Jane Bradbury

Synthetic antimalaria drug enters clinical trials

Researchers supported by funding from the Medicines for Malaria Venture (MMV) have developed a synthetic antimalaria drug that works on the same principle as artemisinin. The new drug OZ277 has entered phase I safety trials in the UK and according to MMV chief executive officer Chris Hentschel “if OZ277 fulfils its early promise it could be registered for use as early as 2008”. Chloroquine which costs US

Epidemic Pseudomonas aeruginosa strain sequenced

0.10 per course has been the mainstay of malaria treatment for more than 50 years. But chloroquine is increasingly impotent against Plasmodium falciparum and the price tag of newer drugs such as artemisinin a natural product isolated from sweet wormwood and its semisynthetic derivatives is beyond the pockets of developing countries. (excerpt)

Human-to-human spread of H5N1—location may matter

Researchers have sequenced the genome of a virulent, transmissible strain of Pseudomonas aeruginosa. Craig Winstanley (University of Liverpool, UK) and colleagues report that LESB58, the earliest archived isolate of the Liverpool epidemic strain, contains six prophages and fi ve other genomic islands. Mutagenesis experiments suggest that several genes in these regions contribute to the in-vivo competitiveness of the epidemic strain. P aeruginosa is the commonest cause of persistent, fatal respiratory infections in patients with cystic fi brosis (CF). “Until about 10 years ago”, explains Winstanley, “we thought that patients always acquired bacteria from the environment.” Then, in the mid 1990s, a single transmissible P aeruginosa strain caused an increase in antibioticresistant infections in the children’s CF unit at the Alder Hey Hospital in Liverpool. “The Liverpool epidemic strain is now the most common single P aeruginosa strain in CF units in England and Wales”, says Winstanley, “and its emergence has led to changes in infection control policies in CF units.” To uncover genetic clues to the epidemic strain’s success, Winstanley’s team sequenced the genome of LESB58, which was obtained from a patient in Liverpool in 1988. They report that, like other P aeruginosa strains, LESB58 has a highly conserved core genome that represents about 90% of the total genomic sequence. The remaining, variable 10%, says Winstanley, contains several large genomic islands and prophages. The researchers then introduced mutations into the LESB58 genome and tested the ability of the mutant bacteria to compete against wild-type bacteria in a rat model of chronic lung infection. Their analysis shows that four genes, present in three prophages and a newly discovered genomic island, contribute to the in vivo competitiveness of LES. “This is a valuable piece of work”, comments CF microbiology expert Tyrone Pitt (Health Protection Agency, London, UK), “as it gives us the full genomic make-up of the Liverpool epidemic strain.” But, warn Pitt and Winstanley, although this research identifi es putative genes that may be involved in the transmissibility and persistence of this strain, their regulation and function will have to be elucidated before new strategies for the management of CF can be developed.

