Thursday, January 26, 2006

Does antibiotic use in agriculture have a greater impact than hospital use?

David L. Smith*, Jonathan Dushoff, J. Glenn Morris

David Smith is a mathematical epidemiologist and infectious disease ecologist at Fogarty International Center, National Institutes of Health, Bethesda, Maryland, United States of America. Jonathan Dushoff is on the research staff in the Department of Ecology and Evolutionary Biology at Princeton University, Princeton, New Jersey, United States of America, and at Fogarty International Center, National Institutes of Health. J. Glenn Morris, Jr., is a physician epidemiologist and specialist in infectious diseases, and chair of the Department of Epidemiology and Preventive Medicine in the School of Medicine, University of Maryland, Baltimore, Maryland, United States of America.

Competing Interests: DLS and JGM received funding four years ago from Pfizer to conduct a risk assessment for the emergence of streptogramin resistance in Enterococcus faecium. JD declares that he has no competing interests.

Published: July 5, 2005
DOI: 10.1371/journal.pmed.0020232

Copyright: This is an open-access article distributed under the terms of the Creative Commons Public Domain Declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.

Abbreviations: ARB, antibiotic-resistant bacteria; VRE, vancomycin-resistant enterococci
Citation: Smith DL, Dushoff J, Morris JG (2005) Agricultural Antibiotics and Human Health. PLoS Med 2(8): e232

*To whom correspondence should be addressed. E-mail:

The views presented in this paper represent the personal views of the authors and do not construe or imply any official position or policy of the Fogarty International Center, National Institutes of Health, Department of Health and Human Services, or the US government.

Like SARS, Ebola, and other emerging infectious diseases, antibiotic resistance in bacteria may have a zoonotic origin [1]. Evidence suggests that antibiotic use in agriculture has contributed to antibiotic resistance in the pathogenic bacteria of humans, but the chain from cause to effect is long and complicated.

Antibiotic use clearly selects for antibiotic resistance, but how far do these effects extend beyond the population where antibiotics are used? Antibiotics and antibiotic-resistant bacteria (ARB) are found in the air and soil around farms, in surface and ground water, in wild animal populations, and on retail meat and poultry [2–9]. ARB are carried into the kitchen on contaminated meat and poultry, where other foods are cross-contaminated because of common unsafe handling practices [10,11]. Following ingestion, bacteria occasionally survive the formidable but imperfect gastric barrier, and colonize the gut [12].

Patterns of colonization (asymptomatic carriage) and infection (symptomatic carriage) in human populations provide additional evidence that ARB occasionally move from animals to humans [13,14]. The strongest evidence comes from the history of the use of antibiotics for growth promotion in Europe. After first Denmark and then the European Union banned the use of antibiotics for growth promotion, prevalence of resistant bacteria declined in farm animals, in retail meat and poultry, and within the general human population [8,15].

Despite the evidence linking bacterial antibiotic resistance on farms to resistance in humans, the impact of agricultural antibiotic use remains controversial [16–19] and poorly quantified. This is partly because of the complex of population-level processes underlying the between-species (“heterospecific”) and within-species, host-to-host (“horizontal”) spread of ARB. To emerge as human pathogens, new strains of ARB must (1) evolve, originating from mutations or gene transfer; (2) spread, usually horizontally among humans or animals, but occasionally heterospecifically; and (3) cause disease.

All three of these steps are complex and imperfectly understood. The emergence of a new type of resistance is a highly random event, which can't be predicted accurately, and may involve multiple steps that preclude perfect understanding even after the fact. Spread is equally complicated and may obscure the origins of resistance. In some cases, emergence of resistance in one bacterial species is a consequence of the emergence and spread in another species, followed by the transfer of resistance genes from one bacterial species to another. Because of the underlying complexity, mathematical models are necessary to develop theory—a qualitative understanding of the underlying epidemiological processes [20–25]. Theory helps researchers organize facts, identify missing information, design surveillance, and analyze data [26].

Horizontal Transmission

Theory clearly shows that the impact of agricultural antibiotic use depends on whether resistant bacteria have high, low, or intermediate horizontal transmission rates in human populations [23,24]. The rate of horizontal transmission among humans is determined by the underlying biology of the pathogen, medical antibiotic use, and hospital infection control, but not by agricultural antibiotic use [22]. On the other hand, a farm where multiple antibiotics are used routinely, universally, and in low quantities for growth promotion is likely to be an excellent environment for the evolution of multiple resistance factors, including some variants that might never have evolved in humans. Thus, even very rare transmission resulting from agricultural antibiotics may have a medical impact by introducing new resistant variants to the human population. The epidemiology of spread in the human population dictates how the impact of agricultural antibiotic use should be assessed.

Zoonotic pathogens, such as Campylobacter and Salmonella, are generally regarded as having low horizontal transmission rates in human populations. While resistance in zoonotic infections should be directly attributable to resistance in the zoonotic reservoir, the impact of agricultural antibiotic use remains controversial [18,27–29]. Zoonotic species could acquire resistance genes from human commensal bacteria during the infection process, but this hypothesis is difficult to test.

For pathogens with high horizontal transmission rates, resistant bacteria will spread rapidly once they have emerged, and prevalence will be maintained at a steady state by horizontal transmission. Thus, the impact of subsequent heterospecific transmission is limited (Figure 1). Nevertheless, one or two heterospecific transmission events could be sufficient to cause the appearance of a highly successful ARB genotype in humans, affecting the timing, nature, and extent of spread within the human population [22]. Not only are such events difficult to trace, but their impact is impossible to measure, since there is no way to know what type of resistance would have appeared and with what temporal pattern, if transfers from animals had been prevented.

The Emergence and Spread of Antibiotic Resistance in Bacteria with High Horizontal Transmission Rates

Emergence and spread begins with a honeymoon period following the approval of a new antibiotic; the honeymoon ends when resistance emerges. Prevalence increases exponentially at first, but it eventually approaches a steady state. The impact of agricultural antibiotic use must be assessed by comparing the observed situation with the counterfactual situation, an imaginary world in which antibiotics were never used in agriculture. The impact of agricultural antibiotic use is, then, the total number of cases of resistance that would not have happened without the use of antibiotics in agriculture. This is approximately the difference between the time of actual emergence and the counterfactual emergence, multiplied by the steady-state prevalence. While we don't know what would have happened in any particular case, we can estimate the likely magnitude of agricultural impacts.

