Cost Of Antibiotic Resistance Research Articles

Decreased thermal niche breadth as a trade-off of antibiotic resistance

Evolutionary theory predicts that adaptations, including antibiotic resistance, should come with associated fitness costs; yet, many resistance mutations seemingly contradict this prediction by inducing no growth rate deficit. However, most growth assays comparing sensitive and resistant strains have been performed under a narrow range of environmental conditions, which do not reflect the variety of contexts that a pathogenic bacterium might encounter when causing infection. We hypothesized that reduced niche breadth, defined as diminished growth across a diversity of environments, can be a cost of antibiotic resistance. Specifically, we test whether chloramphenicol-resistant Escherichia coli incur disproportionate growth deficits in novel thermal conditions. Here we show that chloramphenicol-resistant bacteria have greater fitness costs at novel temperatures than their antibiotic-sensitive ancestors. In several cases, we observed no resistance cost in growth rate at the historic temperature but saw diminished growth at warmer and colder temperatures. These results were consistent across various genetic mechanisms of resistance. Thus, we propose that decreased thermal niche breadth is an under-documented fitness cost of antibiotic resistance. Furthermore, these results demonstrate that the cost of antibiotic resistance shifts rapidly as the environment changes; these context-dependent resistance costs should select for the rapid gain and loss of resistance as an evolutionary strategy.

Code-Sharing in Cost-of-Illness Calculations: An Application to Antibiotic-Resistant Bloodstream Infections.

Background: More data-driven evidence is needed on the cost of antibiotic resistance. Both Japan and England have large surveillance and administrative datasets. Code sharing of costing models enables reduced duplication of effort in research.Objective: To estimate the burden of antibiotic-resistant Staphylococcus aureus bloodstream infections (BSIs) in Japan, utilizing code that was written to estimate the hospital burden of antibiotic-resistant Escherichia coli BSIs in England. Additionally, the process in which the code-sharing and application was performed is detailed, to aid future such use of code-sharing in health economics.Methods: National administrative data sources were linked with voluntary surveillance data within the Japan case study. R software code, which created multistate models to estimate the excess length of stay associated with different exposures of interest, was adapted from previous use and run on this dataset. Unit costs were applied to estimate healthcare system burden in 2017 international dollars (I$).Results: Clear supporting documentation alongside open-access code, licensing, and formal communication channels, helped the re-application of costing code from the English setting within the Japanese setting. From the Japanese healthcare system perspective, it was estimated that there was an excess cost of I$6,392 per S. aureus BSI, whilst oxacillin resistance was associated with an additional I$8,155.Conclusions: S. aureus resistance profiles other than methicillin may substantially impact hospital costs. The sharing of costing models within the field of antibiotic resistance is a feasible way to increase burden evidence efficiently, allowing for decision makers (with appropriate data available) to gain rapid cost-of-illness estimates.

Dysbiosis individualizes the fitness effect of antibiotic resistance in the mammalian gut.

In the absence of antibiotics, it is essential that antibiotic resistance has a fitness cost for microorganisms if suspending antibiotics treatment is to be a useful strategy for reducing antibiotic resistance. However, the cost of antibiotic resistance within the complex ecosystem of the mammalian gut is not well understood. Here, using mice, we show that the same antibiotic resistance mutation can reduce fitness in one host, while being neutral or even increasing fitness in other hosts. Such antagonistic pleiotropy is shaped by the microbiota because resistance in germ-free mice is consistently costly across all hosts, and the host-specific effect on antibiotic resistance is reduced in hosts with similar microbiotas. Using an eco-evolutionary model of competition for resources, we identify a general mechanism that underlies between-host variation and predicts that the dynamics of compensatory evolution of resistant bacteria should be host specific, a prediction that was supported by experimental evolution in vivo. The microbiome of each human is close to unique, and our results suggest that the short-term cost of resistances and their long-term within-host evolution are also highly personalized, a finding that may contribute to the observed variable outcome of withdrawing antibiotics to reduce resistance levels.

