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1.  Significant Reduction of Antibiotic Use in the Community after a Nationwide Campaign in France, 2002–2007 
PLoS Medicine  2009;6(6):e1000084.
Didier Guillemot and colleagues describe the evaluation of a nationwide programme in France aimed at decreasing unnecessary outpatient prescriptions for antibiotics. The campaign was successful, particularly in reducing prescriptions for children.
Background
Overuse of antibiotics is the main force driving the emergence and dissemination of bacterial resistance in the community. France consumes more antibiotics and has the highest rate of beta-lactam resistance in Streptococcus pneumoniae than any other European country. In 2001, the government initiated “Keep Antibiotics Working”; the program's main component was a campaign entitled “Les antibiotiques c'est pas automatique” (“Antibiotics are not automatic”) launched in 2002. We report the evaluation of this campaign by analyzing the evolution of outpatient antibiotic use in France 2000–2007, according to therapeutic class and geographic and age-group patterns.
Methods and Findings
This evaluation is based on 2000–2007 data, including 453,407,458 individual reimbursement data records and incidence of flu-like syndromes (FLSs). Data were obtained from the computerized French National Health Insurance database and provided by the French Sentinel Network. As compared to the preintervention period (2000–2002), the total number of antibiotic prescriptions per 100 inhabitants, adjusted for FLS frequency during the winter season, changed by −26.5% (95% confidence interval [CI] −33.5% to −19.6%) over 5 years. The decline occurred in all 22 regions of France and affected all antibiotic therapeutic classes except quinolones. The greatest decrease, −35.8% (95% CI −48.3% to −23.2%), was observed among young children aged 6–15 years. A significant change of −45% in the relationship between the incidence of flu-like syndromes and antibiotic prescriptions was observed.
Conclusions
The French national campaign was associated with a marked reduction of unnecessary antibiotic prescriptions, particularly in children. This study provides a useful method for assessing public-health strategies designed to reduce antibiotic use.
Editors' Summary
Background
In 1928, Alexander Fleming discovered penicillin, the first antibiotic (a drug that kills bacteria). By the early 1940s, large amounts of penicillin could be made and, in the following decades, several other classes of powerful antibiotics were discovered. For a time, it looked like bacteria and the diseases that they cause had been defeated. But bacteria rapidly became resistant to these wonder drugs and nowadays, antibiotic resistance is a pressing public-health concern. Almost every type of disease-causing bacteria has developed resistance to one or more antibiotic in clinical use, and multidrug-resistant bacteria are causing outbreaks of potentially fatal diseases in hospitals and in the community. For example, multidrug-resistant Streptococcus pneumoniae (multidrug-resistant pneumococci or MRP) is now very common. S. pneumoniae colonize the nose and throat (the upper respiratory tract) and can cause diseases that range from mild ear infections to life-threatening pneumonia, particularly in young children and elderly people.
Why Was This Study Done?
For years, doctors have been prescribing (and patients have been demanding) antibiotics for viral respiratory infections (VRIs) such as colds and flu even though antibiotics do not cure viral infections. This overuse of antibiotics has been the main driving force in the spread of MRP. Thus, the highest rate of S. pneumoniae antibiotic resistance in Europe occurs in France, which has one of the highest rates of antibiotic consumption in the world. In 2001 France initiated “le plan national pour préserver l'efficacité des antibiotiques” to reduce the inappropriate use of antibiotics, particularly for the treatment of VRIs among children. The main component of the program was the “Antibiotiques c'est pas automatique” (“Antibiotics are not automatic”) campaign, which ran from 2002 to 2007 during the winter months when VRIs mainly occur. The campaign included an educational campaign for health care workers, the promotion of rapid tests for diagnosis of streptococcal infections, and a public information campaign about VRIs and about antibiotic resistance. In this study, the researchers evaluate the campaign by analyzing outpatient antibiotic use throughout France from 2000 to 2007.
What Did the Researchers Do and Find?
The researchers obtained information about antibiotic prescriptions and about the occurrence of flu-like illnesses during the study period from the French National Health Insurance database and national disease surveillance system, respectively. After adjusting for variations in the frequency of flu-like illnesses, compared to the preintervention period (2000–2002), the number of antibiotic prescriptions per 100 inhabitants decreased by a quarter over the five winters of the “Antibiotics are not automatic” campaign. The use of all major antibiotic classes except quinolones decreased in all 22 regions of France. Thus, whereas in 2000, more than 70 prescriptions per 100 inhabitants were issued during the winter in 15 regions, by 2006/7, no regions exceeded this prescription rate. The greatest decrease in prescription rate (a decrease of more than a third by 2006/7) was among children aged 6–15 years. Finally, although the rates of antibiotic prescriptions reflected the rates of flu-like illness throughout the campaign, by 2006/7 this relationship was much weaker, which suggests that fewer antibiotics were being prescribed for VRIs.
What Do These Findings Mean?
These findings indicate that the “Antibiotics are not automatic” campaign was associated with a reduction in antibiotic prescriptions, particularly in children. Because the whole French population was exposed to the campaign, these findings do not prove that the campaign actually caused the reduction in antibiotic prescriptions. The observed decrease might have been caused by other initiatives in France or elsewhere or by the introduction of a S. pneumoniae vaccine during the study period, for example. However, an independent survey indicated that fewer members of the public expected an antibiotic prescription for a VRI at the end of the campaign than at the start, that more people knew that antibiotics only kill bacteria, and that doctors were more confident about not prescribing antibiotics for VRIs. Thus, campaigns like “Antibiotics are not automatic” may be a promising way to reduce the overuse of antibiotics and to slow the spread of antibiotic resistance until new classes of effective antibiotics are developed.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000084.
This study is further discussed in a PLoS Medicine Perspective by Stephen Harbarth and Benedikt Huttner
The Bugs and Drugs Web site from the UK National electronic Library of Infection provides information about antibiotic resistance and links to other resources
The US National Institute of Allergy and Infectious Diseases provides information on antimicrobial drug resistance and on pneumococcal pneumonia
The US Centers for Disease Control and Prevention also have information on antibiotic resistance (in English and Spanish)
The European Surveillance of Antimicrobial Consumption Web site provides information on antibiotic consumption in European countries
Les antibiotiques c'est pas automatique provides information about the “Antibiotics are not automatic” campaign (in French)
Information on the Plan National pour Pérserver l'efficacité des antibiotiques is also available (in French)
doi:10.1371/journal.pmed.1000084
PMCID: PMC2683932  PMID: 19492093
2.  Antimicrobial resistance in Canada 
Antibiotic resistance has increased rapidly during the last decade, creating a serious threat to the treatment of infectious diseases. Canada is no exception to this worldwide phenomenon. Data from the Canadian Nosocomial Infection Surveillance Program have revealed that the incidence of methicillin-resistant Staphylococcus aureus, as a proportion of S. aureus isolates, increased from 1% in 1995 to 8% by the end of 2000, and vancomycin-resistant enterococcus has been documented in all 10 provinces since the first reported outbreak in 1995. The prevalence of nonsusceptible Streptococcus pneumoniae in Canada in 2000 was found to be 12%. Human antimicrobial prescriptions, adjusted for differences in the population, declined 11% based on the total number of prescriptions dispensed between 1995 and 2000. There was also a 21% decrease in β-lactam prescriptions during this same period. These data suggest that systematic efforts to reduce unnecessary prescribing of antimicrobials to outpatients in Canada, beginning after a national consensus conference in 1997, may be having an impact. There is, however, still a need for continued concerted efforts on a national, provincial and regional level to quell the rising tide of antibiotic resistance.
PMCID: PMC128402  PMID: 12406948
3.  Declines in Outpatient Antimicrobial Use in Canada (1995–2010) 
PLoS ONE  2013;8(10):e76398.
Background
With rising reports of antimicrobial resistance in outpatient communities, surveillance of antimicrobial use is imperative for supporting stewardship programs. The primary objective of this article is to assess the levels of antimicrobial use in Canada over time.
Methods
Canadian antimicrobial use data from 1995 to 2010 were acquired and assessed by four metrics: population-adjusted prescriptions, Defined Daily Doses, spending on antimicrobials (inflation-adjusted), and average Defined Daily Doses per prescription. Linear mixed models were built to assess significant differences among years and antimicrobial groups, and to account for repeated measurements over time. Measures were also compared to published reports from European countries.
Results
Temporal trends in antimicrobial use in Canada vary by metric and antimicrobial grouping. Overall reductions were seen for inflation-adjusted spending, population-adjusted prescription rates and Defined Daily Doses, and increases were observed for the average number of Defined Daily Doses per prescription. The population-adjusted prescription and Defined Daily Doses values for 2009 were comparable to those reported by many European countries, while the average Defined Daily Dose per prescription for Canada ranked high. A significant reduction in the use of broad spectrum penicillins occurred between 1995 and 2004, coupled with increases in macrolide and quinolone use, suggesting that replacement of antimicrobial drugs may occur as new products arrive on the market.
Conclusions
There have been modest decreases of antimicrobial use in Canada over the past 15 years. However, continued surveillance of antimicrobial use coupled with data detailing antimicrobial resistance within bacterial pathogens affecting human populations is critical for targeting interventions and maintaining the effectiveness of these products for future generations.
doi:10.1371/journal.pone.0076398
PMCID: PMC3797838  PMID: 24146863
4.  Longitudinal surveillance of outpatient β-lactam antimicrobial use in Canada, 1995 to 2010 
INTRODUCTION:
β-lactam antimicrobials are the most commonly prescribed group of antimicrobials in Canada, and are categorized by the WHO as critically and highly important antimicrobials for human medicine. Because antimicrobial use is commonly associated with the development of antimicrobial resistance, monitoring the volume and patterns of use of these agents is highly important.
OBJECTIVE:
To assess the use of penicillin and cephalosporin antimicrobials within Canadian provinces over the 1995 to 2010 time frame according to two metrics: prescriptions per 1000 inhabitant-days and the average defined daily doses dispensed per prescription.
METHODS:
Antimicrobial prescribing data were acquired from the Canadian Integrated Program for Antimicrobial Resistance Surveillance and the Canadian Committee for Antimicrobial Resistance, and population data were obtained from Statistics Canada. The two measures developed were used to produce linear mixed models to assess differences among provinces and over time for the broad-spectrum penicillin and cephalosporin groups, while accounting for repeated measurements at the provincial level.
RESULTS:
Significant differences among provinces were found, as well as significant changes in use over time. A >28% reduction in broad-spectrum penicillin prescribing occurred in each province from 1995 to 2010, and a >18% reduction in cephalosporin prescribing occurred in all provinces from 1995 to 2010, with the exception of Manitoba, where cephalosporin prescribing increased by 18%.
