Team:elan vital korea/Integrated Human Practice
HUMAN PRACTICE
-Integrated Human Practice-
Threat of Antibiotics-Resistance and Countermeasures: Korea
and US
The spread of antibiotic-resistant bacteria is a global health problem that affects nations across borders and boundaries and rapidly spreads throughout the world. These nightmare bacteria pose catastrophic threat to people everywhere in the world.
Our project is Early Detection of Antibiotic Resistant Bacteria using Quorum Sensing. It is closed related to the surveillance and containment of the pathogens. With the understanding, we have conducted case study of Korea and the US on the current status of antibiotic resistant bacteria infection and the countermeasures. We have gathered data on the spread of antibiotic-resistant bacteria and countermeasures taken as well as contemplated in Korea and the US. For this, we have relied on various materials and documentations, and some of them are translated from Korean.
Introduction
On November 11, 1945, Alexander Fleming delivered his Nobel Prize speech. This great man who discovered penicillin warned that bacteria could become resistant to these remarkable drugs. Indeed, the development of each new antibacterial drug has been followed by the detection of resistance to it. The development of resistance is a normal evolutionary process for microorganisms, but it is accelerated by the selective pressure exerted by widespread use of antibacterial drugs. Resistant strains are able to propagate and spread where there is non-compliance with infection prevention and control measures.
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Even considering regional discrepancy in the data quality as well as quantity, resistance patterns for the bacteria of public health importance is sufficient to alarm the world. For example, the proportion resistant of S.aureus to commonly used specific antibiotic drugs exceeded 50% in many countries. Furthermore, there are limitations in effective oral treatment options for some common community-acquired infections in several countries, and that there remain few, if any, treatment options for some common severe and health-care associated infections in many places.
High rates of MRSA imply that treatment for suspected or verified severe S. aureus infections, such as common skin and wound infections, must rely on secondline drugs in many countries, and that standard prophylaxis with first-line drugs for orthopaedic and other surgical procedures will have limited effect in many settings. Second-line drugs for S. aureus are more expensive; also, they have severe side-effects for which monitoring during treatment is advisable, increasing costs even further.
Unfortunately, there is at present no global consensus on methodology and data collection for Antibiotic Resistant
Bacteria surveillance. Routine surveillance in most countries is often based on samples taken from patients with severe infections – particularly infections associated with health care, and those in which first-line treatment has failed. Community-acquired infections are almost certainly underrepresented among samples, leading to gaps in coverage of important patient groups.
It is urgent to develop effective implementation strategies in order to curtail the emergence and spread of AR, and to evaluate the effect of interventions.
Antibiotic resistance has a significant adverse impact on clinical outcomes and leads to higher costs due to consumption of health-care resources. Patients with infections caused by bacteria resistant to a specific antibacterial drug generally have an increased risk of worse clinical outcomes and death, and consume more healthcare resources, than patients infected with the same bacteria not demonstrating the resistance pattern in question.
Although surveillance on antibiotic resistant bacteria has been undertaken for many years in a number of high-income countries, there are still large gaps in knowledge about the status of surveillance capacities worldwide, particularly in resource-limited settings.
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Available data are insufficient to estimate the wider societal impact and economic implications when effective treatment for an infection is completely lost as a result of resistance to all available drugs. The overall health and economic burden resulting from acquired antibiotic resistant bacteria cannot be fully assessed with the presently available data; new methodologies are needed to more precisely assess the total impact of resistance, to better inform health policies and to prioritize the deployment of resources. However, even admitting the lack of reliable information on the financials, the overall cost is highly burden to all nations, even further to the less developed countries. For example, the yearly cost to the US health system alone has been estimated at US $21 to $34 billion dollars, accompanied by more than 8 million additional days in hospital. Because antibiotic resistant bacteria has effects far beyond the health sector, it was projected, nearly 10 years ago, to cause a fall in real gross domestic product (GDP) of 0.4% to 1.6%, which translates into many billions of today’s dollars globally.