Assessing the public acceptability of proposed policy interventions to reduce the misuse of antibiotics in Australia: A report on two community juries.

ObjectiveTo elicit the views of well‐informed community members on the acceptability of proposed policy interventions designed to improve community use of antibiotics in Australia.DesignTwo community juries held in 2016.Setting and participantsWestern Sydney and Dubbo communities in NSW, Australia. Twenty‐nine participants of diverse social and cultural backgrounds, mixed genders and ages recruited via public advertising: one jury was drawn from a large metropolitan setting; the other from a regional/rural setting.Main outcome measureJury verdict and rationale in response to a prioritization task and structured questions.ResultsBoth juries concluded that potential policy interventions to curb antibiotic misuse in the community should be directed towards: (i) ensuring that the public and prescribers were better educated about the dangers of antibiotic resistance; (ii) making community‐based human and animal health‐care practitioners accountable for their prescribing decisions. Patient‐centred approaches such as delayed prescribing were seen as less acceptable than prescriber‐centred approaches; both juries completely rejected any proposal to decrease consumer demand by increasing antibiotic prices.ConclusionThese informed citizens acknowledged the importance of raising public awareness of the risks, impacts and costs of antibiotic resistance and placed a high priority on increasing social and professional accountability through restrictive measures. Their overarching aim was that policy interventions should be directed towards creating collective actions and broad social support for changing antibiotic use through establishing and explaining the need for mechanisms to control and support better prescribing by practitioners, while not transferring the burdens, costs and risks of interventions to consumers.

Costs of antibiotic resistance - separating trait effects and selective effects.

Antibiotic resistance can impair bacterial growth or competitive ability in the absence of antibiotics, frequently referred to as a ‘cost’ of resistance. Theory and experiments emphasize the importance of such effects for the distribution of resistance in pathogenic populations. However, recent work shows that costs of resistance are highly variable depending on environmental factors such as nutrient supply and population structure, as well as genetic factors including the mechanism of resistance and genetic background. Here, we suggest that such variation can be better understood by distinguishing between the effects of resistance mechanisms on individual traits such as growth rate or yield (‘trait effects’) and effects on genotype frequencies over time (‘selective effects’). We first give a brief overview of the biological basis of costs of resistance and how trait effects may translate to selective effects in different environmental conditions. We then review empirical evidence of genetic and environmental variation of both types of effects and how such variation may be understood by combining molecular microbiological information with concepts from evolution and ecology. Ultimately, disentangling different types of costs may permit the identification of interventions that maximize the cost of resistance and therefore accelerate its decline.

Antibiotic resistance: Protecting antibiotics - the declaration of the world alliance against antibiotic resistance.