DISCUSSION:
Significant reductions in the use of these important drugs were observed across Canada from 1995 to 2010. Newfoundland and Labrador and Quebec emerged as divergent from the remaining provinces, with high and low use, respectively.
PMCID: PMC4028666  PMID: 24855480
Antimicrobial use; β-lactam; Broad-spectrum penicillin; Cephalosporin; Penicillin; Provincial variation; Surveillance
5.  Variation in outpatient oral antimicrobial use patterns among Canadian provinces, 2000 to 2010 
One of the most important ways to curb the spread of antibiotic resistance among disease-causing organisms is to ensure the prudent use of antimicrobial agents, thus avoiding selective pressures that drive the spread of resistance. Accordingly, it is important to perform regular surveillance of antibiotic prescribing patterns to identify areas for improvement as well as to act as a benchmark for the measurement of change in future studies. This article, the first of five complementary articles in the current issue of the Journal, summarizes the prescribing pattern of all classes of antibiotics according to time and province in Canada.
BACKGROUND:
The volume and patterns of antimicrobial drug use are key variables to consider when developing guidelines for prescribing, and programs to address stewardship and combat the increasing prevalence of antimicrobial resistant pathogens. Because drug programs are regulated at the provincial level, there is an expectation that antibiotic use may vary among provinces.
OBJECTIVE:
To assess these potential differences according to province and time.
METHODS:
Provincial antimicrobial prescribing data at the individual drug level were acquired from the Canadian Integrated Program for Antimicrobial Resistance Surveillance for 2000 to 2010. Data were used to calculate two yearly metrics: prescriptions per 1000 inhabitant-days and the average defined daily doses per prescription. The proportion of liquid oral prescriptions of total prescriptions was also calculated as a proxy measure for the proportion of prescriptions given to children versus adults. To assess the significance of provincial antimicrobial use, linear mixed models were developed for each metric, accounting for repeated measurements over time.
RESULTS:
Significant differences among provinces were found, as well as significant changes in use over time. Newfoundland and Labrador was found to have significantly higher prescribing rates than all other provinces (P<0.001) in 2010, as well as the mean of all other provinces (P<0.001). In contrast, Quebec exhibited significantly lower prescribing than all other provinces (P<0.001 for all provinces except British Columbia, where P=0.024) and the mean of all other provinces (P<0.001).
DISCUSSION/CONCLUSION:
Reports of reductions in antimicrobial use at the Canadian level are promising, especially prescribing to children; however, care must be taken to avoid the pitfall of the ecological fallacy. Reductions are not consistent among the provinces or among the classes of antimicrobial drugs dispensed in Canada.
PMCID: PMC4028675  PMID: 24855477
Antimicrobial spending; Antimicrobial stewardship; Antimicrobial use; Prescribing patterns; Surveillance
6.  Longitudinal surveillance of outpatient quinolone antimicrobial use in Canada 
INTRODUCTION:
Because antimicrobial use is commonly associated with the development of antimicrobial resistance, monitoring the volume and patterns of use of these agents is important.
OBJECTIVE:
To assess the use of quinolone antimicrobials within Canadian provinces over time.
METHODS:
Antimicrobial prescribing data collected by IMS Health Canada were acquired from the Canadian Integrated Program for Antimicrobial Resistance Surveillance and the Canadian Committee for Antimicrobial Resistance, and were used to calculate two yearly metrics: prescriptions per 1000 inhabitant-days and the mean defined daily doses (DDDs) per prescription. These measures were used to produce linear mixed models to assess differences among provinces and over time, while accounting for repeated measurements.
RESULTS:
The quinolone class of antimicrobials is used similarly among Canadian provinces. Year-to-year increases in quinolone prescribing occurred from 1995 to 2010, with a levelling off in the latter years. Year-to-year decreases in the DDDs per prescription were found to be significant from 2000 to 2010.
DISCUSSION:
Although the overall use of antimicrobials differs significantly among Canadian provinces, the use of the quinolone class does not vary at the provincial level. Results suggest that prescribing of ciprofloxacin may be a potential target for antimicrobial stewardship programs; however, decreases in the average DDDs per prescription suggest continued uptake of appropriate treatment guidelines.
PMCID: PMC4028676  PMID: 24855478
Antimicrobial use; Drug utilization; Quinolones; Surveillance
7.  Key informant interview on antimicrobial resistance (AMR) in some countries in the western pacific region 
Background
The World Health Organization (WHO) selected antimicrobial resistance (AMR) as the theme for World Health Day 2011. The slogan was “Combat Drug Resistance – No action today, no cure tomorrow” A six-point policy package was launched as a core product for World Health Day. It aimed to stimulate extensive and coherent action to overcome the many challenges presented by antimicrobial resistance.
Methods
As a preparation for World Health Day, interviews were conducted with a series of key informants, mainly senior government staff, to assess their awareness of the topic and the interventions proposed in the policy package. Since the key informant interview methodology was used with a small number of interviewees, it may be difficult to demonstrate the validity of the findings.
Results
Key informants from twelve out of fifteen countries responded, which included Fiji (n = 5), Kiribati (n = 1), Lao PDR (n = 2), Malaysia (n = 6), Micronesia (n = 3), Mongolia (n = 5), the Philippines (n = 5), Vietnam (n = 6), Vanuatu (n = 1), Solomon Islands (n = 3), Cambodia (n = 5) and Brunei (n = 1). There was a total of forty-three respondents (n = 43). AMR was widely recognized as a problem. Lack of a coherent, comprehensive and national plan or strategy was noted. Surveillance was often seen as weak and fragmented even where presented. Laboratory capacity was felt to be insufficient across all countries interviewed. The majority of respondents stressed the need for national and local plans to combat AMR including reliable estimates of the financial cost of combating and managing AMR, the need for legislation to control inappropriate use of antimicrobials in food animals and more serious efforts to promote Standard Treatment Guidelines (STGs) and Rational Prescription. Also, importance was highlighted of the need to include infection prevention and control (IPC) as a part of accreditation and registration of health institutions and programs to promote IPC to the general population.
Conclusion
A coalition of interested parties at the local, national and international levels need to generate and sustain the political will to organize a more comprehensive, sustainable, and coherent approach to AMR.
doi:10.1186/1744-8603-9-34
PMCID: PMC3733822  PMID: 23889997
Antimicrobial resistance (AMR); Key informant interview (KII); Western pacific region; World health day; World health organization (WHO)
8.  Does Variation among Provincial Drug Formulary Antimicrobial Listings in Canada Influence Prescribing Rates? 
PLoS ONE  2014;9(9):e107515.
Background
The financial accessibility of antimicrobial drugs to the outpatient community in Canada is governed at the provincial level through formularies. Each province may choose to list particular drugs or impose restriction criteria on products in order to guide prescribing and/or curtail costs. Although changes to formularies have been shown to change patterns in the use of individual products and alter costs, no comparison has been made among the provincial antimicrobial formularies with regards to flexibility/stringency, or an assessment of how these formularies impact overall antimicrobial use in the provinces.
Objectives
To summarize provincial antimicrobial formularies and assess whether their relative flexibility/stringency had a statistical impact upon provincial prescription volume during a one year period.
Methods
Provincial drug plan formularies were accessed and summarized for all prescribed antimicrobials in Canada during 2010. The number of general and restricted benefits for each plan was compiled by antimicrobial classification. Population-adjusted prescription rates for all individual antimicrobials and by antimicrobial class were obtained from the Canadian Integrated Program for Antimicrobial Resistance Surveillance. Correlations between the number of general benefits, restricted benefits, and total benefits with the prescription rate in the provinces were assessed by Spearman rank correlation coefficients.
Results
Formularies varied considerably among the Canadian provinces. Quebec had the most flexible formulary, offering the greatest number of general benefits and fewest restrictions. In contrast, Saskatchewan's formulary displayed the lowest number of general benefits and most restrictions. Correlation analyses detected a single significant result; macrolide prescription rates decreased as the number of general macrolide benefits increased. All other rates of provincial antimicrobial prescribing and measures of flexibility/stringency revealed no significant correlations.
Conclusions
Although antimicrobial formulary listings are used to guide prescribing rates within a province, our analysis of one year's data of the impact of the antimicrobial formulary structure did not correlate with antimicrobial prescribing rates, and other factors are likely to be at play.
doi:10.1371/journal.pone.0107515
PMCID: PMC4159347  PMID: 25203557
9.  Control of antimicrobial resistance in Canada: any lessons to learn? 
Background
Over the past 15 years, repeated national meetings have developed recommendations for a Canadian antimicrobial resistance strategy. Despite this, in 2011 there is no comprehensive, integrated national program with appropriate governance and funding to address antimicrobial resistance.
Findings
The Public Health Agency of Canada supports a reference laboratory for diagnosis and characterization of selected resistant strains, targeted surveillance programs which monitor resistance trends for selected animal and human organisms, development of national infection control guidelines including for antimicrobial resistant organisms, and a few local pilot projects to address community acquired MRSA. Sporadic programs of variable intensity and quality are supported by some provinces, health regions and individual facilities but these are not comprehensive, standardized or integrated. Individual researchers and research groups, however, have published substantial information describing the prevalence and impact of resistance in Canada.
