Antibiotic resistance--action to promote new technologies: report of an EU Intergovernmental Conference held in Birmingham, UK, 12-13 December 2005.

The increase in microorganisms that have developed resistance to currently available antimicrobial agents has become a major cause for concern worldwide. These organisms are widespread in hospitals but also occur increasingly in the community. Some of these strains are multiresistant and the agents available to treat infections caused by them are few and dwindling. Over recent years there have been a number of responses by national, international and professional bodies to this situation, many aimed at curbing this unprecedented growth in resistance, but there is an increasing recognition that a major problem in the management of infections caused by such organisms is the paucity of new drugs, vaccines and diagnostic aids. A conference, organized by the Specialist Advisory Committee on Antimicrobial Resistance (SACAR) on behalf of the UK Department of Health and sponsored by the BSAC, was held in Birmingham in December 2005 with the aim of addressing these problems. Conference attendees included those from academia, industry, funding agencies, healthcare management, the European Medicines Agency (EMEA), the European Centre for Disease Prevention and Control (ECDC), European Directorates and representatives of EU governments. Following a number of keynote presentations which identified major issues, there were a series of workshops which addressed specific questions and produced a number of recommendations. These recommendations were discussed by all delegates. The lack of new anti-infectives and the reasons for this were discussed in some detail. Major pharmaceutical companies no longer find this area as financially rewarding as other therapeutic areas while smaller biotechnology companies, who are seen as more innovative, are hampered by a lack of funding. In spite of a few marked successes, the use of vaccines has had minimal impact in the field of bacterial infections, and progress in this field also suffers from a lack of funding. Diagnostics could aid in the better use of antibacterials but need greater acceptance in the healthcare system, which does not generally appreciate their cost-efficacy. The major recommendations were as follows: (i) Increased efforts are needed to reduce the spread of resistant strains both in the environment and in hospitals--these include improved hygiene and decreased use of some antimicrobials. (ii) Surveillance of resistance is a key factor and improved technology (e.g. IT systems) is needed to improve the potential for surveillance data to inform clinical practice. (iii) Rapid, sensitive and specific diagnostics are urgently needed and the issue of reimbursement needs to be addressed. (iv) More accurate estimates of the cost-efficacy of using anti-infectives and diagnostics are urgently needed. (v) Vaccine technology is available but is underused for the prevention of bacterial infections, particularly those caused by organisms resistant to antimicrobials. (vi) Incentives are required to encourage large pharmaceutical companies to partner small biotechnology companies, which are more innovative and have the potential to deliver the new drugs, diagnostics and vaccines. Modifications to the international regulatory requirements for drug licensing could have a major impact on the time and thus the costs of developing new agents.

Odyssey toward a healthier world.

The 22nd International Congress of Chemotherapy was held in Amsterdam, the Netherlands, July 14, 2001. The congress attracted participants from around the world and covered a broad spectrum of work on microbial infections and cancer, their treatment by antiinfective drugs and their prevention by vaccination. A theme of the congress was "Compassion and Science," and this was picked up in a fascinating albeit slightly controversial symposium on "Health, Human Rights and Infection." There were several well-attended plenary lectures on topical subjects, including prions and variant Creutzfeldt-Jakob disease and on a possible link between autism and infection.

Coping with the rising tide of resistance to antimicrobial agents.

The 11th European Congress of Clinical Microbiology and Infectious Diseases was held in Istanbul, Turkey, from April 2nd to April 4th, 2001. The meeting was attended by approximately 4,500 people. Sessions were well attended and included a number of workshops, keynote lectures, symposia, free papers and posters. As at many chemotherapy meetings in recent years, a major topic was the continuing growth of resistance among all microbes to antimicrobial agents, and this is the topic highlighted in this report.

The battle against microbes and their growing resistance.

Scientists involved in the battle against microbes--and the worrying increase in their immunity to antimicrobial agents--gathered at the Royal College of Physicians, London, U.K., to discuss the current situation and the scope of drug discovery research efforts. In addition to analyzing the clinical implications of rising immunity to antibacterial agents, sessions covered the problem of growing resistance to antiviral, antifungal and antimalarial agents.

The fluoroquinolone antibacterials: past, present and future perspectives.

