MED-NERD
Antibiotic Resistance
Outlines:
- Introduction
- Incidence
- Aetiology and Risk Factors
- Antibiotic-Resistant infections
- Prevention
- References
Introduction:
The mid-20th century were known as “antibiotic era” due to the wide spread use of antibiotics against several infections. Antibiotics have huge significance in multiple fields of medicine including organ transplantation, oncology, rheumatology, immune-modulatory treatments, and other medical demands. Antibiotics have markedly decreased mortality rate especially in children.
Antibiotics may disturb translation, transcription, and cell wall synthesis of bacteria. Some bacterial species can survive antibiotics which represents a challenge to healthcare providers. In 1945, Sir Alexander Fleming, who discovered penicillin and was awarded the Nobel Prize in Medicine, later warned about antibiotics resistance (ABR) due to over‐ and misuse of antibiotics. Penicillin succeeded to control infections in the World War II. Later on, penicillin resistance developed. New agents were developed such as new beta-lactam antibiotics. In 1962 in the United Kingdom and in 1968 in the United States (U.S), the first cases of methicillin-resistant Staphylococcus aureus (MRSA) were reported.
In 1972, Vancomycin was developed for treatment of MRSA and methicillin resistant coagulase-negative staphylococci. Unfortunately, vancomycin resistant cases were identified in 1979 and 1983 in treatment of coagulase-negative staphylococci. New antibiotics were developed from the late 1960s to the early 1980s to solve ABR, which is still a major threat. Factors in humans, animals, and environment may contribute to ABR.
ABR is considered the biggest threat to human health with the increased number of infections (e.g., tuberculosis, salmonellosis, pneumonia, and gonorrhoea) that became resistant to multiple antibiotics resulting in treatment failure. Consequences of ABR include increased mortality rates and higher medical costs.
Bacteria resistant to multiple antibiotics known as multidrug‐resistant (MDR) bacteria or “superbugs” including methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile (C. diff).
In 2019, The latest report from the World Economic Forum in Davos, Switzerland, showed the importance of fighting the rapid and massive spread of infectious diseases. The World Health Organization (WHO), the United Nations (UN), and other organizations work together to reduce antibiotics resistance.
Strict antibiotic prescription instructions and guidelines that reduce the use of antibiotic is necessary to reduce the ABR. Other behaviours that may help in reducing ABR include vaccination, proper food hygiene, washing hands, and practising safer sex to prevent the spread of infections. Increased ABR may lead to post-antibiotic era in which minor injuries and infections can be fatal, so urgent action is required.
Incidence:
-The incidence of ABR and MDR is still rising.
-About 700,000 deaths per year are caused by ABR organisms.
-It is predicted that in 2050, over 10 million deaths per year will be caused by ABR infections.
-The WHO recognized ABR as a major threat to public and global health.
-In 2019, about 1.27 million infections of ABR organisms with approximately 5 million deaths worldwide were reported.
-Over 2.8 million ABR infections yearly occur in the U.S. with about 35,000 deaths according to the Centers for Disease Control and Prevention (CDC)’s Antibiotic Resistance (AR) Threats Report in 2019.
-About 0.2 million neonatal deaths were reported due to MDR organisms-associated sepsis with 0.1 million of these neonatal deaths were reported from China, Congo, Nigeria, Pakistan, and India in 2019.
Aetiology and Risk factors:
The increased number of implanted medical devices (e.g., artificial heart valves, joint prostheses, pacemakers, vascular endo-prostheses) is associated with increased incidence of associated infections, the wide use of antibiotics, antibiotics tolerance, and eventually ABR.
The environment has an important role in dissemination of ABR. Resistance can occur anywhere and at anytime. The mechanism and the conditions by which resistance occurs in the environment are still unclear. Several authors suggested a one-health approach that included human, animal, and environmental factors causing resistance.
The huge number of bacterial cells that present on Earth enables bacteria of rearrangements, gene transfer, genetic variability, and mutations.
Dissemination of ABR infections may be due to socioeconomic factors including travel, displacement, conflict, world trade, human, and animal migration. Close ecosystems are significant in emergence of ABR.