Conclusions
Current review of activities by the Public Health Agency of Canada and initiatives by the National Coordinating Centre for Infectious Diseases may move the country forward in developing an effective national approach to address antimicrobial resistance.
doi:10.1186/2047-2994-1-6
PMCID: PMC3436613  PMID: 22958241
antimicrobial resistance; Canada; antimicrobial stewardship
10.  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 
From 1995 to 2000, a total of 673 Enterococcus faecium and 1,088 Enterococcus faecalis isolates from pigs together with 856 E. faecium isolates from broilers were isolated and tested for susceptibility to four classes of antimicrobial agents used for growth promotion as part of the Danish program of monitoring for antimicrobial resistance. The four antimicrobials were avilamycin, erythromycin, vancomycin, and virginiamycin. Major changes in the use of antimicrobial agents for growth promotion have occurred during the last 6 years in Denmark. The government banned the use of avoparcin in 1995 and of virginiamycin in 1998. Furthermore, the producers have voluntarily stopped all use beginning in 1999. The avoparcin ban in 1995 was followed by a decrease in the occurrence of glycopeptide-resistant E. faecium (GRE) in broilers, from 72.7% in 1995 to 5.8% in 2000. The occurrence of glycopeptide resistance among isolates from pigs remained constant at around 20% from 1995 to 1997. It was shown that, in GRE from pigs, the genes encoding macrolide and glycopeptide resistance were genetically linked and that, following the decrease in the use of tylosin during 1998 and 1999, the occurrence of GRE in pigs decreased to 6.0% in 2000. From 1995 to 1997 the occurrence of erythromycin resistance among E. faecium and E. faecalis isolates from pigs was almost 90%. Use of tylosin decreased considerably during 1998 and 1999, and this decrease was followed by decreases in the occurrence of resistance to 46.7 and 28.1% among E. faecium and E. faecalis isolates from pigs, respectively. Erythromycin resistance among E. faecium isolates from broilers reached a maximum of 76.3% in 1997 but decreased to 12.7% in 2000 concomitantly with more limited use of virginiamycin. Use of virginiamycin increased from 1995 to 1997 and was followed by an increased occurrence of virginiamycin resistance among E. faecium isolates in broilers, from 27.3% in 1995 to 66.2% in 1997. In January 1998 the use of virginiamycin was banned in Denmark, and the occurrence of virginiamycin resistance decreased to 33.9% in 2000. Use of avilamycin increased from 1995 to 1996 and was followed by an increase in avilamycin resistance among E. faecium isolates from broilers, from 63.6% in 1995 to 77.4% in 1996. Since 1996 avilamycin usage has decreased, followed by a decrease in resistance to 4.8% in 2000. Our observations show that it is possible to reduce the occurrence of antimicrobial resistance in a national population of food animals when the selective pressure is removed. Cases in which resistance to vancomycin was linked to resistance to erythromycin were exceptions. In such cases resistance did not decrease until the use of both avoparcin and tylosin was limited.
doi:10.1128/AAC.45.7.2054-2059.2001
PMCID: PMC90599  PMID: 11408222
11.  Antimicrobial susceptibility of hazard analysis critical control point Escherichia coli isolates from federally inspected beef processing plants in Alberta, Saskatchewan, and Ontario 
The Canadian Veterinary Journal  2003;44(9):723-728.
A survey to estimate the prevalence of antimicrobial resistance in Escherichia coli was conducted in 7 Canadian federally inspected processing plants during 2001. Escherichia coli isolates were recovered during routine hazard analysis critical control point sampling from beef carcasses and trim and subsequently tested for their antimicrobial susceptibility by using susceptibility panels.
Of the 2653 isolates analyzed, 68% were sensitive to all 18 antimicrobials tested. For 14 of the 18 antimicrobials evaluated, the percentage of resistant isolates was ≤ 1. Twenty-five percent of the isolates were resistant to tetracycline, 9% to sulfamethoxazole, 7% to streptomycin, and 3% to ampicillin. Multiple resistance was found in 12% of the isolates, with 7% showing resistance to 2 antimicrobials, 2% to 3 antimicrobials, 2% to 4 antimicrobials, and 1% to 5 or more antimicrobials. Forty-five different antimicrobial resistance patterns were observed. The reasons for the development of the antimicrobial resistance were not investigated in this study.
This study was useful as a pilot to help to develop a national antimicrobial resistance surveillance program in Canada. This study indicates that laboratory standardization is possible for consistent results across the country and that the indicator organism, E. coli, is fairly easy to obtain for surveillance but Salmonella are not, due to their low prevalence in beef.
PMCID: PMC340267  PMID: 14524625
12.  Antibiotic Selection Pressure and Macrolide Resistance in Nasopharyngeal Streptococcus pneumoniae: A Cluster-Randomized Clinical Trial 
PLoS Medicine  2010;7(12):e1000377.
Jeremy Keenan and colleagues report that during a cluster-randomized clinical trial in Ethiopia, nasopharyngeal pneumococcal resistance to macrolides was significantly higher in communities randomized to receive azithromycin compared with untreated control communities.
Background
It is widely thought that widespread antibiotic use selects for community antibiotic resistance, though this has been difficult to prove in the setting of a community-randomized clinical trial. In this study, we used a randomized clinical trial design to assess whether macrolide resistance was higher in communities treated with mass azithromycin for trachoma, compared to untreated control communities.
Methods and Findings
In a cluster-randomized trial for trachoma control in Ethiopia, 12 communities were randomized to receive mass azithromycin treatment of children aged 1–10 years at months 0, 3, 6, and 9. Twelve control communities were randomized to receive no antibiotic treatments until the conclusion of the study. Nasopharyngeal swabs were collected from randomly selected children in the treated group at baseline and month 12, and in the control group at month 12. Antibiotic susceptibility testing was performed on Streptococcus pneumoniae isolated from the swabs using Etest strips. In the treated group, the mean prevalence of azithromycin resistance among all monitored children increased from 3.6% (95% confidence interval [CI] 0.8%–8.9%) at baseline, to 46.9% (37.5%–57.5%) at month 12 (p = 0.003). In control communities, azithromycin resistance was 9.2% (95% CI 6.7%–13.3%) at month 12, significantly lower than the treated group (p<0.0001). Penicillin resistance was identified in 0.8% (95% CI 0%–4.2%) of isolates in the control group at 1 year, and in no isolates in the children-treated group at baseline or 1 year.
Conclusions
This cluster-randomized clinical trial demonstrated that compared to untreated control communities, nasopharyngeal pneumococcal resistance to macrolides was significantly higher in communities randomized to intensive azithromycin treatment. Mass azithromycin distributions were given more frequently than currently recommended by the World Health Organization's trachoma program. Azithromycin use in this setting did not select for resistance to penicillins, which remain the drug of choice for pneumococcal infections.
Trial registration
www.ClinicalTrials.gov NCT00322972
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In 1928, Alexander Fleming discovered penicillin, the first antibiotic (a drug that kills bacteria). By the early 1940s, scientists were able to make large quantities of penicillin and, in the following decades, several other classes of powerful antibiotics were discovered. For example, erythromycin—the first macrolide antibiotic—was developed in the early 1950s. For a time, it looked like bacteria and the diseases that they cause had been defeated. But bacteria rapidly become resistant to antibiotics. Under the “selective pressure” of an antibiotic, bacteria that have acquired a random change in their DNA that allows them to survive in the antibiotic's presence outgrow nonresistant bacteria. What's more, bacteria can transfer antibiotic resistance genes between themselves. Nowadays, antibiotic resistance is a major public health concern. Almost every type of disease-causing bacteria has developed resistance to one or more antibiotic in clinical use and multi-drug resistant bacteria are causing outbreaks of potentially fatal diseases in hospitals and in the community.
Why Was This Study Done?
Although epidemiological studies (investigations of the causes, distribution, and control of disease in population) show a correlation between antibiotic use and antibiotic resistance in populations, such studies cannot prove that antibiotic use actually causes antibiotic resistance. It could be that the people who use more antibiotics share other characteristics that increase their chance of developing antibiotic resistance (so-called “confounding”). A causal link between antibiotic use and the development of antibiotic resistance can only be established by doing a randomized controlled trial. In such trials, groups of individuals are chosen at random to avoid confounding, given different treatments, and outcomes in the different groups compared. Here, the researchers undertake a randomized clinical trial to assess whether macrolide resistance is higher in communities treated with azithromycin for trachoma than in untreated communities. Azithromycin—an erythromycin derivative—is used to treat common bacterial infections such as middle ear infections caused by Streptococcus pneumoniae. Trachoma—the world's leading infectious cause of blindness—is caused by Chlamydia trachomatis. The World Health Organization's trachoma elimination strategy includes annual azithromycin treatment of at-risk communities.
What Did the Researchers Do and Find?
In this cluster-randomized trial (a study that randomly assigns groups of people rather than individuals to different treatments), 12 Ethiopian communities received mass azithromycin treatment of children aged 1–10 years old at 0, 3, 6, and 9 months, and 12 control communities received the antibiotic only at 12 months. The researchers took nasopharyngeal (nose and throat) swabs from randomly selected treated children at 0 and 12 months and from randomly selected control children at 12 months. They isolated S. pneumoniae from the swabs and tested the isolates for antibiotic susceptibility. 70%–80% of the children tested had S. pneumoniae in their nose or throat. In the treated group, 3.6% of monitored children were carrying azithromycin-resistant S. pneumoniae at 0 months, whereas 46.9% were doing so at 12 months—a statistically significant increase. Only 9.2% of the monitored children in the untreated group were carrying azithromycin-resistant S. pneumoniae at 12 months, a significantly lower prevalence than in the treated group. Importantly, there was no resistance to penicillin in any S. pneumoniae isolates obtained from the treated children at 0 or 12 months; one penicillin-resistant isolate was obtained from the control children.
What Do These Findings Mean?
These findings indicate that macrolide resistance is higher in nasopharyngeal S. pneumoniae in communities receiving intensive azithromycin treatment than in untreated communities. Thus, they support the idea that frequent antibiotic use selects for antibiotic resistance in populations. Although the study was undertaken in Ethiopian communities with high rates of nasopharyngeal S. pneumoniae carriage, this finding is likely to be generalizable to other settings. Importantly, these findings have no bearing on current trachoma control activities, which use less frequent antibiotic treatments and are less likely to select for azithromycin resistance. The lack of any increase in penicillin resistance, which is usually the first-line therapy for S. pneumoniae infections, is also reassuring. However, although these findings suggest that the benefits of mass azithromycin treatment for trachoma outweigh any potential adverse affects, they nonetheless highlight the importance of continued monitoring for the secondary effects of mass antibiotic distributions.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000377.
The Bugs and Drugs website provides information about antibiotic resistance and links to other resources
The US National Institute of Allergy and Infectious Diseases provides information on antimicrobial drug resistance and on diseases caused by S. pneumoniae (pneumococcal diseases)
The US Centers for Disease Control and Prevention also have information on antibiotic resistance (in English and Spanish)
The World Health Organization has information about the global threat of antimicrobial resistance and about trachoma (in several languages)
More information about the trial described in this paper is available on ClinicalTrials.gov
doi:10.1371/journal.pmed.1000377
PMCID: PMC3001893  PMID: 21179434
13.  Bacterial Pathogens Isolated from Patients with Bloodstream Infection: Frequencies of Occurrence and Antimicrobial Susceptibility Patterns from the SENTRY Antimicrobial Surveillance Program (United States and Canada, 1997) 
The SENTRY Program was established in January 1997 to measure the predominant pathogens and antimicrobial resistance patterns of nosocomial and community-acquired infections over a broad network of sentinel hospitals in the United States (30 sites), Canada (8 sites), South America (10 sites), and Europe (24 sites). During the first 6-month study period (January to June 1997), a total of 5,058 bloodstream infections (BSI) were reported by North American SENTRY participants (4,119 from the United States and 939 from Canada). In both the United States and Canada, Staphylococcus aureus and Escherichia coli were the most common BSI isolates, followed by coagulase-negative staphylococci and enterococci. Klebsiella spp., Enterobacter spp., Pseudomonas aeruginosa, Streptococcus pneumoniae, and β-hemolytic streptococci were also among the 10 most frequently reported species in both the United States and Canada. Although the rank orders of pathogens in the United States and Canada were similar, distinct differences were noted in the antimicrobial susceptibilities of several pathogens. Overall, U.S. isolates were considerably more resistant than those from Canada. The differences in the proportions of oxacillin-resistant S. aureus isolates (26.2 versus 2.7% for U.S. and Canadian isolates, respectively), vancomycin-resistant enterococcal isolates (17.7 versus 0% for U.S. and Canadian isolates, respectively), and ceftazidime-resistant Enterobacter sp. isolates (30.6 versus 6.2% for U.S. and Canadian isolates, respectively) dramatically emphasize the relative lack of specific antimicrobial resistance genes (mecA, vanA, and vanB) in the Canadian microbial population. Among U.S. isolates, resistance to oxacillin among staphylococci, to vancomycin among enterococci, to penicillin among pneumococci, and to ceftazidime among Enterobacter spp. was observed in both nosocomial and community-acquired pathogens, although in almost every instance the proportion of resistant strains was higher among nosocomial isolates. Antimicrobial resistance continues to increase, and ongoing surveillance of microbial pathogens and resistance profiles is essential on national and international scales.