KOREA
In Korea, Korean CDC collected antibiotic-resistance infection cases from hospitals, which shows that 41,883 patients (about 7% of the total hospitalized patients) were infected by antibiotic-resistant bacteria during the first half-year of 2014 (from January 1 to June 30, 2014).
(Source: Korea Center for Disease Control and Prevention, http://www.cdc.go.kr/search/sEngine.jsp?kwd=MRSA%EA%B0
%90%EC%97%BC)
KARMS released annual report in 2014 containing antibiotic resistance infection data gathered from hospitals as well as long term care facilities and small & medium sized clinics. Publishing such data is a clear evidence that the Korean government is keenly aware of the hazards of the antibiotic resistant bacteria and also shows its commitment to deal with the matter systematically. The government adopted a law on the Prevention and Containment of Infectious Diseases in Dec. 2010.
In accordance with the executive order of the law, antibiotic resistance infections including VRSA, VRE, MRSA, MRPA,
MRAB, CRE were designated as “infections to be contained”. The annual reports deals with S. aureus, Enterococcus spp., S. pneumoniae, E. coli , K. pneumoniae , E. cloacae, P. aeruginosa , A. baumannii Following are the results: (Data from General Hospital (more than 300 beds))
Staphylococcus aureus
Medium Sized Hospital
Table * Antimicrobial resistance rates (%) of S. aureus isolated from hospitals
* Including cefoxitin, † Not tested, ‡ Trimethoprim-Sulfamethoxazole, , ∥ Quinupristin-Dalfopristin
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Figure * Antimicrobial resistance rates (%) of S. aureus isolated from general hospitals
Enterococcus faecalis
Table * Antimicrobial resistance rates (%) of E. faecalis isolated from general hospitals
* Not tested
Figure * Antimicrobial resistance rates (%) of E. faecalis isolated from general hospitals
Table * Antimicrobial resistance rates (%) of E. faecium isolated from general hospitals
* Not tested, † Quinupristin-Dalfopristin
Figure * Antimicrobial resistance rates (%) of E. faecium isolated from general hospitals
Streptococcus pneumoniae
Table * Antimicrobial resistance rates (%) of S. pneumoniae isolated from general hospitals
* Not tested, † Trimethoprim-Sulfamethoxazole
Figure * Antimicrobial resistance rates (%) of S. pneumoniae isolated from general hospitals
Major Trend of Antibiotic Resistance
As shown on the above data, among gram positive bacteria, antibiotic resistance of S. pneumoniae against penicillin G increased substantially in 2010 and reduced by 5.6% in 2012. On the other hand, antibiotic resistance of gram-negative bacteria has not much changed except A. baumannii that recorded 71.1% of resistance rate in 2010 and moderately decreased to 69.5% in 2012.
Figure * Resistance trends of Gram-positive cocci isolated from general hospitals
Trend of Antibiotic Resistance Infection (Small & Medium Sized Hospitals)
Staphylococcus aureus
Medium Sized Hospital Table * Antimicrobial resistance rates (%) of S. aureus isolated from hospitals
* Including cefoxitin. † The resistance rates were calculated from automation equipment R/I/S interpretations (upper) and MIC values (lower). ‡ Trimethoprim-Sulfamethoxazole, ∥ Quinupristin-Dalfopristin. § Vancomycin-intermediate S. aureus (VISA) ; 2007(0.2%), 2008(0.3%), 2009(0.2%), 2010(0.1%), 2011(0.0%), 2012(0.1%).
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Figure * Antimicrobial resistance rates (%) of S. aureus isolated from hospitals
Long Term Care Facility Table * Antimicrobial resistance rates (%) of S. aureus isolated from geriatric care hospitals
* Including cefoxitin. † The resistance rates were calculated from automation equipment R/I/S interpretations (upper) and MIC values (lower). ‡ Trimethoprim-Sulfamethoxazole, ∥ Quinupristin-Dalfopristin. § Vancomycin-intermediate S. aureus (VISA); 2007 (0.2%), 2008 (0.3%), 2009 (0.2%), 2010 (0.1%), 2011 (0.0%), 2012(0.0%).
