HMO formularies and care costs

THE LANCET 4, the public health—human rights dialogue. Harvard School of Public Health: International Federation of Red Cross and Red Crescent Societies and Francois-Xavier Bagnoud Center for Health and Human Rights, 1995: 39–47.

Time to ban all antibiotics as animal growth-promoting agents? SIR—The UK was the first country to respond to the threat of antimicrobial resistance due to inclusion of antibiotics in animal feeds and the possible risks to public health. In 1968, the Swann Committee recommended that use of therapeutically prescribed antibiotics as growth promoting additives in animal feeds should be prohibited. In 1970 the ban was put into effect in the UK, and other member states of the EC soon followed. The assumption behind the Swann recommendations was that use of other molecules with coincidental antimicrobial properties would not cause pathogens to develop resistance against therapeutically-used antibiotics. This assumption was wrong, as has clearly been shown for avoparcin and vancomycin.1 New developments— especially increasing problems with multiresistant bacteria and the search for new antibiotics against them—make it necessary to reconsider the Swann recommendations. Because of the prohibition, therapeutic antibiotics which had been regularly used as growth promoters were replaced by other molecules with antimicrobial activity, which were at that time not thought suitable or promising enough to be further developed for registration as therapeutic drugs. Well known examples of these are avoparcin, a glycopeptide, and virginiamycin, a mixture of pristinamycins. These products have since been used in very large quantities (in the Netherlands, about 600 000 kg are fed each year to animals).2 The pharmaceutical industry is having difficulty developing new drugs to combat multiresistance. Although there are now more than 250 antibiotics available for prescription—remarkably, more than 100 are ␤-lactams— these act only against six different bacterial target sites. Reassessments are being made of previously rejected molecules which act against different target sites on bacteria. Some of these agents, which may emerge as so-called new antibiotics for clinical use, are closely related to antimicrobial growth promoters. An example of such a newly released antibiotic is the combination of dalfopristin and quinupristin for treatment of serious infections due to multiresistant gram-positive cocci. Both molecules are pristinamycins and closely related to virginiamycin. Other promising molecules are avilamycin, used as a growth promoter, and pleuromutilin, of which a derivative (tiamulin) is widely used for prevention of swine dysentery.3 Development of new antibiotics derived from these once-rejected molecules may help to overcome bacterial resistance, but only temporarily: if the new antibiotics are overprescribed, resistance against them may be only a matter of time. Certainly it is important that when these new formulations enter clinical practice there is not already in existence a bacterial population able to resist them as a consequence of related compounds being used as growth promoters in animal husbandry. The emergence of resistant bacteria in the intestinal tract of animals fed with growth-promoters is evidenced by the fact that, in countries in which pigs and poultry are fed avoparcin, the animals are commonly colonised with vancomycin-resistant enterococci.1 Such bacteria, or their resistance genes, can reach man via the food chain and, with their selection advantage, replace the susceptible bacterial population. The prevention or management of resistance should probably receive priority over the development of new antibiotics. We believe that it is of utmost importance not to

Vol 348 • August 31, 1996

feed any molecules having antimicrobial properties to animals so as to enhance their growth. Such molecules might be the templates for future new life-saving antibiotics, and cross-resistance is more than likely to occur. The prohibition should not be limited to avoparcin.4 *A E van den Bogaard, E E Stobberingh Department of Medical Microbiology, University of Maastricht, NL-6200 MD Maastricht, Netherlands

1

2

3

4

Klare I, Heier H, Claus H, Reisbrodt R, Witte W. VanA-mediated high-level glycopeptide resistance in Enterococcus faecium from animal husbandry. FEMS Microbiol Lett 1995; 347: 165–71. Bogaard AE van den, Breeuwsma AJ, Julicher CHM, et al. A veterinary antibiotic policy: recommendations of a workgroup. Tijdschr Diergeneesk 1994; 119: 160–83. Zähner H, Fiedler HP. The need for new antibiotics: possible ways forward. In: Hunter PA, Darby GK, Rusell NJ, eds. Fifty years of antimicrobials: past perspectives and future trends. Cambridge: Cambridge University Press, 1995: 67–84. Howarth F, Poulter D. Vancomycin resistance: time to ban avoparcin? Lancet 1996; 347: 1047.