Ebolavirus bides its time in fruit bats

The H5N1 avian infl uenza virus attaches predominantly to cells deep within the human respiratory tract, report two research teams. Although both senior researchers—Thijs Kuiken (Erasmus Medical Center, Rotterdam, Netherlands) and Yoshihiro Kawaoka (University of Wisconsin-Madison, Madison, WI, USA)—stress that many factors aff ect human-to-human transmission of H5N1, the absence of attachment in the upper respiratory tract might, they suggest, contribute to the current ineffi ciency of this process. More than 100 people have been infected by H5N1 but this highly pathogenic virus has rarely, if ever, passed between people. Indeed, given its widespread occurrence within bird fl ocks, relatively few people have caught H5N1 from birds. Could it be, therefore, that only people who get bird fl u have receptors on their cells for H5N1? Flu viruses attach to sialosaccharides on their host cells through haemagglutinin. In human fl u viruses, this protein spike recognises sialic acid linked to galactose by an α2,6 linkage; avian fl u haemagglutinin recognises α2,3-linked sialosaccharides. To investigate whether human cells lack H5N1 receptors, Kawaoka’s team stained material from the human respi ratory tract with lectins specifi c for these two linkages. They found that cells in the upper respiratory tract contain receptors for human fl u viruses but only cells deep in the lungs express avian virus receptors. This receptor distribution, which the researchers confi rmed by examining the binding of avian and human fl u viruses, provides a partial explanation for H5N1’s poor humanto-human trans mission, says Kawaoka. “Because H5N1 viruses don’t grow in the upper portion of the respiratory tract, they cannot be readily transmitted by coughing and sneezing.” Kuiken and his team also investigated H5N1 virus attachment to the human respiratory tract. “We wanted to understand why H5N1 causes pneumonia”, explains Kuiken, “and like Kawaoka, we found that this virus attaches to alveolar type II pneumocytes and to non-ciliated cuboidal epithelial cells in the terminal bronchioles”. The attachment to type II pneumocytes, says Kuiken, provides new insights into the pathogenesis of H5N1 because these cells normally repair damaged lung tissue. But, he cautions, “our results only suggest, rather than prove, an explanation for the poor spread of H5N1 between people”. “These two papers help to defi ne the receptor distribution within the human respiratory tract for avian viruses like H5N1”, comments fl u expert Frederick Hayden (University of Virginia, Charlottesville, VA, USA), “and they fi t well with the clinical observation that H5N1 can cause severe primary viral pneumonia. But the idea that this receptor distribution explains poor person-to-person transmission is only speculation.” And, although mutations in the H5N1 haemagglutinin that change its binding pattern to human cells might take H5N1 a step closer to causing a human pandemic, other adaptations will also be required, conclude Hayden, Kuiken, and Kawaoka.

Changing antibiotic prescribing in hospitals

14 http://infection.thelancet.com Vol 6 January 2006 A reservoir for ebolavirus may, at last, have been identified. Gabon-based researcher Eric Leroy and colleagues report that three species of fruit bat captured near to ebolavirus outbreaks show evidence of infection with the virus. “There have been suspicions that bats might be the reservoir for ebolavirus for some time, mainly based on epidemiological observations”, says Leroy (Institut de Recherche pour le Developpement and Centre International de Recherches Medicales de Franceville, Gabon), “but our data provide the first virological evidence”. Ebolavirus, a member of the Filoviridae family of RNA viruses, causes sporadic outbreaks of often fatal haemorrhagic fever disease in people and non-human primates. To improve infection control, publichealth officials need to know the natural reservoir for ebolavirus but so far its identity has remained unclear. Leroy and colleagues collected more than 1000 bats, birds, and small terrestial vertebrates from three areas in Gabon and the Republic of the Congo just after human and non-human primate outbreaks. They examined their catches for evidence of ebolavirus by looking for ebolavirus-specific antibodies and by testing for nucleotide sequences specific for ebolavirus RNA polymerase. The only animals in which they found such evidence were three species of fruit bat, all of which are present in the regions of Africa where human ebolavirus outbreaks occur. “Other bat species may also harbour the virus without becoming ill”, notes Leroy, “but I think it is unlikely that any other animals are reservoirs for ebolavirus. We don’t know yet whether ebolavirus moves directly from bats to people”, he adds, “but we do know that local people sometimes eat these bats so we can educate them about the danger of this practice”. “This interesting article strongly suggests that fruit bats may serve as a reservoir for ebolavirus”, comments Thomas Geisbert (US Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD, USA), “but before we can definitively say that bats or any other species are a reservoir, we need to isolate the virus itself from the potential reservoir species”. Leroy agrees. “We are trying to do this but it may be difficult because the virus is probably present at very low amounts in the bats”, he explains.