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Figure * Antimicrobial resistance rates (%) of S. aureus isolated from geriatric care hospitals
Small Clinics Table * Antimicrobial resistance rates (%) of S. aureus isolated from clinics
* Including cefoxitin. † The resistance rates were calculated from automation equipment R/I/S interpretations (upper) and MIC values (lower). ‡ Trimethoprim-Sulfamethoxazole, ∥ Quinupristin-Dalfopristin. § Vancomycin-intermediate S. aureus (VISA) ; 2007 (0.2%), 2008 (0.3%), 2009 (0.2%), 2010 (0.1%), 2011 (0.0%), 2012 (0.0%).
Figure * Antimicrobial resistance rates (%) of S. aureus isolated from clinics
Result
Antibiotic Resistance of MRSA against oxacillin from 2007 to 2012 showed the order of higher infection at long term care facilities, hospitals and individual clinics. It is alarming that the infection rate of long term care facilities is around 80%.
Figure * Trends of oxacillin resistance for S. aureus by hospital type
Enterococcus faecalis
Hospitals Table * Antimicrobial resistance rates (%) of E. faecalis isolated from hospitals
Hospitals Table * The resistance rates were calculated from automation equipment R/I/S interpretations (upper) and MIC values (lower).
Hospitals Table Figure * Antimicrobial resistance rates (%) of E. faecalis isolated from hospitals
Long-term Care Facilities
Hospitals Table Table * Antimicrobial resistance rates (%) of E. faecalis isolated from geriatric care hospitals
* The resistance rates were calculated from automation equipment R/I/S interpretations (upper) and MIC values (lower).
Figure * Antimicrobial resistance rates (%) of E. faecalis isolated from geriatric care hospitals
Small Clinics Table * Antimicrobial resistance rates (%) of E. faecalis isolated from clinics
Small Clinics * The resistance rates were calculated from automation equipment R/I/S interpretations (upper) and MIC values (lower).
Small Clinics Figure * Antimicrobial resistance rates (%) of E. faecalis isolated from clinics
Enterococcus faecium
Small Clinics Hospitals Table * Antimicrobial resistance rates (%) of E. faecium isolated from hospitals
Small Clinics Hospitals * Quinupristin-Dalfopristin
Figure * Antimicrobial resistance rates (%) of E. faecium isolated from hospitals
Long-Term Care Facilities
Table * Antimicrobial resistance rates (%) of E. faecium isolated from geriatric care hospitals
* Quinupristin-Dalfopristin
Figure * Antimicrobial resistance rates (%) of E. faecium isolated from geriatric care hospitals
Small Clinics Table * Antimicrobial resistance rates (%) of E. faecium isolated from clinics
* Quinupristin-Dalfopristin
Small Clinics Figure * Antimicrobial resistance rates (%) of E. faecium isolated from clinics
Vancomycin resistance rate of VRE E. faecalis is much lower than that of E. faecium, which is less than 1.0%. Vancomycin resistance rate of E. faecium at the long-term care facilities is rapidly increasing from 20.5% in 2007, 41.7%, 2009, and 55.6% in 2012 respectively. Vancomycin resistance rate at the small clinics is 23.9% in 2012, increased more than twice from 2010, higher than that of hospitals (22.0%) Vancomycin resistance rate of all Enterococcus spp. (including E. faecalis and E. faecium) shows similar level at hospitals and clinics in 2011. However the ratio at the long-term care facility is in gradual increase, registering 23.8%.
Figure * Trends of vancomycin resistance for E. faecalis by hospital type
Figure * Trends of vancomycin resistance for E. faecium by hospital type
Figure * Trends of vancomycin resistance for Enterococcus spp by hospital type
Streptococcus pneumoniae
Hospital Table * Antimicrobial resistance rates (%) of S. pneumoniae isolated from hospitals
Hospital * Trimethoprim-Sulfamethoxazole.