HMO formularies and care costs SIR—The Managed Care Outcomes Project (MCOP) was designed to examine the impact of various cost-containment practices on use of healthcare services by patients in managed care settings. Many studies have supported our finding that formulary restrictions are linked with increased use of nonrestricted drugs or health services. Because formularies and other pharmaceutical management programmes could shift costs to other service areas, it is important to measure their economic and health impacts. Designs of such studies must fit real-world situations. Our study raises important questions about the financial and health consequences of restrictive formularies for anyone striving to provide or purchase quality, cost-effective healthcare. Certainly there are no easy answers, and many opportunities for more research exist. We offer responses to Ross-Degnan and Soumerai’s (May 4, p 1264)1 remarks. In any study of association among variables, an unidentified covariate could influence relations between the independent and dependent variables. Not all independent variables need to be controlled for, only those that may act as confounders. We controlled for many site variables, and included in regression equations those site and patient variables that made correlations between resource use and formulary limitation or multisource drug use least significant. Ross-Degnan and Soumerai do not propose any specific confounding variables that we might have overlooked. They do not explain how “differences between sites could clearly have accounted for” our results, which were adjusted for known and plausible healthcare variables found relevant in earlier studies. They do not explain how differing “patterns of care” might bias our results. Our data justify only cautious inferences about causation, and our interpretation was carefully worded to reflect this caution. We considered the possibility that US health maintenance organisations (HMOs) experiencing high drug use would impose stricter formulary limitations. Since most formulary limitations had been in place for up to 12 years, we hypothesised that formulary limitations either caused higher resource use, or they were not successful in reducing costs. The statistical analysis was chosen a priori. It was no more complex than in other studies involving many potentially interacting variables. We do not understand why RossDegnan and Soumerai feel that differences in formulary limitaton between our centres were small: our data reveal a consistent linear trend between formulary limitation and

619

THE LANCET

healthcare service use. The MCOP study involved 13 000 patients with multiple record reviews over a year and is the most detailed study of managed care variables to date. Finally, the MCOP study was co-sponsored by six participating HMOs and the National Pharmaceutical Council. Researchers had full discretion about study design, execution, and findings, and their papers were closely scrutinised by expert reviewers. It may be true that costcontainment can best be achieved by determining which treatments (with control for patient differences) are associated with better outcomes. Unfortunately, it is not as simple as denying use of a drug or imposing automatic generic substitution. Susan D Horn Institute for Clinical Outcomes Research and Department of Medical Informatics, University of Utah School of Medicine, Salt Lake City, Utah 84109, USA

1

Ross-Degnan D, Soumerai SB. HMO formularies and care costs. Lancet 1996; 348: 1264.

Residual radiation in Hiroshima and Nagasaki SIR—Diagrams recently declassified by the Medical Research Council in the Public Records Office dating from early 1946 show that British doctors and scientists were fully aware that there was substantial residual radiation in the cities of Hiroshima and Nagasaki when the British Commonwealth Occupation Forces (BCOF) were sent in a few months after the two atomic detonations. A memorandum from a British scientist a decade later, now declassified, points to flaws in American studies of radiation illness and genetic effects among the Japanese survivors of the two bombings because they ignored the effects of residual radiation on people who lived in the cities or who entered them after the bombings. Several diagrams show the measurements of residual radiation in Nagasaki in December, 1945, to January, 1946, 4 months after the bombings of August. One diagram also shows residual radiation readings up to 15 km east of Nagasaki which are higher than those at the hypocentre, indicating that assumptions about simple linear relations between distance from the explosion and radiation dose received which have underwritten the major biomedical studies of the effects of nuclear weapons for the past 50 years are erroneous. Those biomedical studies, in turn, have underwritten international regulations about radiation exposure in military, civilian, and medical activities for several decades. At least 20i000 men and women from Britain, Australia, New Zealand, and India formed the BCOF. They arrived in Nagasaki and Hiroshima in the months after the two bombings and many stayed for more than 18 months. Their work involved security operations and clean-up tasks around the two devastated cities. All personnel would have been liable to inhale and ingest suspended radionuclides from the rubble and debris that they worked in and travelled through. Published memoirs show photographs of Australian soldiers playing football on the flattened hypocentre of Hiroshima. Yet all of the governments of the countries who contributed to the BCOF routinely deny claims for compensation from veterans of the BCOF for what they are convinced are their radiogenic injuries. One veterans’ welfare officer in Australia comments that, of the seven teenagers who joined the BCOF, all but one is dead from cancer and the last survivor is in remission. Of 25 men who went on a course with him, only four are left, all in parlous health. Sue Rabbitt Roff Centre for Medical Education, University of Dundee, Dundee DD2 1LR, UK