PMCID: PMC105680  PMID: 9661018
14.  Antimicrobial resistance pattern in a tertiary care hospital: An observational study 
Context:
The number of organisms developing resistance to commonly used antibiotics is increasing among the various generations. The exact national scenario of antimicrobial resistance (AMR) is not known in India owing to the absence of a central monitoring agency.
Aims:
The aim of this study is to identify the group of organisms developing resistance, to know the classes of drugs against, which resistance has emerged and to assess the possible factors that can favor the development of AMR so that antibiotic policy can be formulated for the proper and effective use of antibiotics.
Settings and Design:
An observational study was conducted for a period of 1 year from August 2011 to July 2012 in a tertiary care hospital in Pondicherry.
Subjects and Methods:
Data regarding culture and sensitivity of the organisms isolated from different sources such as urine, blood, wound swab/pus, stool, sputum and tracheal aspirations were collected from the records of the Microbiology Department. Sample processing, identification of organisms to the genus and/or species level and antimicrobial sensitivity were carried out as per the Clinical and Laboratory Standards Institute guidelines on the 999 samples received.
Results:
Out of 999 samples, 125 (12.5%) showed significant growth of organisms exhibiting resistance to either single or multiple drugs. Out of 84 (67.2%) in-patients and 41 (32.8%) out-patient samples, Escherichia was the most common organism isolated with a total of 41 (32.8%), followed by Methicillin sensitive Staphylococcus aureus, 26 (20.8%), Klebsiella 25 (20%), Methicillin resistant Staphylococcus aureus 17 (13.6%), Pseudomonas 10 (8%), Proteus 2 (1.6%), 1 (0.8%) each of Citrobacter and Enterococci. Maximum resistance was observed with commonly used first line antimicrobials such as co-trimoxazole, ampicillin, amoxicillin, amoxyclav, fluoroquinolones, third generation cephalosporins and nalidixic acid. Least resistant or highly sensitive were amikacin, nitrofurantoin, gentamycin and doxycycline among the gram-negative bacteria. Macrolides, clindamycin, gentamycin, nitrofurantoin, vancomycin were the most sensitive antimicrobials against the gram-positive bacteria. Lack of knowledge on the consequences of inappropriate use of antibiotics was exhibited by 63% of subjects in our study.
Conclusions:
AMR was more with hospital acquired organisms and against commonly used antibiotics that are available since long period. Variation of resistance and sensitivity pattern with time and geographical location is identified. Periodic AMR monitoring and rotation of antibiotics are suggested to restrict further emergence of resistance.
doi:10.4103/0976-0105.118797
PMCID: PMC3979270  PMID: 24808672
Antibiotics; antimicrobial resistance; observational study
15.  International Monetary Fund Programs and Tuberculosis Outcomes in Post-Communist Countries 
PLoS Medicine  2008;5(7):e143.
Background
Previous studies have indicated that International Monetary Fund (IMF) economic programs have influenced health-care infrastructure in recipient countries. The post-communist Eastern European and former Soviet Union countries experienced relatively similar political and economic changes over the past two decades, and participated in IMF programs of varying size and duration. We empirically examine how IMF programs related to changes in tuberculosis incidence, prevalence, and mortality rates among these countries.
Methods and Findings
We performed multivariate regression of two decades of tuberculosis incidence, prevalence, and mortality data against variables potentially influencing tuberculosis program outcomes in 21 post-communist countries for which comparative data are available. After correcting for confounding variables, as well as potential detection, selection, and ecological biases, we observed that participating in an IMF program was associated with increased tuberculosis incidence, prevalence, and mortality rates by 13.9%, 13.2%, and 16.6%, respectively. Each additional year of participation in an IMF program was associated with increased tuberculosis mortality rates by 4.1%, and each 1% increase in IMF lending was associated with increased tuberculosis mortality rates by 0.9%. On the other hand, we estimated a decrease in tuberculosis mortality rates of 30.7% (95% confidence interval, 18.3% to 49.5%) associated with exiting the IMF programs. IMF lending did not appear to be a response to worsened health outcomes; rather, it appeared to be a precipitant of such outcomes (Granger- and Sims-causality tests), even after controlling for potential political, socioeconomic, demographic, and health-related confounders. In contrast, non-IMF lending programs were connected with decreased tuberculosis mortality rates (−7.6%, 95% confidence interval, −1.0% to −14.1%). The associations observed between tuberculosis mortality and IMF programs were similar to those observed when evaluating the impact of IMF programs on tuberculosis incidence and prevalence. While IMF programs were connected with large reductions in generalized government expenditures, tuberculosis program coverage, and the number of physicians per capita, non-IMF lending programs were not significantly associated with these variables.
Conclusions
IMF economic reform programs are associated with significantly worsened tuberculosis incidence, prevalence, and mortality rates in post-communist Eastern European and former Soviet countries, independent of other political, socioeconomic, demographic, and health changes in these countries. Future research should attempt to examine how IMF programs may have related to other non-tuberculosis–related health outcomes.
David Stuckler and colleagues show that, in Eastern European and former Soviet Union countries, participation in International Monetary Fund economic programs have been associated with higher mortality rates from tuberculosis.
Editors' Summary
Background.
Tuberculosis—a contagious, bacterial infection—has killed large numbers of people throughout human history. Over the last century improvements in public health began to reduce the incidence (the number of new cases in the population in a given time), prevalence (the number of infected people), and mortality rate (number of people dying each year) of tuberculosis in several countries. Many authorities thought that tuberculosis had become a disease of the past. It has become increasingly clear, however, that regions impacted by health and economic changes since the 1980s have continued to face a high and sometimes increasing burden of tuberculosis. In order to boost funding and resources for combating the global tuberculosis problem, the United Nations has set a target of halting and reversing increases in global tuberculosis incidence by 2015 as one of its Millennium Development Goals. Yet one region of the world—Eastern Europe and the former Soviet Union—is not on track to achieve this goal.
Why Was This Study Done?
To achieve these targets, the World Health Organization (WHO) and tuberculosis physicians' groups promote the expansion of detection and treatment efforts against tuberculosis. But these efforts depend on the maintenance of good health infrastructure to fund and support health-care workers, clinics, and hospitals. In countries with significant financial limitations, the development and maintenance of these health system resources are often dependent upon international donations and financial lending. The International Monetary Fund (IMF) is a major source of capital for resource-deprived countries, but it is unclear whether its economic reform programs have positive or negative effects on health and health infrastructures in recipient countries. There are indications, for example, that recipient countries sometimes reduce their public-health spending to meet the economic targets set by the IMF as conditions for its loans. In this study, the researchers examine the relationship between participating in IMF lending programs of varying sizes and durations by 21 post-communist Central and Eastern European and former Soviet Union countries and changes in tuberculosis incidence, prevalence, and mortality in these countries during the past two decades.
What Did the Researchers Do and Find?
To examine how participation in IMF lending programs affected tuberculosis control in these countries, the researchers developed a series of statistical models that take into account other variables (for example, directly observed therapy programs, HIV rates, military conflict, and urbanization) that might have affected tuberculosis control. Participation in an IMF program, they report, was associated with increases in tuberculosis incidence, prevalence, and mortality rate of about 15%, which corresponds to hundreds of thousands of new cases and deaths in this region. Each additional year of participation increased tuberculosis mortality rates by 4.1%; increases in the size of the IMF loan also corresponded to greater tuberculosis mortality rates. Conversely, when countries left IMF programs, tuberculosis mortality rates dropped by roughly one-third. The authors' further statistical tests indicated that IMF lending was not a positive response to worsened tuberculosis control but precipitated this adverse outcome and that lending from non-IMF sources of funding was associated with decreases in tuberculosis mortality rates. Consistent with these results, IMF (but not non-IMF) programs were associated with reductions in government expenditures, tuberculosis program coverage, and the number of doctors per capita in each country. These findings associated with mortality were also found when analyzing tuberculosis incidence and prevalence data.
What Do These Findings Mean?
These findings indicate that IMF economic programs are associated with significantly worsened tuberculosis control in post-communist Central and Eastern European and former Soviet Union countries, independent of other political, health, and economic changes in these countries. Further research is needed to discover exactly which aspects of the IMF programs were associated with the adverse effects on tuberculosis control reported here and to see whether IMF loans have similar effects on tuberculosis control in other countries or on other non–tuberculosis-related health outcomes. For now, these results challenge the proposition that the forms of economic development promoted by the IMF necessarily improve public health. In particular, they put the onus on the IMF to critically evaluate the direct and indirect effects of its economic programs on public health.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050143.
This study is further discussed in a PLoS Medicine Perspective by Murray and King
The US National Institute of Allergy and Infectious Diseases provides information on all aspects of tuberculosis, including a brief history of the disease
The US Centers for Disease Control and Prevention provide several fact sheets and other information resources about tuberculosis
The World Health Organization provides information (in several languages) on efforts to reduce the global burden of tuberculosis, including information on the Stop TB Strategy and the 2008 report on global tuberculosis control—surveillance, planning, financing
Detailed information about the International Monetary Fund is available on its Web site
An article that asks “Does the IMF constrain health spending in poor countries?” (with a link to a response from the IMF) is provided by the Center for Global Development
doi:10.1371/journal.pmed.0050143
PMCID: PMC2488179  PMID: 18651786
16.  Longitudinal surveillance of outpatient tetracycline, sulfonamide-trimethoprim and ‘other’ antimicrobial use in Canada, 1995 to 2010 
INTRODUCTION:
Monitoring the volume and patterns of use of antimicrobial agents is important in light of antimicrobial resistance.
OBJECTIVE:
To assess the use of three antimicrobial groups – tetracycline, sulfonamide-trimethoprim and ‘other’ antimicrobials – within Canadian provinces over time.