Hospital Figure * Antimicrobial resistance rates (%) of S. pneumoniae isolated from hospitals
Hospital Long-term Care Facilities
Hospital Table * Antimicrobial resistance rates (%) of S. pneumoniae isolated from geriatric care hospitals
Hospital * Trimethoprim-Sulfamethoxazole.
Hospital Figure * Antimicrobial resistance rates (%) of S. pneumoniae isolated from geriatric care hospitals
Individual Clinics Table * Antimicrobial resistance rates (%) of S. pneumoniae isolated from clinics
* Trimethoprim-Sulfamethoxazole.
Figure * Antimicrobial resistance rates (%) of S. pneumoniae isolated from clinics
Analysis of the Antibiotic Resistance Depending on the Patient Type
Antibiotic resistance rates of all medical care providing institutions have shown steady decrease from 2007. In 2007, among 5373 Patients of government operating health centers 16.1% have shown antibiotic resistance and 5.5 % multi-drug resistance. Afterward, the ratios have been slightly decreased each year. Meanwhile antibiotic resistance of private health care institutions is much higher: 29.1% in 2007, 19.8% in 2008, 23.6% in 2009, 21.4% in 2010, and 18.4% in 2011 respectively.
Table * Comparison of resistance rates (%) between public health centers and hospitals
*Any Resistance (%)
Detection System in Korea
MRSA Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most severe antibiotic resistant pathogens causing hospital infection and other diseases such as purulent infection, bacteremia. The isolation ratio of MRSA is gradually increased up to 80% in the hospital, which makes a limitation for treatment of antibiotics because the isolated MRSA show resistance to methicillin as well as other antibiotics. To deal with the spread of MRSA infection, medical community as well as the government have paid acute attention on the surveillance of the infection.
Common used method for the detection of MRSA in the hospitals is Susceptibility Test. Another detection method is
MecA gene by PCR, which is not commonly used in the hospitals because of the cost consideration. However mecA is known to be more accurate than Susceptibility Testing.
Standard Detection Procedure used by Hospitals in Korea
1. Taking Sample
1)Take secretion from infected skin with sterilized swap.
2)Taking phlegm from a potential patient or for those who cannot cough by themselves because of respirator, taking samples by cleansing of respiratory organ or bronchoscopy.
3) Taking urine sample from a potential patent or poley-catheter.
4) Taking blood sample.
2. Conduct susceptibility test
It usually takes 48 hours for a patient to get the result. In case
that the patient asks faster detection, other detection method
such as PCR, DNA sequencing are recommended. The
alternative test can produce the result within a few hours.
MIC (Minimum Inhibitory Concentration) is most commonly used susceptibility test. It is used for the detection of all pathogens. However, pathogens such as Streptococcus, Haemophilus, Neisseria that are hard to be cultivated are not detected by MIC. Mcroscan system that is using automated microdilution and E-test are used for MIC.
Paper Disk Method For the test, spread plate culture and pour plate culture are mostly used. Depending on the type of LB agar plate and testing antibiotics, many manufactures have been offered a variety of testing kit. This method should be done by manual procedure from the beginning to the end. Therefore standardized reliable protocols of the testing method should be developed and well observed.
Agar Dilution Method
The antibiotic to be tested is added to agar, which is then placed in dilution plates and diluted with varying levels of water. After this, the pathogen to be tested is added to each plate, plus a control plate that does not receive any antibiotics. The dilution plates are then incubated at a temperature of 37 degrees C. The plates are then incubated for sixteen to eighteen hours, although incubation time may be less for bacteria populations that divide quickly. After incubation, the plates are examined to determine if bacterial expansion has occurred. The lowest concentration of antibiotics that stopped the spread of the bacteria is considered to be the minimum inhibitory concentration of that bacteria
Agar dilution is considered to be the standard of susceptibility testing, or the most accurate way to measure the resistance of bacteria to antibiotics. The results of agar dilution are easily reproduced and they can be monitored at a much cheaper cost than what is required of other dilution methods. Additionally, up to thirty pathogen samples (plus two controls) can be tested at 0o0nce, so agar dilution is useful for batch tests.