The case where horizontal human transmission rates are intermediate is particularly interesting. If each case in a population generates approximately one new case (a situation we call “quasi-epidemic” transmission), each instance of heterospecific transmission will initiate a long chain of horizontal transmission that eventually burns out. Quasi-epidemic transmission can amplify a relatively low amount of heterospecific transmission and substantially increase prevalence [23–25]. The effect is sustained as long as heterospecific transmission continues. A corollary is that banning agricultural antibiotic use would have maximal benefits if horizontal transmission is quasi-epidemic [24]. Moreover, the effects are most difficult to estimate because both heterospecific and horizontal transmission must be accounted for.

These principles apply to bacteria associated with outpatient antibiotic use and community-acquired infections as well as those that are primarily hospital-acquired. Although quasi-epidemic transmission would seem to be a special case, it may in fact be the rule for many hospital-acquired bacteria because it is the natural endpoint of the interplay between economics and ecology [30]. By spending money on hospital infection control, hospital administrators can reduce nosocomial transmission rates for resistant bacteria. For example, hospitals may screen and isolate patients who are likely to be carriers (i.e., active surveillance) and implement infection-control measures, but this comes at the cost of isolating patients [31]. Total costs are minimized by spending just enough to eliminate (or nearly eliminate) the pathogen; thus, quasi-epidemic transmission is the economic optimum [30].

The Community as a Reservoir for Resistance

Horizontal transmission is further complicated by population structure, such as the movement of humans through hospitals and long-term care facilities. Medical antibiotic use and horizontal transmission rates are high in hospitals, but this is counterbalanced by short hospital stays. An emerging view for hospital-acquired bacterial infections is that persistent asymptomatic carriage plays a key role in the epidemic of resistance. ARB can asymptomatically colonize a person for years: even if the number of other people infected during a single hospital visit is less than one, this number will exceed one when summed over several hospital visits [25,32,33]. Thus, the ecological reservoir of resistance in the community plays an important role in the increasing frequency of resistance in hospital-acquired infections.

Short hospital visits and long persistence times of ARB in people guarantee that some of the costs associated with failed infection control are passed on to other hospitals—new carriers are frequently discharged from one hospital only to be admitted to another hospital later [30]. Thus, the harm done by these ARB is borne by the whole human population, particularly all of the health-care institutions that serve a single catchment population. In economic terms, the damage caused by the carriage of ARB is a kind of pollution.

By comparing the total number of new carriers generated in the community, the impacts of agricultural antibiotic use on hospitals can be compared directly to the impact hospitals have on each other (Figure 2). The rate of heterospecific transmission is intrinsically difficult to measure directly because the risk of exposure and colonization per meal is very small. Nevertheless, agricultural antibiotic use may generate as many carriers as hospitals for the simple reason that the population experiences many more meals than hospital discharges [34]. When agricultural and nosocomial transmission are equally rare in the population, the latter will be much easier to identify and quantify.

How Large Is the Impact of Antibiotic Use in Agriculture?
Comparing the amount of antibiotics used in agriculture with the amount used in medicine means comparing fundamentally different things because they affect the emergence of medically important antibiotic resistance in different ways. For hospital-acquired infections, it is more appropriate to think about ARB carriage in the community as a kind of pollution that flows into hospitals. Thus, the appropriate way to measure impact is by counting how many new carriers are added to the community reservoir from hospital discharges versus from exposure to bacteria that originate on farms. Different formulas describe these processes.
To count ARB carriers among hospital discharges, let x denote the proportion of patients from a hospital (or other institution) that are colonized on discharge. In some discharged patients, resistant bacteria clear quickly, but a fraction, p, become ARB carriers. Some proportion of patients were already carriers at the time of admission, denoted by k. Institutions vary by size, H, and average length of stay (1/s). Thus, the rate that new carriers are discharged from a hospital is given by the formula: sH (px − k). This formula measures the contribution of a hospital to the number of ARB carriers in the community.
For example, a hospital with 400 filled beds (H = 400 people) serves a US population of about 250,000 people. With a five-day average length of stay (the discharge rate is s = 0.2 per patient per day), the hospital discharges about 80 patients each day. If we suppose that 20% of patients acquire resistant bacteria while hospitalized, and one in four of these patients become carriers (px − k = 0.05), a hospital would discharge about four persistently colonized people per day—about 1,460 carriers after one year, or approximately 0.58% of its catchment population.
A different formula characterizes heterospecific transmission, following exposure to ARB on contaminated food. We let g denote the daily per-capita rate that ARB are ingested with a meal. Similarly, we let h denote the proportion of those ARB populations that survive the gastric barrier and persistently colonize. The number of new carriers generated in the community by agricultural antibiotic use in a population of size N is: ghN. For example, if the average person consumes some ARB in 1% of meals (g = 0.03 per person per day), followed by colonization with probability one in 2,000 (h = 0.0005), agricultural antibiotic use would generate about four new carriers per day in a population of 250,000 people, N, approximately the same number as a hospital.
The formulas illustrate a general principle: “A large number of people exposed to a small risk may generate many more cases than a small number exposed to a high risk” [

A Natural Experiment: Glycopeptides and Vancomycin-Resistant Enterococci

Is the impact of agricultural antibiotic use on the emergence and spread of ARB in humans large or small relative to medical antibiotic use? Put another way, are farms or hospitals bigger polluters? A large-scale natural experiment was conducted in the United States and several European countries when each adopted different policies on glycopeptide use in animals (avoparcin) and humans (vancomycin) [16,17,35–37]. Many European countries approved avoparcin for animal growth promotion in the 1970s, but the US did not.

In the early 1980s, demand for vancomycin in US hospitals surged because of increasing aminoglycoside resistance among enterococci and methicillin resistance in Staphylococcus aureus. Physicians in US hospitals also used oral vancomycin for some Clostridium difficile infections [37–39]. In the late 1980s and early 1990s, vancomycin-resistant enterococci (VRE) emerged and spread through US health-care systems. In Europe, hospitals used less vancomycin because most enterococci were sensitive to aminoglycosides, and oral vancomycin was seldom used. VRE still emerged and spread through European hospitals, but the problem has been less severe than in the US [40].