METHODS:
Prescription counts from 1995 to 2010 were acquired for the tetracycline and sulfonamide-trimethoprim groups of antimicrobials, and from 2001 to 2010 for the ‘other’ antimicrobial group. Linear mixed models were produced to assess differences among provinces and over time while accounting for repeated measurements. Prescription rate, defined daily dose per 1000 inhabitant-days and defined daily doses per prescription measures for the year 2009 were also compared with those reported by participating European Union countries to determine where Canadian provinces rank in terms of antimicrobial use among these countries.
RESULTS:
Prescribing of all three groups varied according to province and over time. Tetracycline and sulfonamide-trimethoprim group prescribing were significantly reduced over the study period, by 36% and 61%, respectively. Prescribing of the ‘other’ antimicrobial group increased in all provinces from 2001 to 2010 with the exception of Prince Edward Island, although by varying amounts (10% to 61% increases).
DISCUSSION:
The overall use of antimicrobials in Canada has dropped from 1995 to 2010, and the tetracycline and sulfonamide-trimethoprim groups have contributed to this decline. The use of the ‘other’ antimicrobials has increased, however. These results may suggest that switches are being made among these groups, particularly among the antimicrobials used to treat urinary tract infections.
PMCID: PMC4028667  PMID: 24855481
Antimicrobial use; Metronidazole; Prescribing patterns; Surveillance; Tetracycline
17.  Screening Mammography for Women Aged 40 to 49 Years at Average Risk for Breast Cancer 
Executive Summary
Objective
The aim of this review was to determine the effectiveness of screening mammography in women aged 40 to 49 years at average risk for breast cancer.
Clinical Need
The effectiveness of screening mammography in women aged over 50 years has been established, yet the issue of screening in women aged 40 to 49 years is still unsettled. The Canadian Task Force of Preventive Services, which sets guidelines for screening mammography for all provinces, supports neither the inclusion nor the exclusion of this screening procedure for 40- to 49-year-old women from the periodic health examination. In addition to this, 2 separate reviews, one conducted in Quebec in 2005 and the other in Alberta in 2000, each concluded that there is an absence of convincing evidence on the effectiveness of screening mammography for women in this age group who are at average risk for breast cancer.
In the United States, there is disagreement among organizations on whether population-based mammography should begin at the age of 40 or 50 years. The National Institutes of Health, the American Association for Cancer Research, and the American Academy of Family Physicians recommend against screening women in their 40s, whereas the United States Preventive Services Task Force, the National Cancer Institute, the American Cancer Society, the American College of Radiology, and the American College of Obstetricians and Gynecologists recommend screening mammograms for women aged 40 to 49 years. Furthermore, in comparing screening guidelines between Canada and the United States, it is also important to recognize that “standard care” within a socialized medical system such as Canada’s differs from that of the United States. The National Breast Screening Study (NBSS-1), a randomized screening trial conducted in multiple centres across Canada, has shown there is no benefit in mortality from breast cancer from annual mammograms in women randomized between the ages of 40 and 49, relative to standard care (i.e. physical exam and teaching of breast-self examination on entry to the study, with usual community care thereafter).
At present, organized screening programs in Canada systematically screen women starting at 50 years of age, although with a physician’s referral, a screening mammogram is an insured service in Ontario for women under 50 years of age.
International estimates of the epidemiology of breast cancer show that the incidence of breast cancer is increasing for all ages combined, whereas mortality is decreasing, though at a slower rate. These decreasing mortality rates may be attributed to screening and advances in breast cancer therapy over time. Decreases in mortality attributable to screening may be a result of the earlier detection and treatment of invasive cancers, in addition to the increased detection of ductal carcinoma in situ (DCIS), of which certain subpathologies are less lethal. Evidence from the SEER cancer registry in the United States indicates that the age-adjusted incidence of DCIS has increased almost 10-fold over a 20-year period (from 2.7 to 25 per 100,000).
The incidence of breast cancer is lower in women aged 40 to 49 years than in women aged 50 to 69 years (about 140 per 100,000 versus 500 per 100,000 women, respectively), as is the sensitivity (about 75% versus 85% for women aged under and over 50, respectively) and specificity of mammography (about 80% versus 90% for women aged under and over 50, respectively). The increased density of breast tissue in younger women is mainly responsible for the lower accuracy of this procedure in this age group. In addition, as the proportion of breast cancers that occur before the age of 50 are more likely to be associated with genetic predisposition as compared with those diagnosed in women after the age of 50, mammography may not be an optimal screening method for younger women.
Treatment options vary with the stage of disease (based on tumor size, involvement of surrounding tissue, and number of affected axillary lymph nodes) and its pathology, and may include a combination of surgery, chemotherapy, and/or radiotherapy.
Surgery is the first-line intervention for biopsy confirmed tumours. The subsequent use of radiation, chemotherapy, or hormonal treatments is dependent on the histopathologic characteristics of the tumor and the type of surgery. There is controversy regarding the optimal treatment of DCIS, which is noninvasive.
With such controversy as to the effectiveness of mammography and the potential risk associated with women being overtreated or actual cancers being missed, and the increased risk of breast cancer associated with exposure to annual mammograms over a 10-year period, the Ontario Health Technology Advisory Committee requested this review of screening mammography in women aged 40 to 49 years at average risk for breast cancer. This review is the first of 2 parts and concentrates on the effectiveness of screening mammography (i.e., film mammography, FM) for women at average risk aged 40 to 49 years. The second part will be an evaluation of screening by either magnetic resonance imaging or digital mammography, with the objective of determining the optimal screening modality in these younger women.
Review Strategy
The following questions were asked:
Does screening mammography for women aged 40 to 49 years who are at average risk for breast cancer reduce breast cancer mortality?
What is the sensitivity and specificity of mammography for this age group?
What are the risks associated with annual screening from ages 40 to 49?
What are the risks associated with false positive and false negative mammography results?
What are the economic considerations if evidence for effectiveness is established?
The Medical Advisory Secretariat followed its standard procedures and searched these electronic databases: Ovid MEDLINE, EMBASE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and the International Network of Agencies for Health Technology Assessment.
Keywords used in the search were breast cancer, breast neoplasms, mass screening, and mammography.
In total, the search yielded 6,359 articles specific to breast cancer screening and mammography. This did not include reports on diagnostic mammograms. The search was further restricted to English-language randomized controlled trials (RCTs), systematic reviews, and meta-analyses published between 1995 and 2005. Excluded were case reports, comments, editorials, and letters, which narrowed the results to 516 articles and previous health technology policy assessments.
These were examined against the criteria outlined below. This resulted in the inclusion of 5 health technology assessments, the Canadian Preventive Services Task Force report, the United States Preventive Services Task Force report, 1 Cochrane review, and 8 RCTs.
Inclusion Criteria
English-language articles, and English and French-language health technology policy assessments, conducted by other organizations, from 1995 to 2005
Articles specific to RCTs of screening mammography of women at average risk for breast cancer that included results for women randomized to studies between the ages of 40 and 49 years
Studies in which women were randomized to screening with or without mammography, although women may have had clinical breast examinations and/or may have been conducting breast self-examination.
UK Age Trial results published in December 2006.
Exclusion Criteria
Observational studies, including those nested within RCTs
RCTs that do not include results on women between the ages of 40 and 49 at randomization
Studies in which mammography was compared with other radiologic screening modalities, for example, digital mammography, magnetic resonance imaging or ultrasound.
Studies in which women randomized had a personal history of breast cancer.
Intervention
Film mammography
Comparators
Within RCTs, the comparison group would have been women randomized to not undergo screening mammography, although they may have had clinical breast examinations and/or have been conducting breast self-examination.
Outcomes of Interest
Breast cancer mortality
Summary of Findings
There is Level 1 Canadian evidence that screening women between the ages of 40 and 49 years who are at average risk for breast cancer is not effective, and that the absence of a benefit is sustained over a maximum follow-up period of 16 years.
All remaining studies that reported on women aged under 50 years were based on subset analyses. They provide additional evidence that, when all these RCTs are taken into account, there is no significant reduction in breast cancer mortality associated with screening mammography in women aged 40 to 49 years.
Conclusions
There is Level 1 evidence that screening mammography in women aged 40 to 49 years at average risk for breast cancer is not effective in reducing mortality.
Moreover, risks associated with exposure to mammographic radiation, the increased risk of missed cancers due to lower mammographic sensitivity, and the psychological impact of false positives, are not inconsequential.
The UK Age Trial results published in December 2006 did not change these conclusions.
PMCID: PMC3377515  PMID: 23074501
18.  Systematic Review of Abstinence-Plus HIV Prevention Programs in High-Income Countries 
PLoS Medicine  2007;4(9):e275.
Background
Abstinence-plus (comprehensive) interventions promote sexual abstinence as the best means of preventing HIV, but also encourage condom use and other safer-sex practices. Some critics of abstinence-plus programs have suggested that promoting safer sex along with abstinence may undermine abstinence messages or confuse program participants; conversely, others have suggested that promoting abstinence might undermine safer-sex messages. We conducted a systematic review to investigate the effectiveness of abstinence-plus interventions for HIV prevention among any participants in high-income countries as defined by the World Bank.
Methods and Findings
Cochrane Collaboration systematic review methods were used. We included randomized and quasi-randomized controlled trials of abstinence-plus programs for HIV prevention among any participants in any high-income country; trials were included if they reported behavioural or biological outcomes. We searched 30 electronic databases without linguistic or geographical restrictions to February 2007, in addition to contacting experts, hand-searching conference abstracts, and cross-referencing papers. After screening 20,070 abstracts and 325 full published and unpublished papers, we included 39 trials that included approximately 37,724 North American youth. Programs were based in schools (10), community facilities (24), both schools and community facilities (2), health care facilities (2), and family homes (1). Control groups varied. All outcomes were self-reported. Quantitative synthesis was not possible because of heterogeneity across trials in programs and evaluation designs. Results suggested that many abstinence-plus programs can reduce HIV risk as indicated by self-reported sexual behaviours. Of 39 trials, 23 found a protective program effect on at least one sexual behaviour, including abstinence, condom use, and unprotected sex (baseline n = 19,819). No trial found adverse program effects on any behavioural outcome, including incidence of sex, frequency of sex, sexual initiation, or condom use. This suggests that abstinence-plus approaches do not undermine program messages encouraging abstinence, nor do they undermine program messages encouraging safer sex. Findings consistently favoured abstinence-plus programs over controls for HIV knowledge outcomes, suggesting that abstinence-plus programs do not confuse participants. Results for biological outcomes were limited by floor effects. Three trials assessed self-reported diagnosis or treatment of sexually transmitted infection; none found significant effects. Limited evidence from seven evaluations suggested that some abstinence-plus programs can reduce pregnancy incidence. No trial observed an adverse biological program effect.