Each dilution plate in agar testing has to be manually infected with the pathogen to be tested, so agar dilution testing is both labor intensive and expensive. And agar dilution cannot be used to test more than one pathogen at a time.
Broth Dilution Method
The tube dilution test is the standard method for determining levels of resistance to an antibiotic. Serial dilutions of the antibiotic are made in a liquid medium which is inoculated with a standardized number of organisms and incubated for a prescribed time. The lowest concentration (highest dilution) of antibiotic preventing appearance of turbidity is considered to be the minimal inhibitory concentration (MIC). At this dilution the antibiotic is bacteriostatic.
Varying concentrations of the antibiotics and the bacteria to be tested are then added to the plate. The plate is then placed into a non-CO2 incubator and heated at thirty five degrees C for sixteen to twenty hours. Following the allotted time, the plate is removed and checked for bacterial growth. If the broth became cloudy or a layer of cells formed at the bottom, then bacterial growth has occurred.
The broth dilution method can be used to test the susceptibility of bacteria to multiple antibiotics at once. Broth dilution is also highly accurate. The Other advantages include the commercial availability of plates, the ease of testing and storing the plates, and the ability for the results of some tests to be read by machines. However, the broth dilution method is only effective for testing Bacteroides fragilis. It could potentially be used with other bacteria populations, but the results would have to be correlated with agar dilution tests to be considered reliable. Although the tube dilution test is fairly precise, the test is laborious because serial dilutions of the antibiotic must be made and only one isolate can be tested in each series of dilutions.
ß-Lactamase test
Beta-Lactamase Test is a means of detecting the enzyme beta-lactamase, which confers penicillin resistance to various bacterial organisms by cleaving the beta-lactam ring of penicillin and cephalosporin antibiotics. A wide variety of bacteria produce this enzyme, including both gram-positive and gram-negative organisms. This acidimetric method is recommended for use in testing beta-lactamase production by Neisseria gonorrhoeae, Haemophilus species and Staphylococcus species.
E-Test
Etest, (previously known as Epsilometer test) manufactured by bioMérieux, is a manual in vitro diagnostic device used by laboratories to determine the MIC and whether or not a specific strain of bacterium or fungus is susceptible to the action of a specific antimicrobial. This type of test is most commonly used in healthcare settings to help guiding physicians in treatment of patients by indicating what concentration of antimicrobial successfully would treat the infection.
MIC test has been used as standard test method of the detection of antibiotic resistance in hospitals. It has
weaknesses such frequent error caused by agar LB, disk, tested pathogens, reference strain, and cultivation condition, and lab technician. Another shortcoming of MIC test is the time to get the result. In terms of accuracy and required time, other advanced tests such as mecA PCR Method is recommended by some hospitals. But still majority of detection is being by MIC.
3. Cost of the Detection
Actual cost needed for the detection varies hospitals from hospitals. However average cost of susceptibility test is 55000KW ($50) to 90000KW ($85). For other test, the testing cost is more than 250000KW ($ 200). Testing expense is not covered by mandatory government insurance plan. Thus, if the patient does not have private insurance policy, she should pay by herself.