Antimicrobial prophylaxis for surgery not ideal

See Proc Natl Acad Sci USA 2005; 102: 16043–48 DOI:10.1073/pnas.0503252102 A systematic review of interventions designed to improve antibiotic prescribing practices in hospitals concludes that such approaches do work and can reduce the incidence of antimicrobial resistance and of hospital-acquired infections. “We found lots of evidence that a variety of interventions change practice”, says lead author Peter Davey (Health Informatics Centre, University of Dundee, UK), “but more studies are needed with clinical and microbial outcomes”. Up to 50% of hospital antibiotic use is unnecessary or ineffective and this has contributed to an increase in hospitalacquired infections and the emergence of antibiotic-resistant bacteria. Consequently, says Davey, “there is an increasing focus on prudent prescribing”—the efficient use of antimicrobials to treat or prevent human disease. Davey’s team systematically reviewed published studies on persuasive (advice and feedback) or restrictive (limits placed on antibiotic prescriptions) interventions designed to promote prudent antibiotic prescribing in hospitals. Of 743 studies published between 1980 and 2003, only 66 met the criteria for inclusion in the systematic review. In 77% of these, the intervention improved at least one outcome—eg, the drug regimen used. “This Cochrane review is of great importance”, says Peter Mol (University Medical Center Groningen, The Netherlands), “although the preponderance of developed country study settings inhibits extrapolation to less developed countries. Many efforts are being made to optimise antimicrobial prescribing in hospitals and this review draws attention to the need for rigorous methodologies when studying the effects of such interventions.” “The Cochrane reviewers provide a good road map for anyone wanting to determine which interventions are most effective at changing antibiotic prescribing in hospitals”, adds Thomas Parrino (West Palm Beach Veterans Affairs Medical Center, FL, USA). Where electronic medical records exist, suggest Parrino and Mol, an effective way to improve prescribing is to query physicians as they enter orders for antibiotics into the medical record. In low-tech settings, adds Parrino, “the best approach is to focus on the biggest problems, undertake some social process to achieve change, and then measure the results accurately”.

A new origin for leprosy

Baseline results for the US National Surgical Infection Prevention project (http://www.medqic.org/sip) indicate that US surgeons do not always follow guidelines for antimicrobial prophylaxis before surgery (Arch Surg 2005; 140: 174–82). “Only 56% of patients received antibiotic prophylaxis in the hour before surgery as recommended”, says Dale Bratzler (Oklahoma Foundation for Medical Quality, Oklahoma City, USA). 92·6% were given appropriate antimicrobials but worryingly, antimicrobial prophylaxis was stopped within 24 hours of surgery in only 40·7% of patients, increasing the risk of antibiotic resistance developing. About 3% of operations done in the USA are complicated by surgical site infections. The principle of antimicrobial prophylaxis for the prevention of such infections was first established in the late 1960s and, says Philip S Barie (Weill Medical College of Cornell University, New York, USA), “additional studies show that a single dose of prophylactic antibiotics is sufficient, unless surgery is prolonged, and that postoperative doses accomplish nothing except maybe reassure patients”.

Malaria vaccination could drive parasite evolution.

A comparative genetics analysis indicates that all extant cases of leprosy can be attributed to the global dissemination of a single ancestral clone of Mycobacterium leprae. Joint lead investigator Marc Monot (Institut Pasteur Paris France) explains that M leprae isolates from around the world fall into four groups characterised by specific combinations of three rare single-nucleotide polymorphisms (SNPs). “These SNPs have no effect on the disease caused by M leprae” says Monot “but their pattern of occurrence suggests that leprosy may have originated in east Africa or the near east and spread through human migration to Europe Asia and north Africa before being taken to west Africa and the Americas”. (excerpt)

USA to increase smallpox vaccine stockpile

Vaccination against blood-stage malarial parasites could accelerate their rate of virulence evolution and make parasites more dangerous to nonimmunised individuals warn Margaret Mackinnon and Andrew Read of Edinburgh University (UK) on the basis of experiments in an animal model of malaria. Nevertheless stresses Read “we are strongly pro-vaccination [alongside the use of] other measures to control malaria such as bednets good housing and safe water”. Considerable effort is going into developing malaria vaccines. As of May 2004 nearly 100 vaccines were in development mostly at preclinical stages. “We are interested in how malaria parasites might respond to vaccine pressure” explains Read “and our mathematical models indicate that vaccination might favour aggressive parasites”. (excerpt)