A different pattern emerges for community prevalence of VRE. VRE are rarely found outside of hospitals in the US, except for patients who have a prior history of hospitalization. Community prevalence of VRE in the US is typically less than 1%. In contrast, community prevalence of VRE was estimated at 2%–12% in Europe during the late 1990s, including carriage by people with no history of hospitalization [17,41–48]. In other words, the European community reservoir generated by vancomycin use in hospitals and avoparcin use in agriculture was apparently much larger than the US community reservoir generated only by vancomycin use in hospitals.

The prevalence of VRE in the community declined after the EU banned avoparcin [15]. Thus, avoparcin is at least partly responsible for the reservoir of VRE in the European community, but how much of that reservoir came from avoparcin and how much came from hospitals? To weigh the impact, we subtract the community prevalence of VRE in the US (<1%)>2%). The remainder (>1%) is attributed to avoparcin. This analysis probably underestimates the real impact because vancomycin was used less in European than in US hospitals. Thus, avoparcin use in Europe would appear to be responsible for generating a larger reservoir of VRE in the community than US hospitals. Put another way, the impact of avoparcin use on European hospitals was larger than the impact of US hospitals on one another.


Despite the evidence that avoparcin use has had a large impact on the emergence and spread of VRE by increasing the reservoir of VRE in the EU, some uncertainty continues to surround the clinical significance of VRE strains of animal origin and of the zoonotic origins of resistance in general. Bacterial strains circulating in hospitalized populations may be genetically distinct from those circulating in the general human population [13,17,49]. Thus, bacterial populations are some combination of zoonotic, quasi-epidemic, and epidemic strains. The complexity of bacterial population biology and genetics makes it practically impossible to trace bacteria (or resistance factors) from the farm to the hospital, or to directly attribute some fraction of new infections to agricultural antibiotic use. Asymptomatic carriage of resistance factors by nonfocal commensal bacteria adds to a general risk of resistance, but transfer of resistance among bacterial species is unpredictable and difficult to quantify. Until more evidence is available, it is prudent and reasonable to consider bacteria with resistance genes a general threat [50–52].

It is prudent and reasonable to consider bacteria with resistance genes a general threat.

Some part of the controversy over agricultural antibiotic use has been a disagreement about how to weigh evidence and make decisions when the underlying biological processes are complex. In this case, the effects of agricultural antibiotic use on human health remain uncertain, despite extensive investigation, and the effects may be unknowable, unprovable, or immeasurable by the empirical standards of experimental biology. What should be done when complexity makes an important public-health effect intrinsically difficult to measure? What is an appropriate “null hypothesis” or its equivalent? Should the same standards of proof be used in science and science-based policy? Where should the burden of proof fall?

Scientific assessments for policy should summarize the best state of the science, recognizing that the burdens and standards of proof are necessarily softer because of the uncertainty that is introduced by biological complexity. The best decisions weigh the evidence in light of the inherent uncertainty. The EU banned the use of antibiotics for growth promotion, based on the precautionary principle. The use of the precautionary principle was criticized by some as unscientific in this context. In fact, the intrinsic problem of knowability, posed by the biological complexity of the problem, makes the use of precautionary decision making particularly suitable in this arena. The assumption that plausible dangers are negligible, even when it is known that such dangers are constitutively very difficult to measure, may be more unscientific than the use of precaution.

Summary Points

The emergence and spread of ARB is complex and intrinsically difficult to study; mathematical models can help with understanding underlying mechanisms and guiding policy responses.

Agricultural antibiotic use may generate novel types of ARB that spread to the human population; models can help estimate how much additional disease has been caused by agricultural antibiotic use.

Transmission of ARB from animal to human populations is particularly difficult to measure, as it is the product of a very high exposure rate to potentially contaminated food, and a very low probability of transmission at any given meal.

Depending on the assumptions used, the model suggests that transmission from agriculture can have a greater impact on human populations than hospital transmission.
A comparison of patterns of colonization of VRE in Europe and the United States, which had different patterns of agricultural and hospital antibiotic use, suggests that agricultural antibiotic use can have important quantitative effects on the spread of resistance in the community.