US
The CDC reported that each year in the United States only, at least 2 million people acquire serious infections with bacteria that are resistant to one or more antibiotics designed to treat the very infection. At least 23,000 people die each year as a direct result of these antibiotic-resistant infections. Many more die from other medical conditions that were further complicated by an antibiotic-resistant infection. (Source: Antibiotic Resistant Threats in the United States 2013, Center for Disease Control and Prevention)
In order to cope with the threats, CDC is adopted five major tasks in order to support initiatives of the White House’s National Strategy to Combat Antibiotic Resistant Bacteria (https://www.whitehouse.gov/sites/default/files/docs/carb_national_strategy.pdf)and the President’s Executive Order(https://www.whitehouse.gov/the-press-office/2014/09/18/executive-order-combating-antibiotic-resistant-bacteria)
Slow the Development of Resistant Bacteria and Prevent the Spread of Resistant Infections
Strengthen National One-Health Surveillance Efforts to Combat Resistance
Advance Development and Use of Rapid and Innovative Diagnostic Tests for Identification and Characterization of
Resistant Bacteria
Accelerate Basic and Applied Research and Development for New Antibiotics, Other Therapeutics, and Vaccines
Improve International Collaboration and Capacities for Antibiotic Resistance Prevention, Surveillance, Control, and Antibiotic Research and Development
In order to fully implement the National Strategy for Combating Antibiotic-Resistant Bacteria, the FY16 AR Solution Initiative was adopted. This implementation will include: comprehensive tracking and detection of antibiotic-resistant bacteria, faster outbreak response, insights for research innovation, better patient care, improved prescribing, increased susceptibility testing, nationwide implementation of CDC’s Core Elements of Hospital Antibiotic Stewardship (http://www.cdc.gov/getsmart/healthcare/implementation/core-elements.html), and global partnerships for prevention and detection.
The FY16 budget also supports a $14 million increase for the National Healthcare Safety Network (NHSN)—the nation’s
leading system to track healthcare-associated infections, including antibiotic resistance and antibiotic use—as a
companion to CDC’s FY16 Antibiotic Resistance Solutions Initiative, supporting multiple goals under the National Strategy, including new activities to better understand and monitor sepsis, leading to enhanced prevention to save lives.
One of the elements of the initiative is advance development and use of rapid and innovative diagnostic tests for
identification and characterization of resistant bacteria. FY 16 AR Solution initiative also includes comprehensive tracking and detection of antibiotic-resistant bacteria.
According to the National Action Plan to Combat Antibiotic-Resistant Bacteria released on 27, March, 2015,
Improved detection and control of antibiotic resistance in human and animal pathogens will be achieved through a
“One-Health” approach to disease surveillance that integrates data from multiple monitoring networks. To achieve the goal by 2020 the government has adopted action plan in order to generate significant outcomes.
Action Plan
1
Creation of a regional public health network—the Detect Network of AR Regional Laboratories—for resistance testing, a specimen repository for resistant bacterial strains, and a National Sequence Database of Resistant Pathogens.
2
Routine reporting of antibiotic use and resistance data to National Health Safety Network (NHSN) by 95% of Medicare-eligible hospitals, as well as by Department of Defense and Veterans Affairs healthcare facilities.
3
Routine testing of zoonotic and animal pathogens for antibiotic susceptibility at ten to twenty National Animal Health Laboratory Network (NAHLN) and Veterinary Laboratory Investigation and Response Network (Vet-LIRN) member laboratories, using standardized testing methods and data sharing practices.
Also important is advance development and use of rapid and innovative diagnostic tests for identification and
characterization of resistant bacteria. In order to facilitate the achievement of the task, the government will take the lead with the support of funding agencies such as the National Institutes of Health. When it is achieved researchers are taking advantage of new technologies to develop rapid “point-of-need” diagnostic tests that can be used during a healthcare visit to distinguish between viral and bacterial infections and identify bacterial drug susceptibilities — an innovation that could significantly reduce unnecessary antibiotic use. The availability of new rapid diagnostic tests, combined with ongoing use of culture-based assays to identify new resistance mechanisms, will advance the detection and control of resistant bacteria.
By 2020, significant outcomes in this area will include:
As proved by these efforts, it is critical to detect antibiotic resistant bacteria as early as possible and eventually to develop “point-of-need” diagnostic test. Our project is to contribute to the early detection of antibiotic resistant bacteria by using quorum sensing. We have succeeded to create plasmids to detect antibiotic resistant bacteria though we are aware that it is rudimentary development of such kind but we believe it is used as a proof of concept and with advanced research efforts, it can be further developed to an extent that it
can be used at the health care institutions and nursing homes. Our hope is to develop a simple kit just like diabetic test kit, so that anyone who needs detection of antibiotic resistance can use it.