Conclusions
Many abstinence-plus programs appear to reduce short-term and long-term HIV risk behaviour among youth in high-income countries. Programs did not cause harm. Although generalisability may be somewhat limited to North American adolescents, these findings have critical implications for abstinence-based HIV prevention policies. Suggestions are provided for improving the conduct and reporting of trials of abstinence-plus and other behavioural interventions to prevent HIV.
In their systematic review, Underhill and colleagues found that abstinence-plus programs appear to reduce short-term and long-term HIV risk behavior among youth in high-income countries.
Editors' Summary
Background.
Human immunodeficiency virus (HIV), which causes AIDS, is most often spread through unprotected sex (vaginal, oral, or anal) with an infected partner. Individuals can reduce their risk of becoming infected with HIV by abstaining from sex or delaying first sex, by being faithful to one partner or having few partners, and by always using a male or female condom. Various HIV prevention programs targeted at young people encourage these protective sexual behaviors. Abstinence-only programs (for example, Project Reality in the US) present no sex before marriage as the only means of reducing the risk of catching HIV. Abstinence-plus programs (for example, the UK Apause program) also promote sexual abstinence as the safest behavior choice to prevent HIV infection. However, recognizing that not everyone will remain abstinent, and that in many locations same-sex couples are not permitted to marry, abstinence-plus programs also encourage young people who do become sexually active to use condoms and other safer-sex strategies. Safer-sex programs, a third approach, teach people how to protect themselves from pregnancy and infections and might recommend delaying first sex until they are physically and emotionally ready, but do not promote sexual abstinence over safer-sex strategies such as condom use.
Why Was This Study Done?
There is considerable controversy, particularly in the US, about the relative merits of abstinence-based programs for HIV prevention. Abstinence-only programs, which the US government supports, have been criticized because they provide no information to protect participants who do become sexually active. Critics of abstinence-plus programs contend that teaching young people about safer sex undermines the abstinence message, confuses participants, and may encourage them to become sexually active. Conversely, some people worry that the promotion of abstinence might undermine the safer-sex messages of abstinence-plus programs. Little has been done, however, to look methodically at how these programs change sexual behavior. In this study, the researchers have systematically reviewed studies of abstinence-plus interventions for HIV prevention in high-income countries to get an idea of their effect on sexual behavior.
What Did the Researchers Do and Find?
In an extensive search for existing abstinence-plus studies, the researchers identified 39 trials done in high-income countries that compared the effects on sexual behavior of various abstinence-plus programs with the effects of no intervention or of other interventions designed to prevent HIV infection. All the trials met strict preset criteria (for example, trial participants had to have an unknown or negative HIV status), and all studies meeting the criteria turned out to involve young people in the US, Canada, or the Bahamas, nearly 40,000 participants in total. In 23 of the trials, the abstinence-plus program studied was found to improve at least one self-reported protective sexual behavior (for example, it increased abstinence or condom use) when compared to the other interventions in the trial; none of the trials reported a significant negative effect on any behavioral outcome. Limited evidence from a few trials indicated that some abstinence-plus programs reduced pregnancy rates, providing a biological indicator of program effectiveness. Conversely, there were no indications of adverse biological outcomes such as an increased occurrence of sexually transmitted diseases in any of the trials.
What Do These Findings Mean?
These findings indicate that some abstinence-plus programs reduce HIV risk behavior among young people in North America. Importantly, the findings do not uncover evidence of any abstinence-plus program causing harm. That is, fears that these programs might encourage young people to become sexually active earlier or confuse them about the use of condoms for HIV prevention seem unfounded. These findings may not apply to all abstinence-plus programs in high-income countries, do not include low-income countries, do not specifically address nonheterosexual risk behavior, and are subject to limited reliability in self-reporting of sexual activity by young people. Nonetheless, this analysis provides support for the use of abstinence-plus programs, particularly in light of another systematic review by the same authors (A systematic review of abstinence-only programs for prevention of HIV infection, published in the British Medical Journal), which found that abstinence-only programs did not reduce pregnancy, sexually transmitted diseases, or sexual behaviors that increase HIV risk. Abstinence-plus programs, these findings suggest, represent a reasonable strategy for HIV prevention among young people in high-income countries.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040275.
• US National Institute of Allergy and Infectious Diseases fact sheet on HIV infection and AIDS
• Information from the UK charity AVERT on all aspects of HIV and AIDS, including HIV and AIDS prevention
• US Centers for Disease Control and Prevention fact sheet on HIV/AIDS among young people (in English and Spanish)
• Information on Project Reality, a US abstinence-only program
• Information on Reducing the Risk and on Apause, US and UK abstinence-plus programs, respectively
doi:10.1371/journal.pmed.0040275
PMCID: PMC1976624  PMID: 17880259
19.  Economic Appraisal of Ontario's Universal Influenza Immunization Program: A Cost-Utility Analysis 
PLoS Medicine  2010;7(4):e1000256.
Beate Sander and colleagues assess the cost-effectiveness of the program that provides free seasonal influenza vaccines to the entire population of Ontario, Canada.
Background
In July 2000, the province of Ontario, Canada, initiated a universal influenza immunization program (UIIP) to provide free seasonal influenza vaccines for the entire population. This is the first large-scale program of its kind worldwide. The objective of this study was to conduct an economic appraisal of Ontario's UIIP compared to a targeted influenza immunization program (TIIP).
Methods and Findings
A cost-utility analysis using Ontario health administrative data was performed. The study was informed by a companion ecological study comparing physician visits, emergency department visits, hospitalizations, and deaths between 1997 and 2004 in Ontario and nine other Canadian provinces offering targeted immunization programs. The relative change estimates from pre-2000 to post-2000 as observed in other provinces were applied to pre-UIIP Ontario event rates to calculate the expected number of events had Ontario continued to offer targeted immunization. Main outcome measures were quality-adjusted life years (QALYs), costs in 2006 Canadian dollars, and incremental cost-utility ratios (incremental cost per QALY gained). Program and other costs were drawn from Ontario sources. Utility weights were obtained from the literature. The incremental cost of the program per QALY gained was calculated from the health care payer perspective. Ontario's UIIP costs approximately twice as much as a targeted program but reduces influenza cases by 61% and mortality by 28%, saving an estimated 1,134 QALYs per season overall. Reducing influenza cases decreases health care services cost by 52%. Most cost savings can be attributed to hospitalizations avoided. The incremental cost-effectiveness ratio is Can$10,797/QALY gained. Results are most sensitive to immunization cost and number of deaths averted.
Conclusions
Universal immunization against seasonal influenza was estimated to be an economically attractive intervention.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Annual outbreaks (epidemics) of influenza—a viral disease of the nose, throat, and airways—make millions of people ill and kill about 500,000 individuals every year. In doing so, they impose a considerable economic burden on society in terms of health care costs and lost productivity. Influenza epidemics occur because small but frequent changes in the viral proteins to which the immune system responds mean that an immune response produced one year by exposure to an influenza virus provides only partial protection against influenza the next year. Annual immunization with a vaccine that contains killed influenza viruses of the major circulating strains can boost this natural immunity and greatly reduce a person's chances of catching influenza. Consequently, many countries run seasonal influenza vaccine programs. These programs usually target people at high risk of complications from influenza and individuals likely to come into close contact with them, and people who provide essential community services. So, for example, in most Canadian provinces, targeted influenza immunization programs (TIIPs) offer free influenza vaccinations to people aged 65 years or older, to people with chronic medical conditions, and to health care workers.
Why Was This Study Done?
Some experts argue, however, that universal vaccination might provide populations with better protection from influenza. In 2000, the province of Ontario in Canada decided, therefore, to introduce a universal influenza immunization program (UIIP) to provide free influenza vaccination to everyone older than 6 months, the first large program of this kind in the world. A study published in 2008 showed that, following the introduction of the UIIP, vaccination rates in Ontario increased more than in other Canadian provinces. In addition, deaths from influenza and influenza-related use of health care facilities decreased more in Ontario than in provinces that continued to offer a TIIP. But is universal influenza vaccination good value for money? In this study, the researchers evaluate the cost-effectiveness of the Ontario UIIP by comparing the health outcomes and costs associated with its introduction with the health outcomes and costs associated with a hypothetical continuation of targeted influenza immunization.
What Did the Researchers Do and Find?
The researchers used data on TIIP and UIIP vaccine uptake, physician visits, emergency department visits, hospitalizations for influenza, and deaths from influenza between 1997 and 2004 in Ontario and in nine Canadian states offering TIIPs, and Ontario cost data, in their “cost-utility” analysis. This type of analysis estimates the additional cost required to generate a year of perfect health (a quality-adjusted life-year or QALY) through the introduction of an intervention. QALYs are calculated by multiplying the time spent in a certain health state by a measure of the quality of that health state. The researchers report that the cost of Ontario's UIIP was about twice as much as the cost of a TIIP for the province. However, the introduction of the UIIP reduced the number of influenza cases by nearly two-thirds and reduced deaths from influenza by more than a quarter compared with what would have been expected had the province continued to offer a TIIP, an overall saving of 1,134 QALYs. Furthermore, the reduction in influenza cases halved influenza-related health care costs, mainly because of reductions in hospitalization. Overall, this means that the additional cost to Ontario of saving one QALY through the introduction of the UIIP was Can$10,797, an “incremental cost-effectiveness ratio” of $10,797 per QALY gained.
What Do These Findings Mean?
In Canada, an intervention is considered cost-effective from the point of view of a health care purchaser if it costs less than Canadian $50,000 to gain one QALY. These findings indicate, therefore, that for Ontario the introduction of the UIIP is economically attractive. Indeed, the researchers calculate that even if the costs of the UIIP were to double, the additional cost of saving one QALY by introducing universal immunization would remain below $50,000. Other “sensitivity” analyses undertaken by the researchers also indicate that universal immunization is likely to be effective and cost-effective in Ontario if other key assumptions and/or data included in the calculations are varied within reasonable limits. Given these findings, the researchers suggest that a UIIP might be an appealing intervention in other Canadian provinces and in other high-income countries where influenza transmission and health-care costs are broadly similar to those in Ontario.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000256.
A PLoS Medicine Research Article by Kwong and colleagues describes how the introduction of universal influenza immunization in Ontario altered influenza-related health care use and deaths in the province
Wikipedia pages are available on QALYs and on cost-utility analysis (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
Bandolier, an independent online journal about evidence-based health-care, provides information about QALYs and their use in cost-utility analysis
The UK National Institute for Health and Clinical Excellence has a webpage on Measuring effectiveness and cost-effectiveness: the QALY
doi:10.1371/journal.pmed.1000256
PMCID: PMC2850382  PMID: 20386727
20.  Antimicrobial stewardship in pediatrics: focusing on the challenges clinicians face 
BMC Pediatrics  2014;14:212.