The history of the development of the quinolones is described from the first quinolone, nalidixic acid, via the first 6-fluorinated quinolone norfloxacin, to the latest extended-spectrum fluoroquinolones. The structural modifications made to the basic quinolone and naphthyridone nucleus and to the side chains have allowed improvements to be made such that the next group of fluoroquinolones after norfloxacin, exemplified by ciprofloxacin, had high activity against gram-negative species and a number of atypical pathogens, good-to-moderate activity against gram-positive species and were well absorbed and distributed. These compounds have been successfully used in the clinic for a decade and the size of the market has risen in recent years to only a little less than that for penicillins and macrolides. Notwithstanding the broad spectrum of these compounds, defects became evident. The growth in understanding of structure activity relationships with fluoroquinolones has enabled the development of even better compounds. The targets in fluoroquinolone research during the last few years include: improvements in pharmacokinetic properties, greater activity against gram-positive cocci and anaerobes, activity against fluoroquinolone-resistant strains, and improvements in activity against non-fermentative gram-negative species. The compounds developed in the recent years have fulfilled some but not all of these goals; improved bioavailability is one target achieved with most of the more recent compounds allowing for once-daily dosing. Gatifloxacin, moxifoxacin and trovafloxacin have all greatly improved the activity against gram-positive cocci, particularly pneumococci, and against anaerobes. They are not quite as active as ciprofloxacin against Enterobacteriaceae, and show no substantial improvements in activity against non-fermentative species. Clinafloxacin, gemifloxacin and sitafloxacin have even better activity against gram-positive cocci and are as active as ciprofloxacin against most gram-negatives, though gemifloxacin is less active than the other new compounds against gram-negative anaerobes. These three compounds do retain some activity against a number of ciprofloxacin-resistant species (gram-positive and gram-negative), but whether this activity will be adequate for clinical use is at present unclear. Both clinafloxacin and sitafloxacin contain a chloro substituent at position 8 of the quinolone nucleus. A halogen at this position in a number of compounds, though giving good activity, has also been associated with phototoxicity. Several fluoroquinolones have had to be withdrawn or strictly limited in their use post-marketing and in some cases no obvious relationship can be seen between the adverse effects and structural features, making this an area for urgent research.

Biochemical and microbial changes during the storage of minimally processed cantaloupe.

The effect of storage time on pH, titratable acidity, degrees Brix, organic acids, sugars, amino acids, and color of minimally processed cantaloupe melon (Cucumis melo L. var. reticulatus Naud. cv. Mission) was determined at 4 degrees C and 20 degrees C. Changes in most of the biochemical parameters with storage time were relatively slow at the lower temperature. At 20 degrees C, a 17% loss in soluble solids and a 2-fold increase in acidity occurred after 2 days. Organic acid content also increased considerably with time at this temperature as a result of the production of lactic acid. Oxalic, citric, malic, and succinic acids were the organic acids, and glucose, fructose, and sucrose were the sugars present in the freshly cut cantaloupe. Malic acid concentration decreased concurrently with lactic acid production indicating the possible involvement of anaerobic malo-lactic fermentation along with sugar utilization by lactic acid bacteria. The effect of storage on microbial growth was determined at 4, 10, and 20 degrees C. Gram-negative stained rods grew at a slower rate at 4 degrees C and 10 degrees C than the Gram-positive mesophilic bacteria that dominated microorganism growth at 20 degrees C. Eighteen amino acids were identified in fresh cantaloupe: aspartic acid, glutamic acid, asparagine, serine, glutamine, glycine, histidine, arginine, threonine, alanine, proline, tyrosine, valine, methionine, isoleucine, leucine, phenyl alanine, and lysine. The dominant amino acids were aspartic acid, glutamic acid, arginine, and alanine. Total amino acid content decreased rapidly at 20 degrees C, but only a slight decrease occurred at 4 degrees C after prolonged storage. Changes in lightness (L), chroma, and hue at both temperatures indicate the absence of browning reactions. The results indicate the potential use of lactic acid and lactic acid bacteria as quality control markers in minimally processed fruits.

The antifungal activity of mupirocin.

The antibacterial agent mupirocin (pseudomonic acid A) is used as a topical agent in the treatment of superficial infections by Gram-positive bacteria, particularly Staphylococcus aureus. However, we demonstrate here that the compound also inhibits the growth of a number of pathogenic fungi in vitro, including a range of dermatophytes and Pityrosporum spp. It inhibited the incorporation of amino acids and precursors of RNA, but not that of acetate, by Trichophyton mentagrophytes. It also inhibited the isoleucyl-tRNA synthetase from Candida albicans, indicating a mechanism of action similar to that in bacteria. When administered topically, mupirocin was efficacious in a T. mentagrophytes ringworm model in guinea pigs. These results suggest that mupirocin could have clinical utility for superficial infections caused by dermatophytes.

The properties and use of penicillins in the veterinary field, with special reference to skin infections in dogs and cats.

The use of the penicillins in veterinary dermatology is discussed. An outline is provided of the main penicillins used in the veterinary field. These include benzyl penicillin, penicillin V, ampicillin, amoxycillin, co-amoxiclav and oxacillin. An increase in ß-lactamase production among strains of Staphylococcus intermedius, the principal canine pathogen in pyoderma, has been seen in recent years. Thus only those penicillins with resistance to ß-lactamase (co-amoxiclav or isoxazolyl penicillins) are likely to be of value in treating canine pyoderma. However, feline, porcine and equine staphylococcal dermatoses, and other veterinary dermatoses such as the actinomycoses, dermatophilosis and erysipelothrix, usually respond well to most penicillins, whether or not they resist ß-lactamase.

The 20th International Congress of Chemotherapy.