Antibiotic resistance (ABR) is a very serious public health issue. Antibiotics have been “miracle” drugs during many years, but their activity has been reduced sharply by many mechanisms of resistance. New mechanisms make the strains of Gram-negative bacteria resistant to the 3rd generation cephalosporins, and carbapenems. It is very urgent to act to slow down this phenomenon by global and international programs. We must, in particular, use far fewer antibiotics, which must be actively protected like a precious treasure. The increase in antibiotic resistant bacteria poses a major healthcare threat. In the face of an almost complete absence of new antimicrobial drugs in development,[1] ABR has become one of the main public health problems of our time. Margret Chan, general director of the World Health Organization, warned recently: “Post antibiotic era is almost upon us.” David Cameron, the UK prime minister, recently called for a “global action to tackle the growing threat of resistance to antibiotics.” Antibiotics are a unique class of medications because of their potential societal impact; use of an antibiotic in a single patient can select for ABR that can spread to other people, animals, and the environment, making an antibacterial used in one patient ineffective for many others. Bacterial resistance can evolve rapidly. As bacteria acquire resistance mechanisms, the altered bacterial genetic material coding for resistance mechanisms can be transmitted at times readily between bacteria, broadening the reach and extent of resistance. Treatment failures because of multidrug resistant (MDR) bacteria, once rare, notable, and limited to hospitals, now occur very commonly in hospitals, in particular in the Intensive Care Unit, and increasingly in the community as well. Methicillin-resistant Staphylococcus aureus (MRSA) infections, in particular due to community-acquired MRSA,[2] are extremely prevalent in many countries, including some European ones (European Center for Diseases Control and Prevention. EARSS-Net database. http://www.ecdc.europa.eu),[3] the USA, South America and Asia. Prevalence of MRSA infections decreased in the last few years in many European countries, and this can be considered as a very positive and promising result. Vancomycin-resistant enterococci (VRE) are also very frequent, with large differences between countries. In the European point prevalence study organized by ECDC,[4] VRE prevalence was going from 1% to >50%. The prevalence of Escherichia coli and Klebsiella pneumoniae harboring extended-spectrum beta lactamases is increasing regularly worldwide[5] reaching 50-70% for E. coli in some European or Asian countries.[3,5] In the European point prevalence study, prevalence of K. pneumoniae with carbapenemases was going from 1% to >50%.[4,6] Some infections are nowadays due to bacteria resistant to all antibiotics (Pan resistance). Those infections require very complex associations of high doses of old and new antibiotics, and mortality is very high. It is estimated that at a minimum 25,000 patients in Europe and 23,000 in the USA die each year from infections caused by resistant bacteria (CDC, ECDC). The cost of ABR is tremendous, whether measured as the personal and societal burden of illness, death rates, or healthcare costs. Although it is a never-ending phenomenon, ABR is directly related to the volume of antibiotics used. We are using increasing amounts of antibiotics in health care and agriculture, and discharging these active drugs into the environment.[7] The impact of widespread antibiotic use is enormous, promoting the development and dissemination of antimicrobial resistance. We must change how antibiotics are used and adopt proactive strategies, similar to those used to save endangered species.[8] Preservation of the efficacy of antibiotics and to the stabilization of antibiotic-susceptible bacterial ecosystems should be global goals. Safeguarding antibiotics will require a concerted effort by patients and prescribers. The primary goal of world alliance against antibiotic resistance (WAAAR) is to raise awareness about the urgency and magnitude of the threat and to promote an international dialogue to assist in effective responses. WAAAR is a group of 700 individuals from 55 different countries representing all the key stakeholders (physicians, veterinarians, microbiologists, surgeons, pharmacists, nurses, evolutionary biologists, ecologists, environmentalists, patient advocacy groups). The Alliance receives support from >140 learned societies or professional groups throughout the world. WAAAR is a nonprofit organization open to professionals and consumers worldwide. WAAAR receives no funding from the pharmaceutical industry. The Alliance, in particular through this declaration, is dedicated to lobbying actively for an antibiotic preservation and to raising awareness among antibiotic prescribers, politicians and policy-makers, patient safety and advocacy groups, the pharmaceutical industry, international health organizations and the general population. Individual actions, no matter how well intended, are doomed to failure unless there is an international dialogue, a common sense of purpose, and broad consensus on how best to proceed.[9]

Epidemiological control of drug resistance and compensatory mutation under resistance testing and second-line therapy

The fitness cost of antibiotic resistance in the absence of treatment raises the possibility that prudent use of drugs may slow or reverse the rise of resistance. Unfortunately, compensatory mutations that lower this cost may lead to entrenched resistance. Here, we develop a mathematical model of resistance evolution and compensatory mutation to determine whether reversion to sensitivity can occur, and how disease control might be facilitated by a second-line therapy. When only a single antibiotic is available, sensitive bacteria reach fixation only under treatment rates so low that hardly any cases are treated. We model a scenario in which drug sensitivity can be accurately tested so that a second-line therapy is administered to resistant cases. Before the rise of resistance to the second drug, disease eradication is possible if resistance testing and second-line treatment are conducted at a high enough rate. However, if double drug resistance arises, the possibility of disease eradication is greatly reduced and compensated resistance prevails in most of the parameter space. The boundary separating eradication from fixation of compensated resistance is strongly influenced by the underlying basic reproductive number of the pathogen and drug efficacy in sensitive cases, but depends less on the resistance cost and compensation. When double resistance is possible, the boundary is affected by the relative strengths of resistance against the two drugs in the double-resistant-compensated strain.