Improper use of antibiotics in humans and animals, not following guidelines, and contaminated environment are major causes of ABR. Soil, farm waste, hospital, hospital, industrial, and other polluted areas are examples of environmental reservoirs of ABR emergence.
Overuse of antibiotics:
Over use of antibiotics is one of the major causes of ABR emergence. Genes in bacteria can be inherited or acquired from a mobile genetic elements (e.g., plasmids). ABR can be transferred among bacterial species through horizontal gene transfer (HGT). Mutations can cause spontaneous resistance. Antibiotics are available over the counter without a prescription in many countries. Easy access and cheap prices of antibiotics increase their overuse and therefore, their resistance.
Inappropriate prescription of antibiotics:
It was found that about 30% to 50% of cases were given inappropriate agents and duration of antibiotic therapy. About 30% to 60% of antibiotics used in intensive care units (ICUs), were found inappropriate and unnecessary. In addition to ABR, unnecessary antibiotics have multiple side effects and complications. Excessive and inappropriate antibiotics can enhance genetic mutations and HGT leading to ABR. Broad proteomic alterations in Bacteroides fragilis were caused by sub-inhibitory concentrations of piperacillin and/or tazobactam.
Extensive Agricultural Use:
About 35 years ago, the transfer of resistant bacteria by farm animals to humans was first identified by finding high rates of ABR in the intestinal flora of farm animals and farmers.
Antibiotics are used in livestock as growth supplements worldwide. In the U.S., about 80% of antibiotics are used to prevent infections and stimulate growth in animals, leading to better health of animals and production of high-quality products. When humans eat food, they ingest these antibiotics.
Recently, it was found that resistant organisms reach humans through consuming meat products. First, antibiotics used in animals enhance the emergence of ABR bacteria, food products transmit resistant bacteria to humans, and eventually resistant-bacterial infections arise in humans.
About 90% of antibiotics used in animals become secreted in stool and urine, that in turn become transmitted through water sources and surfaces. In the western and southern U.S., tetracyclines and streptomycin are used as pesticides in fruit trees. Using antibiotics in agriculture increases resistance of organisms and alters environmental ecology. Not only agricultural/animals antibiotics cause resistance but also antimicrobials used for hygiene may lead to resistance by limiting immunity development against antigens.
Development of Few New Antibiotics:
Development of new antibiotics can help in resistant infections, but there are many economic and industrial obstacles. About 15 out of the 18 largest pharmaceutical companies stopped developing new antibiotic agents. Funding issues and economic crisis have limited antibiotic research. The prevention of ABR is mainly focused on prescription limitations and guidelines. Even if new antibiotic agents are developed, physicians reserve the new agents for the worst cases or serious illnesses and continue to prescribe the old agents.
The time for emergence of ABR is unpredictable. Moreover, antibiotics are less effective and less profitable in treatment of chronic diseases (e.g., asthma, diabetes, psychiatric disorders, gastro-oesophageal reflux) which also decrease the chances of developing new antibiotic agents by pharmaceutical companies. The Infectious Diseases Society of America (IDSA) announced developing antimicrobial agents against extensively resistant gram-negative bacteria (e.g., Pseudomonas aeruginosa, Enterobacteriaceae, Acinetobacter baumannii). MRSA is a major health problem globally against which new antibiotics are being developed.
Examples of Antibiotic-Resistant bacterial infections:
A national survey by specialists of infectious-disease in 2011, conducted by the IDSA Emerging Infections Network, showed that over 60% of participants within the preceding year had seen a resistant, untreatable bacterial infection. ABR is considered a crisis threatening the global health. The resistant S. aureus and Enterococcus species represent the main problem among gram-positive bacteria. In the U.S., MRSA cause deaths even more than HIV/AIDS, emphysema, homicide, and Parkinson’s disease.
Another group of resistant pathogens is Vancomycin-resistant enterococci (VRE) developing resistance against multiple antibiotics. Streptococcus pneumoniae and Mycobacterium tuberculosis are respiratory pathogens that developed antibiotic resistance worldwide representing epidemic.