620

Preimplantation genetic diagnosis of ␤-thalassaemia SIR—Ray and colleagues (June 15, p 1696)1 describe an approach to preimplantation genetic diagnosis of ␤-thalassaemia major. We have been working towards the same goal using non-radioactive single-strand conformation polymorphism (SSCP) analysis.2 The initial request for preimplantation genetic diagnosis came from a couple of Italian origin, each carrying different mutations within the first intron (intervening sequence 1 at nucleotides 6 and 110 [nt 6, nt 110]). Nested primer sets were designed to provide a 223 base pair (bp) product that encompassed both of these mutation sites as well as those at nt 1 and nt 5, since these are common within the various UK ethnic groups. DNA strands from single somatic cells—from carriers, and from homozygous and compound heterozygous affected patients—were PCR-amplified with high efficiency (95% for buccal cells, 100% for lymphocytes and fibroblasts). Buccal cells from a normal individual and single cleavage stage blastomeres from human embryos were also used (table). SSCP analysis of denatured DNA products was done with automated gel electrophoresis (Phastsystem Pharmacia, Uppsala, Sweden).3 Under non-denaturing conditions each single-stranded molecule of DNA adopts a specific conformation allowing identification of each allele and the direct diagnosis of heterozygotes and compound heterozygotes. The amplified products from all 292 single cells were assigned the correct genetic diagnosis and, significantly, there was no allele-specific amplification failure (allele drop-out) in over 200 cells of heterozygous genotype (table) compared with 14% in the study by Ray and colleagues.1 The fact that no allele drop-out was encountered could be due to differences in the buffers in the two studies used to lyse the cells before amplification. We believe that our strategy has advantages over that proposed by Ray and colleagues. Since the PCR product is directly visualised as single DNA strands on the gel following electrophoresis, the mutant allele is immediately obvious without the additional step of restriction digest that may be a source of error. Similarly, the direct visualisation of each allele allows immediate detection of allele drop-out. Finally, our approach is more versatile in that it can detect all of the most common ␤-thalassaemia mutations in the UK population with little or no change in methodology. We thank F F Chebab (San Francisco), J M Old (Oxford), I Hussein (Cairo), M Petrou (London) for patient samples, and the IVF Unit, Hammersmith Hospital, for donated embryos; the work was sponsored by HRH E-S F El-Hashemite and the Medical Research Council.

N El-Hashemite, D Wells, *J D A Delhanty Human Genetics Group, Galton Laboratory, University College, London NW1 2HE, UK

Single cells

Mutation

Buccal Buccal Fibroblast Lymphocyte Buccal Buccal Buccal Blastomere

·· IVSI IVSI IVSI IVSI IVSI IVSI ··

Total

nt 6/IVSI nt 110 nt 110/n nt 1/IVSI nt 5 nt 110/n nt 1/n 110/IVSI 110

Number

Amplified

33 53 21 15 79 35 58 10

31 53 21 15 78 30 54 10

304

292

Genetic diagnosis n/n CHet m/n CHet m/n m/n m/m n/n

n=normal; CHet=compound heterozygote; m=mutant.

Table: Amplification of 233 bp fragment from intron I of ␤-globin gene and detection of ␤-thalassaemia mutations at IVS-1, nt 1, 5, 6, and 110 by SSCP analysis

Vol 348 • August 31, 1996