Cost of Antibiotic Resistance and the Geometry of Adaptation

The distribution of effects of beneficial mutations is key to our understanding of biological adaptation. Yet, empirical estimates of this distribution are scarce, and its functional form is largely unknown. Theoretical models of adaptation predict that the functional form of this distribution should depend on the distance to the optimum. Here, we estimate the rate and distribution of adaptive mutations that compensate for the effect of a single deleterious mutation, which causes antibiotic resistance. Using a system with multiple molecular markers, we estimate the distribution of fitness effects of mutations at two distances from the adaptive peak in 60 populations of Escherichia coli. We find that beneficial mutations, which can contribute to compensatory evolution, occur at very high rates, of the order of 10−5 per genome per generation and can be detected within a few tens of generations. They cause an average fitness increase of 2.5% and 3.6%, depending on the cost of resistance, which is expected under Fisher's geometrical model of adaptation. Moreover, we provide the first description of the distribution of beneficial mutations, segregating during the process of compensatory evolution, to antibiotic resistances bearing different costs. Hence, these results have important implications to understanding the spread and maintenance of antibiotic resistance in bacteria.

Offsetting virulence and antibiotic resistance costs by MRSA

The prevalence of diverse MRSA (methicillin-resistant Staphylococcus aureus) types in both hospital and community settings is a major health problem worldwide. Here we compare hospital-acquired MRSAs with large type II SCCmec elements with those prevalent in both hospital and community settings with smaller type IV SCCmec elements. We find that the type II but not the type IV SCCmec element causes the bacteria to reduce their levels of costly toxin expression. We compare the relative growth rates of these MRSA types and show that the type II SCCmec carrying MRSAs are more affected than those carrying type IV elements and from this we hypothesize that offsetting the costs associated with antibiotic resistance and toxin expression is why the type II are confined to hospital environments where antibiotic use, the prevalence of immunocompromised individuals and vector-mediated transmission is high. In contrast, those MRSAs that are also successful in the community can maintain their high levels of toxin expression due to a lower fitness burden associated with the smaller SCCmec element.

Antimicrobial resistances do not affect colonization parameters of intestinal E. coli in a small piglet group

BackgroundAlthough antimicrobial resistance and persistence of resistant bacteria in humans and animals are major health concerns worldwide, the impact of antimicrobial resistance on bacterial intestinal colonization in healthy domestic animals has only been rarely studied. We carried out a retrospective analysis of the antimicrobial susceptibility status and the presence of resistance genes in intestinal commensal E. coli clones from clinically healthy pigs from one production unit with particular focus on effects of pheno- and/or genotypic resistance on different nominal and numerical intestinal colonization parameters. In addition, we compared the occurrence of antimicrobial resistance phenotypes and genotypes with the occurrence of virulence associated genes typical for extraintestinal pathogenic E. coli.ResultsIn general, up to 72.1% of all E. coli clones were resistant to ampicillin, chloramphenicol, kanamycin, streptomycin, sulfamethoxazole or tetracycline with a variety of different resistance genes involved. There was no significant correlation between one of the nominal or numerical colonization parameters and the absence or presence of antimicrobial resistance properties or resistance genes. However, there were several statistically significant associations between the occurrence of single resistance genes and single virulence associated genes.ConclusionThe demonstrated resistance to the tested antibiotics might not play a dominant role for an intestinal colonization success in pigs in the absence of antimicrobial drugs, or cross-selection of other colonization factors e.g. virulence associated genes might compensate "the cost of antibiotic resistance". Nevertheless, resistant strains are not outcompeted by susceptible bacteria in the porcine intestine.Trial RegistrationThe study was approved by the local animal welfare committee of the "Landesamt für Arbeitsschutz, Gesundheitsschutz und technische Sicherheit" Berlin, Germany (No. G0037/02).

