Roger Finch

PROSPECTIVE STUDY OF THE AETIOLOGY AND OUTCOME OF PNEUMONIA IN THE COMMUNITY

A prospective one-year study of community pneumonia was conducted in Nottingham. 236 of 251 episodes of pneumonia (defined as an acute lower respiratory tract infection, for which antibiotics were prescribed, associated with new focal signs on examination of the chest) were investigated. Acute radiographic changes were present in 93 (39%). A pathogen was identified in 129 (55%) episodes, with Streptococcus pneumoniae, Haemophilus influenzae, and influenza viruses those most frequently identified. Mycoplasma pneumoniae was uncommon and infection with Legionella pneumophila was found in only 1 episode. Hospital admission was required in 52 (22%) episodes. 7 patients died (3%), all but one of the deaths occurring in patients who had been admitted to hospital. Pneumonia in the community is common but few people die of it. Initial antibiotic therapy should always cover S pneumoniae and H influenzae.

Lack of development of new antimicrobial drugs: a potential serious threat to public health.

Antimicrobial resistance is threatening the management of infections such as pneumonia, tuberculosis, malaria, and AIDS. In the past, resistance could be handled by development of new drugs active against resistant microbes. However, the pharmaceutical industry has reduced its research efforts in infections; genomics has not delivered the anticipated novel therapeutics; new regulatory requirements have increased costs; antibiotic use in common infections-eg, bronchitis and sinusitis-is questioned; and, compared with other drugs, return on investments is lower for antimicrobials. To avoid a serious threat to public health, academia, biotechnology and pharmaceutical industry, regulators, and healthcare providers must find solutions to this problem. Academia should concentrate on technologies to unlock new drug targets, and industry on drug candidates. In addition, regulators and pharmaceutical companies should agree on new clinical-trial designs so that information on therapeutic efficacy is generated in fewer patients-eg, by studying pharmacodynamics of antimicrobials in patients with defined infections.

Discovery research: the scientific challenge of finding new antibiotics

The dwindling supply of new antibiotics largely reflects regulatory and commercial challenges, but also a failure of discovery. In the 1990s the pharmaceutical industry abandoned its classical ways of seeking antibiotics and instead adopted a strategy that combined genomics with high-throughput screening of existing compound libraries. Too much emphasis was placed on identifying targets and molecules that bound to them, and too little emphasis was placed on the ability of these molecules to permeate bacteria, evade efflux and avoid mutational resistance; moreover, the compound libraries were systematically biased against antibiotics. The sorry result is that no antibiotic found by this strategy has yet entered clinical use and many major pharmaceutical companies have abandoned antibiotic discovery. Although a raft of start-up companies-variously financed by venture capital, charity or public money--are now finding new antibiotic compounds (some of them very promising in vitro or in early trials), their development through Phase III depends on financial commitments from large pharmaceutical companies, where the discouraging regulatory environment and the poor likely return on investment remain paramount issues.

Antibiotic resistance—the interplay between antibiotic use in animals and human beings

Summary Antibiotic-resistant bacteria were first identified in the 1940s, but while new antibiotics were being discovered at a steady rate, the consequences of this phenomenon were slow to be appreciated. Today, the excessive use of antibiotics compounded by the paucity of new agents on the market has meant the problem of antibiotic resistance is fast escalating into a global health crisis. There is no doubt that misuse of these drugs in human beings has contributed to the increasing rates of resistance, but recently the use of antibiotics in food animals and its consequent effect on resistance levels in people has also come under scrutiny. Antimicrobials are used therapeutically and prophylactically in animals. More controversially, antimicrobials are also used as growth promoters to improve the ability of the animal to convert feed into body mass. Some argue that the impact of use of antibiotics in animals—whether therapeutic or as growth promoters—pales by comparison with human use, and that efforts should be concentrated on the misuse of antibiotics in people. Others warn of the dangers of unregulated and unnecessary use of antibiotics, especially growth promoters in animal husbandry. There is a growing concern over the transmission of resistant bacteria via the food chain. Many questions will be difficult to resolve, such as how do you distinguish the fraction of resistance in human beings that originated from animals? If we wait to see evidence that a significant amount of antibiotic resistance really does come through the food chain, will it be too late for action? In this forum, we present different perspectives from both human and animal medicine, to better understand the complexity of the problem of antibiotic resistance and examine the challenges that lie ahead.