Background
Antimicrobial use is very common in hospitalized children. An assessment of clinician’s prevailing knowledge and clinical approach to prescribing antimicrobials is helpful in order to develop the best strategies for successful stewardship programs. The objectives of the study were to determine fundamental knowledge of principles, approach to antimicrobial use through the clinical vignettes and to identify perceived challenges in decreasing antimicrobial use.
Methods
A questionnaire was developed by subject matter experts and pretested to ensure validity. Using a cross-sectional prospective design, the questionnaire was completed anonymously by staff and trainee physicians at a single tertiary care pediatric hospital between late November 2011 and February 2012.
Results
Of 159 eligible physicians, 86 (54.1%) responded, of which 77 (46 staff and 31 trainees) reported regularly prescribing antimicrobials. The majority of physicians had modest knowledge of factors that would increase risk of resistance however, less than 20% had correct knowledge of local resistance patterns for common bacteria. Almost half of physicians correctly answered the clinical vignettes. Over half of trainees and one third of staff relied most on online manuals for information regarding antimicrobials to assist prescription decision-making. Overall, physicians perceived that discontinuing empiric antimicrobials was the most difficult to achieve to decrease antibiotic use.
Conclusions
Our results highlight several challenges that pediatric practioners face with respect to knowledge and approach to antimicrobial prescribing. Pediatric stewardship programs could in this setting focus on discontinuing antimicrobials appropriately and promoting local antibiograms in the proper clinical setting to decrease overall use of antimicrobials.
doi:10.1186/1471-2431-14-212
PMCID: PMC4236642  PMID: 25164768
Antimicrobial stewardship; Pediatrics; Knowledge
21.  Knowledge and beliefs on antimicrobial resistance among physicians and nurses in hospitals in Amhara Region, Ethiopia 
Background
Antimicrobial resistance (AMR) is a major global public health problem both in hospital and community acquired infections. The present study assessed the knowledge and beliefs on AMR among physicians and nurses in 13 hospitals in Amhara region, Ethiopia, which is a low-income country.
Methods
A cross-sectional study using a self-administered questionnaire was applied.
Results
A total of 385 participants (175 physicians and 210 nurses) took part in the study. Sixty five percent of physicians and 98% of nurses replied that they need training on antimicrobial stewardship. Only 48% of physicians and 22.8% of nurses had exposures for local antibiogram data. Overall, 278 (72.2%) of participants were knowledgeable about AMR. Majority of participants agreed or strongly agreed AMR as worldwide and national problem but few considered AMR as problem in their own hospitals. The two most important factors mentioned for AMR development were patients’ poor adherence to prescribed antimicrobials (86%) and overuse of antibiotics (80.5%). The most leading local factors identified for AMR development were: self-antibiotic prescription (53.5%), lack of access to local antibiogram data (12.3%) and prescriber poor awareness about AMR (9.2%). Factors perceived for excessive antibiotic prescriptions were: patient drive (56%), treatment failure (79%), unknown febrile illnesses (39.7%) and upper respiratory tract infections (33.4%).
Conclusion
Majority of physicians and nurses lack up to-date knowledge on AMR. Unavailability of local antibiogram data, self-prescription by patients and poor awareness on AMR are areas of interventions for prevention and control of AMR.
doi:10.1186/2050-6511-15-26
PMCID: PMC4032864  PMID: 24887310
Antimicrobial resistance; Knowledge; Belief; Ethiopia
22.  Engaging the private sector to improve antimicrobial use in the community: experience from accredited drug dispensing outlets in Tanzania 
Objectives
A public-private partnership in Tanzania launched the accredited drug dispensing outlet (ADDO) program to improve access to quality medicines and pharmaceutical services in rural areas. ADDO dispensers play a potentially important role in promoting the rational use of antimicrobials, which helps control antimicrobial resistance (AMR). The study objectives were to 1) improve dispensing practices of antimicrobials, 2) build ADDO dispensers’ awareness of the consequences of misusing antimicrobials, and 3) educate consumers on the correct use of antimicrobials through the use of printed materials and counseling.
Methods
Our intervention targeted ADDO dispensers and community members in Kilosa district. We promoted AMR awareness using posters hung in public places, health facilities, and ADDOs; sensitizing 84 health care providers on AMR issues; and providing training and on-site support for 124 ADDO dispensers to increase their AMR knowledge and dispensing skills. Baseline and endline assessments included direct observation of dispensers’ practices; interviews with ADDO dispensers (71 at baseline and 68 at endline) regarding dispensing experiences; 230 exit interviews with ADDO customers regarding use of antimicrobials during monitoring visits; and review of ADDO records. Indicators were based on product availability, dispensing practices, customers’ knowledge of how to take their medicines, and dispenser and public awareness of the AMR threat.
Results
Availability of tracer antimicrobials increased by 26% (p = 0.0088), and the proportion of ADDOs with unauthorized items decreased from 53% to 13% (p = 0.0001). The percentage of ADDO dispensers following good dispensing practices increased from an average of 67% in the first monitoring visit to an average of 91% during the last visit (p = 0.0001). After the intervention, more dispensers could name more factors contributing to AMR and negative consequences of inappropriate antimicrobial use, and over 95% of ADDO customers knew important information about the medicines they were dispensed.
Conclusions
Providing educational materials and equipping ADDO dispensers with knowledge and tools helps significantly improve community medicine use and possibly reduces AMR. The number of community members who learned about AMR from ADDO dispensers indicates that they are an important source of information on medicine use.
doi:10.1186/2052-3211-7-11
PMCID: PMC4177420  PMID: 25298887
Antimicrobial resistance; Drug seller; Medicine use; Private sector; Tanzania
23.  Collagen Cross-Linking Using Riboflavin and Ultraviolet-A for Corneal Thinning Disorders 
Executive Summary
Objective
The main objectives for this evidence-based analysis were to determine the safety and effectiveness of photochemical corneal collagen cross-linking with riboflavin (vitamin B2) and ultraviolet-A radiation, referred to as CXL, for the management of corneal thinning disease conditions. The comparative safety and effectiveness of corneal cross-linking with other minimally invasive treatments such as intrastromal corneal rings was also reviewed. The Medical Advisory Secretariat (MAS) evidence-based analysis was performed to support public financing decisions.
Subject of the Evidence-Based Analysis
The primary treatment objective for corneal cross-linking is to increase the strength of the corneal stroma, thereby stabilizing the underlying disease process. At the present time, it is the only procedure that treats the underlying disease condition. The proposed advantages for corneal cross-linking are that the procedure is minimally invasive, safe and effective, and it can potentially delay or defer the need for a corneal transplant. In addition, corneal cross-linking does not adversely affect subsequent surgical approaches, if they are necessary, or interfere with corneal transplants. The evidence for these claims for corneal cross-linking in the management of corneal thinning disorders such as keratoconus will be the focus of this review.
The specific research questions for the evidence review were as follows:
Technical: How technically demanding is corneal cross-linking and what are the operative risks?
Safety: What is known about the broader safety profile of corneal cross-linking?
Effectiveness - Corneal Surface Topographic Affects:
What are the corneal surface remodeling effects of corneal cross-linking?
Do these changes interfere with subsequent interventions, particularly corneal transplant known as penetrating keratoplasty (PKP)?
Effectiveness -Visual Acuity:
What impacts does the remodeling have on visual acuity?
Are these impacts predictable, stable, adjustable and durable?
Effectiveness - Refractive Outcomes: What impact does remodeling have on refractive outcomes?
Effectiveness - Visual Quality (Symptoms): What impact does corneal cross-linking have on vision quality such as contrast vision, and decreased visual symptoms (halos, fluctuating vision)?
Effectiveness - Contact lens tolerance: To what extent does contact lens intolerance improve after corneal cross-linking?
Vision-Related QOL: What is the impact of corneal cross-linking on functional visual rehabilitation and quality of life?
Patient satisfaction: Are patients satisfied with their vision following the procedure?
Disease Process:
What impact does corneal cross-linking have on the underling corneal thinning disease process?
Does corneal cross-linking delay or defer the need for a corneal transplant?
What is the comparative safety and effectiveness of corneal cross-linking compared with other minimally invasive treatments for corneal ectasia such as intrastromal corneal rings?
Clinical Need: Target Population and Condition
Corneal ectasia (thinning) disorders represent a range of disorders involving either primary disease conditions, such as keratoconus (KC) and pellucid marginal corneal degeneration, or secondary iatrogenic conditions, such as corneal thinning occurring after laser in situ keratomileusis (LASIK) refractive surgery.
Corneal thinning is a disease that occurs when the normally round dome-shaped cornea progressively thins causing a cone-like bulge or forward protrusion in response to the normal pressure of the eye. The thinning occurs primarily in the stroma layers and is believed to be a breakdown in the collagen process. This bulging can lead to irregular astigmatism or shape of the cornea. Because the anterior part of the cornea is responsible for most of the focusing of the light on the retina, this can then result in loss of visual acuity. The reduced visual acuity can make even simple daily tasks, such as driving, watching television or reading, difficult to perform.
Keratoconus is the most common form of corneal thinning disorder and involves a noninflammatory chronic disease process of progressive corneal thinning. Although the specific cause for the biomechanical alterations in the corneal stroma is unknown, there is a growing body of evidence suggesting that genetic factors may play an important role. Keratoconus is a rare disease (< 0.05% of the population) and is unique among chronic eye diseases because it has an early onset, with a median age of 25 years. Disease management for this condition follows a step-wise approach depending on disease severity. Contact lenses are the primary treatment of choice when there is irregular astigmatism associated with the disease. Patients are referred for corneal transplants as a last option when they can no longer tolerate contact lenses or when lenses no longer provide adequate vision.
Keratoconus is one of the leading indications for corneal transplants and has been so for the last 3 decades. Despite the high success rate of corneal transplants (up to 20 years) there are reasons to defer it as long as possible. Patients with keratoconus are generally young and a longer-term graft survival of at least 30 or 40 years may be necessary. The surgery itself involves lengthy time off work and postsurgery, while potential complications include long-term steroid use, secondary cataracts, and glaucoma. After a corneal transplant, keratoconus may recur resulting in a need for subsequent interventions. Residual refractive errors and astigmatism can remain challenges after transplantation, and high refractive surgery and regraft rates in KC patients have been reported. Visual rehabilitation or recovery of visual acuity after transplant may be slow and/or unsatisfactory to patients.