A serious group of pathogens is Gram-negative organisms due to their resistance to almost all available antibiotics. Pan-resistant gram-negative bacilli and MDR are major threat in medical field. Most of the threatening and serious infections by gram-negative organisms are caused by Pseudomonas aeruginosa, Enterobacteriaceae (mostly Klebsiella pneumoniae), and Acinetobacter. Extended-spectrum beta-lactamase-producing Escherichia coli and Neisseria gonorrhoeae are some of the MDR gram-negative organisms emerging widely.
Methicillin-Resistant Staphylococcus Aureus:
MRSA infection has emerged widely in the Americas, Europe, and the Asia-Pacific region and is considered one of the most common antibiotic-resistant infections emerging in hospitals, community, and in animals. About 11,285 deaths yearly are due to MRSA infection. MRSA infection is resistant to penicillin-like beta-lactam antibiotics. Some drugs may be still effective against MRSA such as linezolid, daptomycin, tigecycline, glycopeptides (e.g., vancomycin and teicoplanin), and some new beta-lactams (e.g., ceftaroline and ceftobiprole). The widespread of MRSA infection represents a major challenge as most of the infection-control systems are directed mainly against health care–associated infections (HAIs).
The mechanism of developing resistance against anti-MRSA drugs is mainly through bacterial mutations , moreover transfer of resistance to linezolid and glycopeptide antibiotics has been reported. Strict hygiene measures in hospitals contributed to decreasing the incidence of HAI MRSA infections. The total rates of invasive MRSA decreased 31% from 2005 to 2011 and this proves the effectiveness of infection control measures against MRSA infection. However, the incidence of community-acquired MRSA infection has increased during the past decade.
Vancomycin-Resistant Enterococci (VRE):
Enteroccoci cause infections mainly in hospitals and healthcare facilities (e.g., surgical-site, bloodstream, urinary tract infections). VRE infections have lower incidence than MRSA infections but still represent a major challenge. Enterococcus faecium and Enterococcus faecalis cause most VRE infections. In the U.S., about 66,000 HAI Enterococci infections occur yearly. About 30% of hospital-acquired enterococcal infections are vancomycin-resistant with estimated 1,300 deaths occur yearly.
Antibiotics that can be used in case of VRE include: linezolid, quinupristin/dalfopristin, tigecycline, and daptomycin may also be used.
Drug-Resistant Streptococcus pneumoniae:
S.Pneumoniae causes multiple infections including bacterial pneumonia, bloodstream, ear, sinus infections, and meningitis. Drug-Resistant S.Pneumoniae leads to about 1.2 million infections with 7,000 deaths each year mainly affecting old age (50 -65 years of age or older). S.Pneumoniae developed resistance to penicillin (e.g., amoxicillin) and erythromycins (e.g., azithromycin). About 30% of severe S. pneumoniae infections are fully resistant to at least one or more of the used antibiotics. In 2010, a new pneumococcal conjugate vaccine (PCV13) was developed protecting against resistant pneumococcus strains (13 strains) leading to decreased incidence of resistant pneumococcus infections.
Drug-Resistant Mycobacterium Tuberculosis:
In 2012, it was reported by the World Health Organization (WHO) that about 170,000 deaths were due to drug-resistant tuberculosis (TB) infections. Incomplete, unavailable treatment, and a lack of new drugs are the main causes of resistant TB. Some TB infections may be resistant to the first-line drugs (e.g., isoniazid, rifampicin). The resistant cases may require longer duration of treatment with more expensive drugs and more side effects. Some resistant infections are known as Extensively drug-resistant TB (XDR-TB) that is resistant to first-line drugs, fluoroquinolones, and second-line drugs (e.g., capreomycin, amikacin, kanamycin). Applying TB infection prevention and management program decrease the incidence of drug-resistant TB and XDR-TB.
Carbapenem-Resistant Enterobacteriaceae (CRE):
This group is almost resistant to all available antibiotics including carbapenems. Some gram-negative Enterobacteriaceae organisms (e.g., K. pneumoniae, Escherichia coli) have an enzyme known as New Delhi metallo-beta-lactamase (NDM-1) leading to resistance to nearly all beta-lactams, including carbapenems. About 140,000 infections caused by health care–associated Enterobacteriaceae occur in the U.S. yearly with 9,300 caused by CRE. About 600 deaths yearly are due to carbapenem-resistant E. coli and carbapenem-resistant Klebsiella species.