Taylor LH, Latham SM, Woolhouse MEJ (2001) Risk factors for human disease emergence. Philos Trans R Soc Lond B Biol Sci 356: 983–989. Find this article online
Hamscher G, Pawelzick HT, Sczesny S, Nau H, Hartung J (2003) Antibiotics in dust originating from a pig-fattening farm: A new source of health hazard for farmers? Environ Health Perspect 111: 1590–1594. Find this article online
Zahn JA (2001) Evidence for transfer of tylosin and tylosin-resistant bacteria in air from swine production facilities using sub-therapeutic concentrations of Tylan in feed. J Anim Sci 79: 189. Find this article online
Iversen A, Kuhn I, Rahman M, Franklin A, Burman LG, et al. (2004) Evidence for transmission between humans and the environment of a nosocomial strain of Enterococcus faecium. Environ Microbiol 6: 55–59. Find this article online
Gilliver MA, Bennett M, Begon M, Hazel SM, Hart CA (1999) Antibiotic resistance found in wild rodents. Nature 401: 233–234. Find this article online
Osterblad M, Norrdahl K, Korpimaki E, Huovinen P (2001) Antibiotic resistance. How wild are wild mammals? Nature 409: 37–38. Find this article online
Chee-Sanford JC, Aminov RI, Krapac IJ, Garrigues-Jeanjean N, Mackie RI (2001) Occurrence and diversity of tetracycline resistance genes in lagoons and groundwater underlying two swine production facilities. Appl Environ Microbiol 67: 1494–1502. Find this article online
Emborg HD, Andersen JS, Seyfarth AM, Andersen SR, Boel J, et al. (2003) Relations between the occurrence of resistance to antimicrobial growth promoters among Enterococcus faecium isolated from broilers and broiler meat. Int J Food Microbiol 84: 273–284. Find this article online
Kmmerer K (2004) Resistance in the environment. J Antimicrob Chemother 54: 311–320. Find this article online
Mattick K, Durham K, Domingue G, Jorgensen F, Sen M, et al. (2003) The survival of foodborne pathogens during domestic washing-up and subsequent transfer onto washing-up sponges, kitchen surfaces and food. Int J Food Microbiol 85: 213–216. Find this article online
Gorman R, Bloomfield S, Adley CC (2002) A study of cross-contamination of food-borne pathogens in the domestic kitchen in the Republic of Ireland. Int J Food Microbiol 76: 143–150. Find this article online
Sorensen TL, Blom M, Monnet DL, Frimodt-Moller N, Poulsen RL, et al. (2001) Transient intestinal carriage after ingestion of antibiotic-resistant Enterococcus faecium from chicken and pork. N Engl J Med 345: 1161–1166. Find this article online
Willems RJ, Top J, vanden Braak N, van Belkum A, Endtz H, et al. (2000) Host specificity of vancomycin-resistant Enterococcus faecium. J Infect Dis 182: 816–823. Find this article online
Bruinsma N, Willems RJL, van den Bogaard AE, van Santen-Verheuevel M, London N, et al. (2002) Different levels of genetic homogeneity in vancomycin-resistant and -susceptible Enterococcus faecium isolates from different human and animal sources analyzed by amplified-fragment length polymorphisms. Antimicrob Agents Chemother 46: 2779–2783. Find this article online
Aarestrup FM, Seyfarth AM, Emborg HD, Pedersen K, Hendriksen RS, et al. (2001) Effect of abolishment of the use of antimicrobial agents for growth promotion on occurrence of antimicrobial resistance in fecal enterococci from food animals in Denmark. Antimicrob Agents Chemother 45: 2054–2059. Find this article online
Wegener HC, Aarestrup FM, Jensen LB, Mammerum AM, Bager F (1999) Use of antimicrobial growth promoters in food animals and Enterococcus faecium resistance to therapeutic antimicrobial drugs in Europe. Emerg Infect Dis 5: 329–335. Find this article online
Bonten MJ, Willems R, Weinstein RA (2001) Vancomycin-resistant enterococci: Why are they here, and where do they come from? Lancet Infect Dis 1: 314–325. Find this article online
Phillips I, Casewell M, Cox T, de Groot B, Friis C, et al. (2004) Does the use of antibiotics in food animals pose a risk to human health? A critical review of published data. J Antimicrob Chemother 53: 28–52. Find this article online
Jensen VF, Neimann J, Hammerum AM, Molbak K, Wegener HC (2004) Does the use of antibiotics in food animals pose a risk to human health? An unbiased review? J Antimicrob Chemother 54: 274–275. Find this article online
Bonten MJ, Austin DJ, Lipsitch M (2001) Understanding the spread of antibiotic resistant pathogens in hospitals: Mathematical models as tools for control. Clin Infect Dis 33: 1739–1746. Find this article online
Lipsitch M, Singer RS, Levin BR (2002) Antibiotics in agriculture: When is it time to close the barn door? Proc Natl Acad Sci U S A 99: S572–S574. Find this article online
Smith DL, Harris AD, Johnson JA, Silbergeld EK, Morris JG Jr (2002) Animal antibiotic use has an early but important impact on the emergence of antibiotic resistance in human commensal bacteria. Proc Natl Acad Sci U S A 99: 6434–6439. Find this article online
Smith DL, Johnson JA, Harris AD, Furuno JP, Perencevich EN, et al. (2003) Assessing risks for a pre-emergent pathogen: Virginiamycin use and the emergence of streptogramin resistance in Enterococcus faecium. Lancet Infect Dis 3: 241–249. Find this article online
Kelly L, Smith DL, Snary EL, Johnson JA, Harris AD, et al. (2004) Animal growth promoters: To ban or not to ban? A risk assessment approach. Int J Antimicrob Agents 24: 205–212. Find this article online
Smith DL, Dushoff J, Perencevich EN, Harris AD, Levin SA (2004) Persistent colonization and the spread of antibiotic resistance in nosocomial pathogens: Resistance is a regional problem. Proc Natl Acad Sci U S A 101: 3709–3714. Find this article online
Becker NG (1989) Analysis of infectious disease data. London: Chapman and Hall. 224 p.
Wegener HC, Aarestrup FM, Gerner-Smidt P, Bager F (1999) Transfer of antibiotic resistant bacteria from animals to man. Acta Vet Scand Suppl 92: 51–57. Find this article online
Aarestrup FM, Engberg J (2001) Antimicrobial resistance of thermophilic Campylobacter. Vet Res 32: 311–321. Find this article online
Luber P, Wagner J, Hahn H, Bartelt E (2003) Antimicrobial resistance in Campylobacter jejuni and Campylobacter coli strains isolated in 1991 and 2001–2002 from poultry and humans in Berlin, Germany. Antimicrob Agents Chemother 47: 3825–3830. Find this article online
Smith DL, Levin SA, Laxminarayan R (2005) Strategic interactions in multi-institutional epidemics of antibiotic resistance. Proc Natl Acad Sci U S A 102: 3153–3158. Find this article online
Perencevich EN, Fisman DN, Lipsitch M, Harris AD, Morris JG Jr, et al. (2004) Projected benefits of active surveillance for vancomycin-resistant enterococci in intensive care units. Clin Infect Dis 38: 1108–1115. Find this article online
Bonten MJ, Hayden MK, Nathan C, Rice TW, Weinstein RA (1998) Stability of vancomycin-resistant enterococcal genotypes isolated from long-term-colonized patients. J Infect Dis 177: 378–382. Find this article online
Cooper BS, Medley GF, Stone SP, Kibbler CC, Cookson BD, et al. (2004) Methicillin-resistant Staphylococcus aureus in hospitals and the community: Stealth dynamics and control catastrophes. Proc Natl Acad Sci U S A 101: 10223–10228. Find this article online
Rose G (1992) The strategy of preventive medicine. Oxford: Oxford University Press. 160 p.
Martone WJ (1998) Spread of vancomycin-resistant enterococci: Why did it happen in the United States? Infect Control Hosp Epidemiol 19: 539–545. Find this article online
Cetinkaya Y, Falk P, Mayhall CG (2000) Vancomycin-resistant enterococci. Clin Microbiol Rev 13: 686–707. Find this article online
Rice LB (2001) Emergence of vancomycin-resistant enterococci. Emerg Infect Dis 7: 183–187. Find this article online
Morris JG Jr, Shay DK, Hebden JN, McCarter RJ Jr, Perdue BE, et al. (1995) Enterococci resistant to multiple antimicrobial agents, including vancomycin. Establishment of endemicity in a university medical center. Ann Intern Med 123: 250–259. Find this article online
Kirst HA, Thompson DG, Nicas TI (1998) Historical yearly usage of vancomycin. Antimicrob Agents Chemother 42: 1303–1304. Find this article online
Schouten MA, Hoogkamp-Korstanje JA, Meis JF, Voss A European VRE Study Group (2000) Prevalence of vancomycin-resistant enterococci in Europe. Eur J Clin Microbiol Infect Dis 19: 816–822. Find this article online
van der Auwera P, Pensart N, Korten V, Murray BE, Leclercq R (1996) Influence of oral glycopeptides on the fecal flora of human volunteers: Selection of highly glycopeptide-resistant enterococci. J Infect Dis 173: 1129–1136. Find this article online
Gordts B, van Landuyt H, Ieven M, Vandamme P, Goossens H (1995) Vancomycin-resistant enterococci colonizing the intestinal tracts of hospitalized patients. J Clin Microbiol 33: 2842–2846. Find this article online
Endtz HP, van den Braak N, van Belkum A, Kluytmans JA, Koeleman JG, et al. (1997) Fecal carriage of vancomycin-resistant enterococci in hospitalized patients and those living in the community in The Netherlands. J Clin Microbiol 35: 3026–3031. Find this article online
Schouten MA, Voss A, Hoogkamp-Korstanje JA (1997) VRE and meat. Lancet 349: 1258. Find this article online
van den Braak N, Kreft A, van Belkum D, Verbrugh H, Endtz H (1997) Vancomycin-resistant enterococci in vegetarians. Lancet 350: 146–147. Find this article online
van den Bogaard AE, Mertens P, London NH, Stobberingh EE (1997) High prevalence of colonization with vancomycin- and pristinamycin-resistant enterococci in healthy humans and pigs in The Netherlands: Is the addition of antibiotics to animal feeds to blame? J Antimicrob Chemother 40: 454–456. Find this article online
van den Braak N, van Belkum A, van Keulen M, Vliegenthart J, Verbrugh HA, et al. (1998) Molecular characterization of vancomycin-resistant enterococci from hospitalized patients and poultry products in The Netherlands. J Clin Microbiol 36: 1927–1932. Find this article online
Stobberingh E, van den Bogaard A, London N, Driessen C, Top J, et al. (1999) Enterococci with glycopeptide resistance in turkeys, turkey farmers, turkey slaughterers, and (sub)urban residents in the south of The Netherlands: Evidence for transmission of vancomycin resistance from animals to humans? Antimicrob Agents Chemother 43: 2215–2221. Find this article online
Leavis HL, Willems RJ, Top J, Spalburg E, Mascini EM, et al. (2003) Epidemic and nonepidemic multidrug-resistant Enterococcus faecium. Emerg Infect Dis 9: 1108–1115. Find this article online
Hammerum AM, Fussing V, Aarestrup FM, Wegener HC (2000) Characterization of vancomycin-resistant and vancomycin-susceptible Enterococcus faecium isolates from humans, chickens, and pigs by RiboPrinting and pulsed-field gel electrophoresis. J Antimicrob Chemother 45: 677–680. Find this article online
Sundsfjord A, Simonsen GS, Courvalin P (2001) Human infections caused by glycopeptide-resistant Enterococcus spp: Are they a zoonosis? Clin Microbiol Infect 7. Suppl 4 16–33. Find this article online
Bogo Jensen L, Willems AE, van den Bogaard RJ (2003) Genetic characterization of glycopeptide-resistant enterococci of human and animal origin from mixed pig and poultry farms. APMIS 111: 669–772. Find this article online