Over 4,000 participants from all over the world attended the 20th International Congress of Chemotherapy (ICC) between 29th June-3rd July, 1997, in Sydney. Anti-infective and cancer chemotherapy were discussed in a wide context, with presentations being made on new products, compounds in development and current clinical approaches. Inevitably in a congress of this size, there were many sessions running concurrently (usually nine), with several simultaneous poster sessions as well. A common theme currently at many chemotherapy congresses is the growth of resistance to existing agents, and the ICC was no exception. Resistance to Gram-positive cocci is a particular problem, and many sessions were devoted to this subject. This report attempts to highlight just some of the aspects of antibacterial chemotherapy presented at the meeting. New fluoroquinolones formed a major topic that attracted a number of poster sessions and symposia, continuing a trend seen in recent years. The streptogramins offer an alternative approach to combating Gram-positive infections, and a symposium was devoted to these compounds.

Topical steroid use in the treatment of ocular alkali burns.

BACKGROUND: Ocular alkali burns can be associated with a poor visual outcome. The release of collagenases and proteases after the injury leads to corneoscleral melting. The role of topical steroids in such patients is controversial as they have been postulated to exacerbate corneoscleral melting. METHODS: 30 patients were reviewed retrospectively after admission to King's College Hospital with alkali burns between 1990 and 1993. All patients were treated with an intense and prolonged regimen of topical steroids and topical and systemic vitamin C. RESULTS: 22 patients had mild injuries and eight had severe injuries as estimated by the Roper-Hall grading system. 23 patients were treated with topical steroids for > 10 days and 22 patients were treated with topical vitamin C for more than 10 days. One patient with a severe injury developed corneoscleral melting. CONCLUSION: Prolonged treatment with topical steroids when used in conjunction with topical vitamin C is not associated with corneoscleral melting.

Jealousy induction as a predictor of power and the use of other control methods in heterosexual relationships.

26 male and 87 female college students filled out Stets' Psychological Aggression Scale, Stets' Interpersonal Control Scale, Straus' Physical Violence Scale, and Fisch and Brainerd's Use and Approval of Jealousy-inducing Behaviors Scale. Use and approval of jealousy-inducing behaviors were good predictors of high need for interpersonal control and the use of psychological aggression. The use of jealousy-inducing behaviors but not the approval of these behaviors was a strong predictor of physical aggression in romantic relationships.

Synthesis and antifungal selectivity of new derivatives of amphotericin B modified at the C-13 position.

The syntheses of the first amphotericin B derivatives to be modified solely at the C-13 hemiketal position are described. Selective functionalisation at this position is facilitated by use of the allyl ester as a C-16 carboxylate protecting group on the amphotericin B nucleus. In in vitro tests all compounds showed markedly reduced haemolytic activity against mammalian erythrocytes while two of the novel 13-alkoxy derivatives retained good antifungal activity.

Timing of removal of sutures in control of post-operative astigmatism.

A prospective, randomised study was carried out in 135 patients to determine whether the time of removal of continuous sutures in the relief of post-operative astigmatism had any effect on subsequent changes in cylinder power or axis. After uncomplicated extracapsular cataract extraction with a corneal section and continuous 10/0 nylon suture, patients with more than 3 dioptres of cylinder were allocated to have their suture removed at 6, 9 or 12 weeks post-operatively. Visual and optical outcome were assessed 1 week after suture removal and at 6 months. Although the time of removal did not affect the change in cylindrical power, the subsequent refraction was more stable when the suture was removed at 12 weeks. However, initial against-the-rule astigmatism did not significantly change after suture removal and resulted in an unsatisfactory final prescription. Suture removal should therefore be performed at 12 weeks, glasses should not be prescribed early, and a poor outcome may be anticipated in those initially against-the-rule.

Candida cell wall mannan in the vagina and its association with the signs and symptoms of vaginal candidosis.

Measurement of Candida cell wall polysaccharide (mannan) with an enzyme-linked immunosorbent assay (ELISA) was evaluated as an alternative to viable counting for the enumeration of yeast cell numbers in the human vagina. A statistically significant association was found between mannan levels and the number of colony forming units in vaginal washings collected from 40 women infected with Candida albicans (r = 0.81), indicating the accuracy of mannan levels in reflecting yeast cell load in vulvo-vaginal candidosis. Subsequent comparisons revealed a significant association between mannan levels and clinical signs in the vagina, so reflecting the importance of vulvitis and vaginitis as clinical markers for determining the severity of infection. No association was found between yeast load and the clinical symptoms, indicating the high degree of patient subjectivity. Estimation of mannan levels could be developed and used for the rapid laboratory investigation of chronic vulvo-vaginal candidosis.

6-(substituted methylene)penems, potent broad spectrum inhibitors of bacterial beta-lactamase. II. Racemic furyl and thienyl derivatives.

A series of racemic 6-(substituted methylene)penems have been prepared. These compounds contain a 5-membered monoheteroaromatic ring at C-8. The antibacterial/synergistic and beta-lactamase inhibitory activities of both E- and Z-isomers and 2-substituted derivatives are compared.