Educational interventions to improve antibiotic use in the community: report from the International Forum on Antibiotic Resistance (IFAR) colloquium, 2002.

National and international strategies for the control of antibiotic resistance recommend education for health-care professionals and the public to promote prudent antibiotic use. This paper, based on discussions at the 2002 colloquium of the International Forum on Antibiotic Resistance (IFAR), provides an international discourse between theoretical approaches to behaviour change and practical experience gained in large-scale antibiotic use educational campaigns. Interventions are more likely to be effective if their aim is to change behaviour, rather than provide information. They should target all relevant groups, especially parents, children, day-care staff, and health-care professionals. They should use clear and consistent messages concerning bacterial versus viral infection, prudent antibiotic use, symptomatic treatment, and infection-control measures (eg, handwashing). Campaigns should use a range of communications using pilot-testing, strong branding, and sociocultural adaptation. Prime-time television is likely to be the most effective public medium, while academic detailing is especially useful for health-care professionals. Multifaceted interventions can improve antibiotic prescribing to some degree. However, there are few data on their effects on resistance patterns and patient outcomes, and on their cost-effectiveness. Current research aims include the application of behaviour-change models, the development and validation of prudent antibiotic prescribing standards, and the refinement of tools to assess educational interventions.

Systematic Review of Antimicrobial Drug Prescribing in Hospitals

Standardizing methods and reporting could improve interventions that reduce Clostridium difficile–associated diarrhea and antimicrobial drug resistance.

Practical Considerations and Guidelines for the Management of Community-Acquired Pneumonia

SummaryCommunity-acquired pneumonia (CAP) is a common condition which has a significant mortality. The management of a patient with CAP is centred around assessment and correction of gas exchange and fluid balance together with administration of appropriate antibiotics. Up to 10 different pathogens regularly cause CAP, of which Streptococcus pneumoniae is the most important. These different pathogens cannot be distinguished by clinical features or simple laboratory tests. Microbiological tests are slow and insensitive, so empirical therapy is necessary, at least initially. Accurate assessment of illness severity is the most important factor determining initial management, since this assists the decision of whether to admit the patient to hospital in addition to guiding antibiotic choice and route of administration.Two different approaches to severity assessment are outlined. Our antibiotic recommendation for empirical therapy for the patient managed at home and the previously fit patient admitted to hospital is amoxicillin. Amoxicillin/clavulanate plus a macrolide is our choice for the severely ill previously fit patient and a third-generation cephalosporin plus a macrolide is recommended for the severely ill patient with comorbidity. Alternative pathogens and specific treatment regimens are also described. There may be several causes of treatment failure, and in patients who fail to respond to therapy, it is essential to review all the initial clinical and laboratory information, which if necessary must be repeated.

The Staphylococcus aureus and Staphylococcus epidermidis transferrin-binding proteins are expressed in vivo during infection.