Plos Medicine

Wednesday, January 25, 2006

IBS Study Shows That Targeted Antibiotics Lead To Long-Lasting Improvement In Symptoms

Category: Irritable-Bowel Syndrome News

Article Date: 07 Dec 2005 - 9:00am (UK)

Researchers at Cedars-Sinai have found that a nonabsorbable antibiotic - one that stays in the gut - may be an effective long-term treatment for irritable bowel syndrome (IBS). The findings, which showed that participants benefited from the antibiotic use even after the course of treatment ended, support previously published research identifying small intestine bacterial overgrowth (SIBO) as a possible cause of the disease.


Cedars-Sinai Medical Center

Tuesday, January 24, 2006

FDA Investigates Death Linked to Antibiotic

FDA Investigates Death Linked to Antibiotic

Three cases of severe liver problems and one death have been reported after patients were given a certain antibiotic. The U.S. Food and Drug Administration is investigating whether the drug telithromycin (Ketek) is responsible.

A patient at Carolinas Medical Center in Charlotte, N.C., died after taking telithromycin. Another had to have a liver transplant, while the third survived a drug-induced case of hepatitis after Ketek was discontinued.

“Because these liver problems are significant and somewhat.... unpredictable, the FDA is evaluating this... medicine in both the U.S. and abroad.... to determine whether additional warning guidance is merited," said FDA spokeswoman Susan Bro.


FDA Issues Alert On Sanofi Antibiotic Ketek

01-20-06 02:41 PM EST

WASHINGTON -(Dow Jones)- The Food and Drug Administration issued a public health advisory Friday after doctors at Carolinas Medical Center in Charlotte reported that one patient died from liver failure and another required a liver transplant in cases that might be linked to an antibiotic marketed by Sanofi- Aventis (SNY).

Doctors also said one patient developed drug-induced hepatitis but later recovered. The antibiotic is sold under the brand name Ketek and was approved by the FDA on April 1, 2004.
The FDA said it was investigating the reports and was conducting a review of other adverse events related to the drug.