Economic Burden of Adult Pharyngitis: The Payer's Perspective

Objectives Although not recommended by practice guidelines, physicians frequently prescribe an antibiotic for adults with viral pharyngitis. The financial burden of this practice, from the payer's perspective, has not been previously evaluated. The purpose of this study was to estimate those expenditures. Methods A cost-of-illness study was performed to estimate annual expenditures of pharyngitis management from the payer's perspective. National Ambulatory Care Survey data were used to represent current patterns of ambulatory care visits and antibiotic prescriptions for adult pharyngitis. Direct and antibiotic resistance costs were summed to estimate total expenditures for pharyngitis management. Resistance costs were calculated using a model linking the effect of antibiotic consumption to the cost consequences of resistant Streptococcus pneumoniae infection. Sensitivity analyses compared cost outcomes of current practice, adherence to pharyngitis management guidelines from the Infectious Diseases Society of America (IDSA), and nonantibiotic treatment. Results In the base-case analysis, reflecting current practice patterns, total expenditures were $1.2 billion with antibiotic resistance contributing 36% ($426 million). IDSA guideline adherence decreased costs to $559 million with resistance accounting for 6.8% ($37.9 million). Guideline adherence plus reducing office visits by 30% decreased costs to $372 million, with only 1.4% ($5.3 million) due to resistance. Additional cost-savings of $88 million were realized by using a nonantibiotic treatment strategy. Conclusions Current practice imposed a substantial economic burden on the payer, while guideline adherence resulted in cost reductions, especially in terms of resistance, emphasizing that antibiotic prescribing habits have broad economic consequences. Relevant stakeholders, payers, physicians, and other health-care providers should revisit efforts to encourage adherence to pharyngitis guidelines to reduce health-care costs.

The cost of antibiotic resistance--from the perspective of a bacterium.

The possession of an antibiotic resistance gene clearly benefits a bacterium when the corresponding antibiotic is present. But does the resistant bacterium suffer a cost of resistance (i.e. a reduction in fitness) when the antibiotic is absent? If so, then one strategy to control the spread of resistance would be to suspend the use of a particular antibiotic until resistant genotypes declined to low frequency. Numerous studies have indeed shown that resistant genotypes are less fit than their sensitive counterparts in the absence of antibiotic, indicating a cost of resistance. But there is an important caveat: these studies have put antibiotic resistance genes into naïve bacteria, which have no evolutionary history of association with the resistance genes. An important question, therefore, is whether bacteria can overcome the cost of resistance by evolving adaptations that counteract the harmful side-effects of resistance genes. In fact, several experiments have shown that the cost of antibiotic resistance may be substantially diminished, even eliminated, by evolutionary changes in bacteria over rather short periods of time. As a consequence of this adaptation of bacteria to their resistance genes, it becomes increasingly difficult to eliminate resistant genotypes simply by suspending the use of antibiotics.

The cost of antibiotic resistance from a bacterial perspective

The emergence, spread and stability of antibiotic resistance in a bacterial population will be determined by several factors including (a) the volume of drug use, (b) the rate of formation of resistant mutants, (c) the biological cost of resistance and (d) the rate and extent of the genetic compensation of the costs. Generally, resistance is associated with a cost, suggesting that the frequency of resistant bacteria might decline when the use of antibiotics is decreased. However, evolution to reduce these costs, without a concomitant loss of resistance, can occur and result in a stabilization of the resistant bacteria in the population. The rate and trajectory of this compensatory evolution is dependent on the bacterial species, the specific resistance mutation and the environmental conditions under which evolution occurs. Copyright 2000 Harcourt Publishers Ltd.

Cycling of antibiotics: an approach to circumvent resistance in specialized units of the hospital

Cycling of antibiotics: an approach to circumvent resistance in specialized units of the hospital