Staphylococci express a 42 kDa cell-wall-associated protein which functions as a receptor for the mammalian iron-binding glycoprotein transferrin. To determine whether this transferrin-binding protein (TBP) is expressed during infection, Staphylococcus aureus and Staphylococcus epidermidis were grown in vivo in chambers implanted intraperitoneally in rats. SDS-PAGE and Western blotting of cell wall proteins prepared from staphylococci recovered directly from the chambers revealed the presence of both the TBP and bacterial-surface-associated rat transferrin. To obtain evidence for the in vivo expression of the staphylococcal TBPs in humans, sera and human peritoneal dialysate (HPD) from non-infected patients undergoing continuous ambulatory peritoneal dialysis (CAPD) and sera from healthy human volunteers were screened for anti-TBP antibodies. Western immunoblots revealed that three out of ten samples from the latter group, seven out of ten HPD samples and ten of ten CAPD patient serum samples contained antibodies to the TBP of both S. aureus and S. epidermidis. To gain further insights into the appearance of TBP antibodies, HPD samples were collected over time from CAPD patients whose HPD samples taken immediately after catheter insertion lacked anti-TBP antibodies. In two of these patients, each of whom experienced an episode of peritonitis due to S. epidermidis or Staphylococcus hominis, antibodies to the TBP appeared in the HPD collected immediately post-infection. To determine whether such TBP antibodies were capable of blocking interactions between transferrin and its staphylococcal receptor, HPD immunoglobulin fractions were purified using protein A-Sepharose beads. In competition assays, these immunoglobulins blocked the binding of 125I-labelled transferrin both to whole bacteria and to the isolated 42 kDa TBPs of S. aureus and S. epidermidis. These provide evidence to show that staphylococcal TBPs are expressed in vivo during infection.

Antibacterial activity of quinupristin/dalfopristin. Rationale for clinical use.

SummaryMost Gram-positive organisms are highly susceptible to the streptogramin, quinupristin/dalfopristin (RP 59500; Synercid®). Minimum inhibitory concentrations for 90% of isolates (MIC90) were ≤ 1 mg/L for Staphylococcus aureus, S. epidermidis, S. haemolyticus, Streptococcus pneumoniae, S. pyogenes and Listeria monocytogenes. Importantly, quinupristin/dalfopristin shows similar activity against methicillin-susceptible and -resistant strains of S. aureus, and streptococci with benzylpenicillin (penicillin G)- or erythromycin-acquired resistance. Enterococci have varying susceptibility to quinupristin/dalfopristin, although most isolates tested are susceptible to the drug, including vancomycin-resistant and multiresistant Enterococcus faecium. E. faecalis are generally the least susceptible.Among the Gram-negative respiratory pathogens Moraxella catarrhalis is susceptible and Haemophilus influenzae is moderately susceptible to quinupristin/dalfopristin; however, Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter spp. are resistant. The drug is active against anaerobic organisms tested, including Clostridium perfringens, Lactobacillus spp., Bacteroides fragilis and Peptostreptococcus. Synergy has been demonstrated in vancomycin-resistant and multiresistant E. faecium, and methicillin-sensitive and -resistant S. aureus with the combination of vancomycin and quinupristin/dalfopristin.Quinupristin/dalfopristin shows antibacterial activity in vivo in animal models of infection, including methicillin-sensitive and -resistant S. aureus infection in rabbits, S. aureus and S. pneumoniae in mice, and erythromycin-sensitive and -resistant viridans group streptococci infections in rats.The drug is rapidly bactericidal against Gram-positive organisms (with the exception of enterococci) at concentrations similar to or within 4-fold of the MIC, and it has a long postantibiotic effect both in vitro and in vivo.

STREPTOBACILLUS MONILIFORMIS ISOLATED FROM BLOOD IN FOUR CASES OF HAVERHILL FEVER: First Outbreak in Britain

During February, 1983, an outbreak of an unusual febrile illness occurred in over 130 children attending a boarding school in Chelmsford, Essex. The clinical features included fever, an erythematous rash that was most prominent on the hands and feet, arthralgia, and the subsequent development of a sore throat. The nature and distribution of the rash varied considerably between patients and at different stages of illness. At first a viral aetiology was regarded as most likely. When Streptobacillus moniliformis was later isolated from the blood of 4 of the patients with moderately severe illnesses it became apparent that an outbreak of Haverhill fever had occurred at this school. The most probable source of the outbreak was raw milk, since all 4 patients had consumed raw milk at the school shortly before the onset of symptoms and there was no evidence of person-to-person spread of infection.