The three case reports were released Friday in an online edition of the Annals of Internal Medicine. The article describing the liver problems will appear in the March 21 print edition.
"These cases could represent an unusual clustering of a rare, idiosyncratic drug reaction at one medical center," said John S. Hanson, one of the article's authors and hepatologist with the liver transplant center at Carolinas Medical Center. "However, the severity of liver injury in two of our patients warrants this report in the medical literature and will alert other physicians to this possible link with telithromycin."

Until the FDA review is complete, FDA spokeswoman Susan Bro said the agency isn't making any new recommendations regarding the prescribing practices for Ketek.
She said patients on Ketek should not stop the medication. However, she said patients taking Ketek should contact their physician if they notice yellowing of their eyes or skin or other problems such as blurry vision.

"At this time, FDA advises health-care providers to monitor patients taking telithromycin (Ketek) for symptoms of possible liver problems including jaundice or elevated liver enzymes," the agency said in a statement.

The drug's label, which is aimed at physicians, discusses the possibility of liver dysfunction with the drug. Rare liver problems have been seen with Ketek and similar antibiotics.
A Sanofi spokesman did not return two messages left for comment Friday.

The three cases of liver problems were discovered either during treatment or shortly after the patients started taking Ketek. The patients were not on other medications but two of the three of them reported regular alcohol use.

Researchers said there's no proof that Ketek, known generically as telithromycin, caused the liver problems but that "caution is advised in prescribing this drug pending additional postmarketing surveillance data."

Dr. Hanson said despite the three reports there's "not enough data to indicate major changes in prescribing habits."

According to the article, 10 reports of liver problems have been reported to the FDA involving Ketek as of June 2005. However, researchers said that in eight of those cases patients were also on other medications.

Ketek was approved to kill bacteria that cause sinus infections, bronchitis and pneumonia. It's in a group of medicine known as macrolides that includes erythromycin, Pfizer Inc.'s (PFE) Zithromax and Abbott Laboratories' (ABT) Biaxin.

The drug's label said that cases of liver problems had been reported but that they were "generally reversible." The label warns of possible vision problems.
"Based on the pre-marketing clinical data, it appeared that the risk of liver injury with telithromycin was similar to that of other marketed antibiotics," the FDA said.
-By Jennifer Corbett Dooren, Dow Jones Newswires; 202-862-9294; (END) Dow Jones Newswires
01-20-06 1441ET
Copyright (c) 2006 Dow Jones & Company, Inc.

Sunday, January 22, 2006

Intracellular Staphylococcus aureus and antibiotic resistance: Implications for treatment of staphylococcal osteomyelitis.


Jan 2006

Ellington JK, Harris M, Hudson MC, Vishin S, Webb LX, Sherertz R.

Department of Orthopaedic Surgery, Carolinas Medical Center, 1000 Blythe Boulevard, Charlotte, North Carolina 28223.

Staphylococcus aureus is responsible for 80% of human osteomyelitis. It can invade and persist within osteoblasts. Antibiotic resistant strains of S. aureus make successful treatment of osteomyelitis difficult. Null Hypothesis: antibiotic sensitivities of S. aureus do not change after exposure to the osteoblast intracellular environment. Human and mouse osteoblast cultures were infected and S. aureus cells were allowed to invade. Following times 0, 12, 24, and 48 h ( +/- the addition of erythromycin, clindamycin, and rifampin at times 0 or 12 h), the osteoblasts were lysed and intracellular bacteria enumerated. Transmission electron microscopy was performed on extracellular and intracellular S. aureus cells. In mouse osteoblasts, administration of bacteriostatic antibiotics at time 0 prevented the increase in intracellular S. aureus. If the antibiotics were delayed 12 h, this did not occur. When rifampin (bactericidal) was introduced at time 0 to human and mouse osteoblasts, there was a significant decrease in number of intracellular S. aureus within osteoblasts compared to control. If rifampin was delayed 12 h, this did not occur. Significant time-dependent S. aureus structural changes were observed after exposure to the osteoblast intracellular environment. These studies demonstrate that once S. aureus is established intracellularly for 12 h, the bacteria are less sensitive to antibiotics capable of eukaryotic cell penetration (statistically significant). These antibiotic sensitivity changes could be due in part to the observed structural changes. This leads to the rejection of our null hypotheses that the antibiotic sensitivities of S. aureus are unaltered by their location. (c) 2005 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.PMID: 16419973

[PubMed - in process]

Saturday, January 21, 2006

Death Reported From Novel Antibiotic

By ANDREW BRIDGES, Associated Press Writer

Fri Jan 20, 8:14 PM ET

WASHINGTON - Researchers reported Friday three cases of severe liver problems, including one death, in patients at a North Carolina hospital after they began taking a novel antibiotic

Federal regulators said they were reviewing an unknown number of U.S. cases involving the drug, telithromycin, and were consulting with their counterparts overseas.

One patient at Carolinas Medical Center in Charlotte, N.C., died after taking telithromycin, which is marketed as Ketek, researchers at the hospital said. Another required and received a liver transplant, while the third recovered from drug-induced hepatitis after treatment with Ketek was stopped.

The severity of the cases warranted the researchers' alerting doctors to what they called a "possible link with telithromycin," said Dr. John Hanson, who works in the liver transplant center at Carolinas Medical Center.

The reports do not prove the drug caused the problems, researchers said. Nor is there enough information to support major changes in how the drug is prescribed, Hanson said. Two of the three patients reported some use of alcohol, although there was no prior evidence of liver damage.

The cases are discussed in a paper to be published March 21 in the journal Annals of Internal Medicine. The journal released an electronic version on Friday.

The drug is made by Sanofi-Aventis. A company spokeswoman did not immediately return a message seeking comment left midday Friday.

The Food and Drug Administration approved the drug, marketed as Ketek, in 2004 for treatment of acute bacterial infections from chronic bronchitis, acute bacterial sinusitis and community-acquired pneumonia. On Friday, FDA spokeswoman Susan Bro said the agency would comb through its databases for other reports of liver problems in patients treated with the drug.

