, multicommunity intervention

Parental knowledge about antibiotic use: results of a cluster-randomized, multicommunity intervention
Pediatrics. 2007 Apr

Huang SS,
Rifas-Shiman SL,
Kleinman K,
Kotch J,
Schiff N,
Stille CJ,
Steingard R,
Finkelstein JA.
Department of Ambulatory Care and Prevention, Harvard Medical School and Harvard Pilgrim Health Care, 133 Brookline Ave, 6th Floor, Boston, MA 02215. sshuang@partners.org.

OBJECTIVE. The goal was to determine the impact of a community-wide educational intervention on parental misconceptions likely contributing to pediatric antibiotic overprescribing.

METHODS. We conducted a cluster-randomized trial of a 3-year, community-wide, educational intervention directed at parents of children <6>

RESULTS. There were 1106 (46%) and 2071 (40%) respondents to the 2000 and 2003 surveys, respectively. Between 2000 and 2003, the proportion of parents who answered >/=7 of 10 knowledge questions correctly increased significantly in both intervention (from 52% to 64%) and control (from 54% to 61%) communities. We did not detect a significant intervention impact on knowledge regarding appropriate antibiotic use in the population overall. In a subanalysis, we did observe a significant intervention effect among parents of Medicaid-insured children, who began with lower baseline knowledge scores.

CONCLUSIONS. Although knowledge regarding appropriate use of antibiotics is improving without additional targeted intervention among more socially advantaged populations, parents of Medicaid-insured children may benefit from educational interventions to promote judicious antibiotic use. These findings may have implications for other health education campaigns.

PMID: 17403840 [PubMed - in process]

Colistin is Effective in the Treatment of Multidrug-Resistant Pseudomonas aeruginosa Infections in Cancer Patients.

Colistin is Effective in the Treatment of Multidrug-Resistant Pseudomonas aeruginosa Infections in Cancer Patients.
Antimicrob Agents Chemother. 2007 Mar 26

Hachem RY,
Chemaly RF,
Ahmar CA,
Jiang Y,
Boktour MR,
Rjaili GA,
Bodey GP,
Raad II.
The University of Texas M. D. Anderson Cancer Center, Department of Infectious Diseases, Houston, Texas, and Staten Island University Hospital, Staten Island, New York.

Background: The increasing incidence of infections caused by multidrug-resistant Pseudomonas aeruginosa is a worldwide health problem. Because no new anti-pseudomonal agents are expected to be available in the near future, we evaluated the safety and efficacy of colistin, an old drug with bactericidal activity against this organism.

Methods: We collected clinical and demographic data on 95 cancer patients diagnosed with multidrug-resistant P. aeruginosa between January 2001 and January 2004 and treated with either colistin (colistin group) or at least one active anti-pseudomonal agent (a beta-lactam antibiotic or quinolone) (control group). We compared both groups.

Results: Thirty-one patients had been treated with colistin and 64 had been treated with an anti-pseudomonal non-colistin-containing regimen. Compared with the control group, patients in the colistin group had lower median age (52 vs 62 years; P = 0.012), but more likely to have had nosocomial infections (87% vs 64%; P = 0.02). Twenty-five patients (81%) in the colistin group and 40 patients (63%) in the control group had an APACHE II score of >15 (P = 0.074). Overall clinical response rate was 52% in the colistin group versus 31% in the non-colistin group (P = 0.055). Multiple logistic regression analysis showed that those patients treated with colistin were 2.9 times (95% CI: 1.1 to 7.6) more likely to experience a clinical response to therapy than were those in the control group (P = 0.026).

Conclusions: Colistin therapy was at least as effective and as safe as beta-lactam antibiotics and quinolones in the treatment of multidrug-resistant P. aeruginosa infections and, hence, may be a useful or preferred alternative therapy for this infection in cancer patients.

Antimicrobial Agents and Chemotherapy Online

Will The Plague Pathogen Become Resistant To Antibiotics?

Will The Plague Pathogen Become Resistant To Antibiotics?
Mar 21 2007

Science Daily — A small piece of DNA that helps bacteria commonly found in US meat and poultry resist several antibiotics has also been found in the plague bacillus Yersinia pestis, gene sequence researchers report.

The ability to resist many of the antibiotics used against plague has been found so far in only a single case of the disease in Madagascar. But because the same ability is present in other kinds of bacteria from a broad range of livestock, antibiotic resistance could potentially spread to other Y. pestis and also other bacterial pathogens. In a paper published March 21 in the new journal PLoS ONE, the authors say this possibility "represents a significant public health concern."
Genetic ability to disable antibiotics, including multidrug resistance (MDR) sequences, is carried on plasmids, small circles of DNA that are passed easily between bacteria. In this study, the same MDR plasmids found in the Y. pestis from Madagascar were also present in bacteria such as Salmonella and Escherichia coli found in retail samples of beef, pork, chicken, and turkey from several US states.

"What we've done is revealed a mechanism for the acquisition of multidrug resistance in Y. pestis. Obviously, this is an event that might have serious human health consequences. But the sequencing work we've done has given us a way to monitor this plasmid in future," says senior author Jacques Ravel of The Institute for Genomic Research (TIGR) in Rockville, MD.
"The fact that we found a plasmid usually found in Salmonella in Y. pestis is a big problem. It also raises a question about how this happened, how it went from one to the other. But that's a question we cannot answer in this paper," Ravel notes. He urges a new monitoring program to track MDR in Y. pestis.

MDR Salmonella and E. coli have been found in droppings from wild geese, raising the possibility that wild animals might be able to spread MDR far beyond the livestock where it originated, Ravel notes.

"When we identified the first Y. pestis strain resistant to multiple antibiotics, we warned that if this type of strain spreads or emerges again, it would pose a serious health problem" says co-author Elisabeth Carniel, head of the Yersinia Research Unit at the Institut Pasteur in Paris. "The discovery that the multiresistance plasmid acquired by the plague bacillus is widespread in environmental bacteria reinforces this warning".

There have been many plague epidemics in human history, and Y. pestis is believed to have killed an estimated 200 million people. Plague is now regarded as a re-emerging disease, with small outbreaks all over the world. Because plague is often fatal, Y. pestis is a potential agent for bioterrorism. There is no vaccine, but antibiotics are useful for treatment and for preventing the disease's spread. The researchers observe, "Our data imply that high levels of MDR in the causative agent of plague may rapidly evolve naturally, and present a vital biomedical, public health, and biodefense threat."

The paper resulted from an international collaboration among researchers at TIGR, a division of the J. Craig Venter Institute, the Institut Pasteur in Paris, the Agricultural Research Service of the US Department of Agriculture, and the US Food and Drug Administration. This work was performed at the National Institute of Allergy and Infectious Diseases-funded Microbial Sequencing Center managed by TIGR.

Citation: Welch TJ, Fricke WF, McDermott PF, White DG, Rosso M, et al (2007) Multiple Antimicrobial Resistance in Plague: An Emerging Public Health Risk. PLoS ONE 2(3): e309. doi:10.1371/journal.pone.0000309

Science Daily

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