Description of Technology/Therapy
Corneal cross-linking involves the use of riboflavin (vitamin B2) and ultraviolet-A (UVA) radiation. A UVA irradiation device known as the CXL® device (license number 77989) by ACCUTECH Medical Technologies Inc. has been licensed by Health Canada as a Class II device since September 19, 2008. An illumination device that emits homogeneous UVA, in combination with any generic form of riboflavin, is licensed by Health Canada for the indication to slow or stop the progression of corneal thinning caused by progressive keratectasia, iatrogenic keratectasia after laser-assisted in situ keratomileusis (LASIK) and pellucid marginal degeneration. The same device is named the UV-X® device by IROCMedical, with approvals in Argentina, the European Union and Australia.
UVA devices all use light emitting diodes to generate UVA at a wavelength of 360-380 microns but vary in the number of diodes (5 to 25), focusing systems, working distance, beam diameter, beam uniformity and extent to which the operator can vary the parameters. In Ontario, CXL is currently offered at over 15 private eye clinics by refractive surgeons and ophthalmologists.
The treatment is an outpatient procedure generally performed with topical anesthesia. The treatment consists of several well defined procedures. The epithelial cell layer is first removed, often using a blunt spatula in a 9.0 mm diameter under sterile conditions. This step is followed by the application of topical 0.1% riboflavin (vitamin B2) solution every 3 to 5 minutes for 25 minutes to ensure that the corneal stroma is fully penetrated. A solid-state UVA light source with a wavelength of 370 nm (maximum absorption of riboflavin) and an irradiance of 3 mW/cm2 is used to irradiate the central cornea. Following treatment, a soft bandage lens is applied and prescriptions are given for oral pain medications, preservative-free tears, anti-inflammatory drops (preferably not nonsteroidal anti-inflammatory drugs, or NSAIDs) and antibiotic eye drops. Patients are recalled 1 week following the procedure to evaluate re-epithelialization and they are followed-up subsequently.
Evidence-Based Analysis Methods
A literature search was conducted on photochemical corneal collagen cross-linking with riboflavin (vitamin B2) and ultraviolet-A for the management of corneal thinning disorders using a search strategy with appropriate keywords and subject headings for CXL for literature published up until April 17, 2011. The literature search for this Health Technology Assessment (HTA) review was performed using the Cochrane Library, the Emergency Care Research Institute (ECRI) and the Centre for Reviews and Dissemination. The websites of several other health technology agencies were also reviewed, including the Canadian Agency for Drugs and Technologies in Health (CADTH) and the United Kingdom’s National Institute for Clinical Excellence (NICE). The databases searched included OVID MEDLINE, MEDLINE IN-Process and other Non-Indexed Citations such as EMBASE.
As the evidence review included an intervention for a rare condition, case series and case reports, particularly for complications and adverse events, were reviewed. A total of 316 citations were identified and all abstracts were reviewed by a single reviewer for eligibility. For those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search.
Inclusion Criteria
English-language reports and human studies
patients with any corneal thinning disorder
reports with CXL procedures used alone or in conjunction with other interventions
original reports with defined study methodology
reports including standardized measurements on outcome events such as technical success, safety effectiveness, durability, vision quality of life or patient satisfaction
systematic reviews, meta-analyses, randomized controlled trials, observational studies, retrospective analyses, case series, or case reports for complications and adverse events
Exclusion Criteria
nonsystematic reviews, letters, comments and editorials
reports not involving outcome events such as safety, effectiveness, durability, vision quality or patient satisfaction following an intervention with corneal implants
reports not involving corneal thinning disorders and an intervention involving CXL
Summary of Evidence Findings
In the Medical Advisory Secretariat evidence review on corneal cross-linking, 65 reports (16 case reports) involving 1403 patients were identified on the use of CXL for managing corneal thinning disorders. The reports were summarized according to their primary clinical indication, whether or not secondary interventions were used in conjunction with CXL (referred to as CXL-Plus) and whether or not it was a safety-related report.
The safety review was based on information from the cohort studies evaluating effectiveness, clinical studies evaluating safety, treatment response or recovery, and published case reports of complications. Complications, such as infection and noninfectious keratitis (inflammatory response), reported in case reports, generally occurred in the first week and were successfully treated with topical antibiotics and steroids. Other complications, such as the cytotoxic effects on the targeted corneal stroma, occurred as side effects of the photo-oxidative process generated by riboflavin and ultraviolet-A and were usually reversible.
The reports on treatment effectiveness involved 15 pre-post longitudinal cohort follow-up studies ranging from follow-up of patients’ treated eye only, follow-up in both the treated and untreated fellow-eye; and follow-up in the treated eye only and a control group not receiving treatment. One study was a 3-arm randomized control study (RCT) involving 2 comparators: one comparator was a sham treatment in which one eye was treated with riboflavin only; and the other comparator was the untreated fellow-eye. The outcomes reported across the studies involved statistically significant and clinically relevant improvements in corneal topography and refraction after CXL. In addition, improvements in treated eyes were accompanied by worsening outcomes in the untreated fellow-eyes. Improvements in corneal topography reported at 6 months were maintained at 1- and 2-year follow-up. Visual acuity, although not always improved, was infrequently reported as vision loss. Additional procedures such as the use of intrastromal corneal ring segments, intraocular lenses and refractive surgical practices were reported to result in additional improvements in topography and visual acuity after CXL.
Considerations for Ontario Health System
The total costs of providing CXL therapy to keratoconus patients in Ontario was calculated based on estimated physician, clinic, and medication costs. The total cost per patient was approximately $1,036 for the treatment of one eye, and $1,751 for the treatment of both eyes. The prevalence of keratoconus was estimated at 4,047 patients in FY2011, with an anticipated annual incidence (new cases) of about 148 cases. After distributing the costs of CXL therapy for the FY2011 prevalent keratoconus population over the next 3 years, the estimated average annual cost was approximately $2.1 million, of which about $1.3 million would be physician costs specifically.
Conclusion
Corneal cross-linking effectively stabilizes the underlying disease, and in some cases reverses disease progression as measured by key corneal topographic measures. The affects of CXL on visual acuity are less predictable and the use of adjunct interventions with CXL, such as intrastromal corneal ring segments, refractive surgery, and intraocular lens implants are increasingly employed to both stabilize disease and restore visual acuity. Although the use of adjunct interventions have been shown to result in additional clinical benefit, the order, timing, and risks of performing adjunctive interventions have not been well established.
Although there is potential for serious adverse events with corneal UVA irradiation and photochemical reactions, there have been few reported complications. Those that have occurred tended to be related to side effects of the induced photochemical reactions and were generally reversible. However, to ensure that there are minimal complications with the use of CXL and irradiation, strict adherence to defined CXL procedural protocols is essential.
Keywords
Keratoconus, corneal cross-linking, corneal topography, corneal transplant, visual acuity, refractive error.
PMCID: PMC3377552  PMID: 23074417
24.  Implementation of an antimicrobial stewardship program on the medical-surgical service of a 100-bed community hospital 
Background
Antimicrobial stewardship has been promoted as a key strategy for coping with the problems of antimicrobial resistance and Clostridium difficile. Despite the current call for stewardship in community hospitals, including smaller community hospitals, practical examples of stewardship programs are scarce in the reported literature. The purpose of the current report is to describe the implementation of an antimicrobial stewardship program on the medical-surgical service of a 100-bed community hospital employing a core strategy of post-prescriptive audit with intervention and feedback.
Methods
For one hour twice weekly, an infectious diseases physician and a clinical pharmacist audited medical records of inpatients receiving systemic antimicrobial therapy and made non-binding, written recommendations that were subsequently scored for implementation. Defined daily doses (DDDs; World Health Organization Center for Drug Statistics Methodology) and acquisition costs per admission and per patient-day were calculated monthly for all administered antimicrobial agents.
Results
The antimicrobial stewardship team (AST) made one or more recommendations for 313 of 367 audits during a 16-month intervention period (September 2009 – December 2010). Physicians implemented recommendation(s) from each of 234 (75%) audits, including from 85 of 115 for which discontinuation of all antimicrobial therapy was recommended. In comparison to an 8-month baseline period (January 2009 – August 2009), there was a 22% decrease in defined daily doses per 100 admissions (P = .006) and a 16% reduction per 1000 patient-days (P = .013). There was a 32% reduction in antimicrobial acquisition cost per admission (P = .013) and a 25% acquisition cost reduction per patient-day (P = .022).
Conclusions
An effective antimicrobial stewardship program was implemented with limited resources on the medical-surgical service of a 100-bed community hospital.
doi:10.1186/2047-2994-1-32
PMCID: PMC3499185  PMID: 23043720
Antimicrobial stewardship; ASP; Small community hospital
25.  The challenges and successes of implementing a sustainable antimicrobial resistance surveillance programme in Nepal 
BMC Public Health  2014;14:269.
Background
Antimicrobial resistance (AMR) is a major global public health concern and its surveillance is a fundamental tool for monitoring the development of AMR. In 1998, the Nepalese Ministry of Health (MOH) launched an Infectious Disease (ID) programme. The key components of the programme were to establish a surveillance programme for AMR and to develop awareness among physicians regarding AMR and rational drug usage in Nepal.
Methods
An AMR surveillance programme was established and implemented by the Nepalese MOH in partnership with the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR, B) from 1998 to 2003. From 2004 to 2012, the programme was integrated and maintained as a core activity of the National Public Health Laboratory (NPHL) and resulted in an increased number of participating laboratories and pathogens brought under surveillance. The main strategies were to build national capacity on isolation, identification and AMR testing of bacterial pathogens, establish laboratory networking and an External Quality Assessment (EQA) programme, promote standardised recording and reporting of results, and to ensure timely analysis and dissemination of data for advocacy and national policy adaptations. The programme was initiated by nine participating laboratories performing AMR surveillance on Vibrio cholerae, Shigella spp., Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria gonorrhoeae.
Results
The number of participating laboratories was ultimately increased to 13 and the number of pathogens under surveillance was increased to seven (Salmonella spp. was added to the surveillance programme in 2002 and extended spectrum β-lactamase producing Escherichia coli in 2011). From 1999 to 2012, data were available on 17,103 bacterial isolates. During the AMR programme, we observed changing trends in serovars/ species for Salmonella spp., Shigella spp. and V. cholerae and changing AMR trend for all organisms. Notably, N. gonorrhoeae isolates demonstrated increasing resistance to ciprofloxacin. Additionally, the performance of the participating laboratories improved as shown by annual EQA data evaluation.
Conclusions
This Nepalese AMR programme continues and serves as a model for sustainable surveillance of AMR monitoring in resource limited settings.
doi:10.1186/1471-2458-14-269
PMCID: PMC4234382  PMID: 24650008
Antimicrobial resistance surveillance; Nepal; Respiratory pathogens; Enteric pathogens; Sexually transmitted disease pathogens

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