"Because these liver problems are significant and somewhat idiosyncratic or unpredictable, the FDA is evaluating the use of this medicine in both the U.S. and abroad where it is used and marketed to determine whether additional warning guidance is merited," Bro said.
Bro cautioned that patients on the drug who experience any sort of liver distress, including jaundice, should talk to their doctors immediately.

On the Net:

Food and Drug Administration

Sanofi-Aventis Ketek information

Thursday, January 12, 2006

Topical Antibiotic: Clindamycin

Description Return to top

Clindamycin ( klin-da-MYE-sin) belongs to the family of medicines called antibiotics. Topical clindamycin is used to help control acne. It may be used alone or with one or more other medicines that are used on the skin or taken by mouth for acne. Topical clindamycin may also be used for other problems as determined by your doctor.

Clindamycin is available only with your doctor's prescription, in the following dosage forms:

Foam (U.S.)
Gel (U.S.)
Solution (U.S. and Canada)
Suspension (U.S.)

Before Using This Medicine Return to top

In deciding to use a medicine, the risks of using the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For topical clindamycin, the following should be considered:

Allergies—Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any of the other clindamycins (by mouth or by injection) or to lincomycin. Also tell your health care professional if you are allergic to any other substances, such as preservatives or dyes.

Pregnancy—Clindamycin has not been studied in pregnant women. However, this medicine has not been shown to cause birth defects or other problems in animal studies.

Breast-feeding—Small amounts of topical clindamycin are absorbed through the skin. It is possible that small amounts of the medicine may pass into the breast milk. However, this medicine has not been reported to cause problems in nursing babies.

Children—Studies on this medicine have been done only in adult patients, and there is no specific information comparing use of this medicine in children up to 12 years of age with use in other age groups.

Older adults—Many medicines have not been studied specifically in older people. Therefore, it may not be known whether they work exactly the same way they do in younger adults.

Although there is no specific information comparing use of this medicine in the elderly with use in other age groups, this medicine is not expected to cause different side effects or problems in older people than it does in younger adults.

Other medicines—Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your health care professional if you are using any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Other medical problems—The presence of other medical problems may affect the use of topical clindamycin. Make sure you tell your doctor if you have any other medical problems, especially:
History of stomach or intestinal disease (especially colitis, including colitis caused by antibiotics, or enteritis)—These conditions may increase the chance of side effects that affect the stomach and intestines

Proper Use of This Medicine Return to top

Before applying this medicine, thoroughly wash the affected areas with warm water and soap, rinse well, and pat dry.

When applying the medicine, use enough to cover the affected area lightly. You should apply the medicine to the whole area usually affected by acne, not just to the pimples themselves. This will help keep new pimples from breaking out.

You should avoid washing the acne-affected areas too often. This may dry your skin and make your acne worse. Washing with a mild, bland soap 2 or 3 times a day should be enough, unless you have oily skin. If you have any questions about this, check with your doctor.

Topical clindamycin will not cure your acne. However, to help keep your acne under control, keep using this medicine for the full time of treatment, even if your symptoms begin to clear up after a few days. You may have to continue using this medicine every day for months or even longer in some cases. If you stop using this medicine too soon, your symptoms may return. It is important that you do not miss any doses.

For patients using the topical foam form of clindamycin:

After washing or shaving, it is best to wait 30 minutes before applying this medicine. The alcohol in it may irritate freshly washed or shaved skin.

This medicine contains alcohol and is flammable. Do not use near heat, near open flame, or while smoking.

To apply this medicine:

Do not dispense clindamycin topical foam directly onto your hands because the foam will begin to melt on contact with warm skin.

Remove the clear cap. Align the black mark with the nozzle of the actuator.

Hold the can upright and press firmly to dispense. Dispense amount that will cover the affected area(s) directly into the cap or onto a cool surface.

The can may be placed under cold running water if the can seems warm or the foam seems runny.

A small amount of topical foam should be picked up with your fingertips and massaged gently into the affected areas until the foam disappears.

Unused medicine that was removed from the can should be throw away.

Since this medicine contains alcohol, it will sting or burn. In addition, it has an unpleasant taste if it gets on the mouth or lips. Therefore, do not get this medicine in the eyes, nose, or mouth, or on other mucous membranes.

Spread the medicine away from these areas when applying. If this medicine does get in the eyes, wash them out immediately, but carefully, with large amounts of cool tap water. If your eyes still burn or are painful, check with your doctor.

It is important that you do not use this medicine more often than your doctor ordered. It may cause your skin to become too dry or irritated.

For patients using the topical solution form of clindamycin:

After washing or shaving, it is best to wait 30 minutes before applying this medicine. The alcohol in it may irritate freshly washed or shaved skin.

This medicine contains alcohol and is flammable. Do not use near heat, near open flame, or while smoking.

To apply this medicine:

This medicine comes in a bottle with an applicator tip, which may be used to apply the medicine directly to the skin.

Use the applicator with a dabbing motion instead of a rolling motion (not like a roll-on deodorant, for example).

Tilt the bottle and press the tip firmly against your skin. If needed, you can make the medicine flow faster from the applicator tip by slightly increasing the pressure against the skin. If the medicine flows too fast, use less pressure. If the applicator tip becomes dry, turn the bottle upside down and press the tip several times to moisten it.

Since this medicine contains alcohol, it will sting or burn.

In addition, it has an unpleasant taste if it gets on the mouth or lips. Therefore, do not get this medicine in the eyes, nose, or mouth, or on other mucous membranes. Spread the medicine away from these areas when applying. If this medicine does get in the eyes, wash them out immediately, but carefully, with large amounts of cool tap water. If your eyes still burn or are painful, check with your doctor.

It is important that you do not use this medicine more often than your doctor ordered. It may cause your skin to become too dry or irritated.

For patients using the topical suspension form of clindamycin:

Shake well before applying.


The dose of topical clindamycin will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of topical clindamycin. If your dose is different, do not change it unless your doctor tells you to do so.

The number of doses you use each day, the time allowed between doses, and the length of time you use the medicine depend on the medical problem for which you are using clindamycin.

For topical dosage form (foam):

For acne:

Adults and children 12 years of age and over—Apply once a day to areas affected by acne.

Infants and children up to 12 years of age—Use and dose must be determined by your doctor.

For topical dosage forms (gel, solution, and suspension):

For acne:

Adults and children 12 years of age and over—Apply two times a day to areas affected by acne.

Infants and children up to 12 years of age—Use and dose must be determined by your doctor.

Missed dose

If you miss a dose of this medicine, apply it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.


To store this medicine:

Keep out of the reach of children.
Store away from heat and direct light.
Keep the medicine from freezing.

Do not keep outdated medicine or medicine no longer needed. Be sure that any discarded medicine is out of the reach of children.

Precautions While Using This Medicine Return to top

If your acne does not improve within about 6 weeks, or if it becomes worse, check with your health care professional. However, treatment of acne may take up to 8 to 12 weeks before full improvement is seen.

If your doctor has ordered another medicine to be applied to the skin along with this medicine, it is best to apply them at different times. This may help keep your skin from becoming too irritated. Also, if the medicines are used at or near the same time, they may not work properly.

For patients using the topical solution form of clindamycin:

This medicine may cause the skin to become unusually dry, even with normal use. If this occurs, check with your doctor.

In some patients, clindamycin may cause diarrhea.

Severe diarrhea may be a sign of a serious side effect. Do not take any diarrhea medicine without first checking with your doctor . Diarrhea medicines may make your diarrhea worse or make it last longer.

For mild diarrhea, only diarrhea medicine containing attapulgite (e.g., Kaopectate, Diasorb) may be taken. Other kinds of diarrhea medicine (e.g., Imodium A.D. or Lomotil) should not be taken. They may make your condition worse or make it last longer.

If you have any questions about this or if mild diarrhea continues or gets worse, check with your health care professional.

You may continue to use cosmetics (make-up) while you are using this medicine for acne.

However, it is best to use only “water-base” cosmetics. Also, it is best not to use cosmetics too heavily or too often. They may make your acne worse. If you have any questions about this, check with your doctor.

Side Effects of This Medicine Return to top

Side Effects of This Medicine

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:


Abdominal or stomach cramps, pain, and bloating (severe); diarrhea (watery and severe), which may also be bloody; fever; increased thirst; nausea or vomiting; unusual tiredness or weakness; weight loss (unusual)—these side effects may also occur up to several weeks after you stop using this medicine

Also, check with your doctor as soon as possible if any of the following side effects occur:

Less common

Skin rash, itching, redness, swelling, or other sign of irritation not present before use of this medicine

Other side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. However, check with your doctor if any of the following side effects continue or are bothersome:

More common

Dryness, scaliness, or peeling of skin (for the topical solution)

Less common

Abdominal pain; diarrhea (mild); headache; irritation or oiliness of skin; stinging or burning feeling of skin

Other side effects not listed above may also occur in some patients. If you notice any other effects, check with your doctor.

Brand Names
Return to top

In the U.S.—

Cleocin T Gel
Cleocin T Lotion
Cleocin T Topical Solution
Evoclin Topical Foam

In Canada—

Dalacin T Topical Solution

Medline Plus

Monday, January 09, 2006

Replidyne Submits New Drug Application (NDA) for Orapem(TM) (Faropenem Medoxomil)

Replidyne Submits New Drug Application (NDA) for Orapem(TM) (Faropenem Medoxomil) to U.S. Food and Drug Administration

LOUISVILLE, Colo., Jan. 9 /PRNewswire/ -- Replidyne, Inc., a privatelyheld biopharmaceutical company focused on the discovery and development of newanti-infective drugs, announced that the Company has submitted a New DrugApplication (NDA) to the U.S. Food and Drug Administration for Orapem(TM)(faropenem medoxomil) for the treatment of the following conditions: acutebacterial sinusitis, community acquired pneumonia, acute exacerbations ofchronic bronchitis and uncomplicated skin and skin structure infections. ThisNDA is the first marketing approval submission for Orapem(TM) worldwide andwas submitted in the electronic common technical document (eCTD) format. It isalso the first NDA submission for the Company.

The Orapem(TM) submission is primarily based on data from eleven Phase IIIclinical trials which assessed the clinical and microbiological efficacy aswell as the safety and tolerability profile of Orapem(TM) in treatingrespiratory tract and skin infections. The safety database included more than5,000 Orapem(TM) treated patients from clinical trials.

"The submission of the Orapem(TM) NDA represents a significant achievementby Replidyne, and the culmination of the efforts of a dedicated team. It alsomarks a substantial step in the Company's growth as we now expand our focustoward commercialization," said Kenneth J. Collins, president and CEO ofReplidyne. "We have been aggressive in our efforts to build a pipeline ofnovel antibacterial programs and the submission of the NDA for Orapem(TM)validates those efforts. If approved, it will mark the introduction of thefirst oral antibiotic of the penem class to be marketed in the United States."

Replidyne acquired exclusive rights to Orapem(TM) in March 2004 fromDaiichi Asubio Pharma Co., Ltd. for the U.S. and Canada and an exclusiveoption to the rest of the world, except Japan. Orapem(TM) was discovered byscientists at Suntory Institute for Biomedical Research, now Daiichi AsubioPharma Co., Ltd. and is manufactured by Nippon Soda Co., Ltd. (Tokyo, Japan).

About Orapem(TM) Orapem(TM) is an ester prodrug derivative of faropenem, one of the mostwell-studied members of the penem class and the only penem that is orallybioavailable. The prodrug form of faropenem offers a dramatically improvedoral bioavailability and leads to higher systemic concentrations of the drug.

About Replidyne, Inc. Replidyne is a biopharmaceutical company focused on developing andcommercializing innovative anti-infective products. Replidyne's currentdevelopment programs include higher dose/shorter course therapy, additionalindications for adults, and a pediatric formulation of Orapem(TM). TheCompany's pipeline also includes a topical anti-bacterial product, REP8839,which has a novel mechanism of action for addressing the major challenge ofmethicillin-resistant Staphylococcus aureus (MRSA). Replidyne also hasdiscovery programs directed to the inhibition of bacterial DNA replication,which could result in therapies to treat a wide range of antibiotic-resistantbacteria.

For additional information about Replidyne, Inc