MDR Pseudomonas Aeruginosa:
P. Aeruginosa causes multiple infections including pneumonia, urinary tract, surgical-site, and bloodstream infections. About 13% of health care–associated P. aeruginosa infections are MDR occurring in the U.S. yearly with 400 deaths. Some MDR P. aeruginosa are almost resistant to all available antibiotics such as cephalosporins, fluoroquinolones, aminoglycosides, and carbapenems.
MDR Acinetobacter:
Acinetobacter causes multiple infections including pneumonia and bloodstream infections mainly in severe cases on mechanical ventilation. In the U.S., approximately 12,000 health care–acquired Acinetobacter infections occur each year with 500 deaths, 63% of these cases are MDR.
Extended-spectrum beta-lactamase (ESBL)-Producing Enterobacteriaceae:
ESBL-producing Enterobacteriaceae produce a broad-spectrum beta-lactamase enzyme making them resistant to penicillin and cephalosporin antibiotics. About 26,000 HAIs and 1,700 deaths each year are caused by ESBL-producing Enterobacteriaceae.
Drug-resistant Neisseria gonorrhoeae:
Gonorrhea can easily spread causing complications in reproductive tract and is associated with discharge and inflammation of pharynx, cervix, urethra, and rectum. About 800,000 gonorrhea cases occur each year according to the Centers for Disease Control and Prevention (CDC) representing the second most common infection in the U.S. Cephalosporin-resistant N. gonorrhoeae is resistant to antibiotics including tetracyclines, penicillins, and fluoroquinolones. According to the CDC, ceftriaxone and azithromycin or doxycycline are the first-line treatment for gonorrhea.
Prevention:
Antibiotic resistance is increased due to the excessive use and misuse of antibiotics. Application of some measures at the individual and society levels may help to reduce the resistance.
Individuals:
-Using antibiotics only prescribed by health professional.
-Following health professional advice regarding the use of antibiotics.
-Never share antibiotics, Never use leftover antibiotics.
-Regular washing hands, proper hygiene, vaccination, and practicing safer sex may help preventing infections.
-Following the WHO Keys for safe preparation of food (keep clean, separate raw and cooked, cook thoroughly, keep food at safe temperatures, use safe water and raw materials).
-Choosing food that has not been treated with antibiotics.
Policy makers:
-Improving antibiotic-resistant infections surveillance.
-Implementation of prevention and control measures.
-Applying national action plan to detect antibiotic resistance.
-Providing information about the effect and outcomes of antibiotic resistance.
-Promote the appropriate use of antibiotics.
Health professionals:
-Ensuring clean environment and instruments in health care sites.
-Prescribing antibiotics only when needed according to the recent guidelines.
-Reporting antibiotic resistant cases to the surveillance system.
-Describing the proper method of using antibiotics to patients and other individual preventive measures.
Healthcare industry:
-Investing in research and developing new antibiotics and vaccines.
Agriculture sector:
-Giving antibiotics to animals according to the veterinary prescription.
-Avoiding antibiotics use in animals for or growth promotion or to prevent diseases.
-Animals vaccination in order to reduce the use of antibiotics.
-Applying proper measures in production and processing of foods whether from animal or plant sources.
-Improving hygiene and animal welfare.
References:
(1) Huemer M, Mairpady Shambat S, Brugger SD, Zinkernagel AS. Antibiotic resistance and persistence-Implications for human health and treatment perspectives. EMBO Rep. 2020 Dec 3;21(12):e51034.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726816/
(2) Bengtsson-Palme J, Kristiansson E, Larsson DGJ. Environmental factors influencing the development and spread of antibiotic resistance. FEMS Microbiol Rev. 2018 Jan 1;42(1):fux053.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812547/
(3) Aslam B, Khurshid M, Arshad MI, Muzammil S, Rasool M, Yasmeen N, Shah T, Chaudhry TH, Rasool MH, Shahid A, Xueshan X, Baloch Z. Antibiotic Resistance: One Health One World Outlook. Front Cell Infect Microbiol. 2021 Nov 25;11:771510.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8656695/
(4) Ghosh D, Veeraraghavan B, Elangovan R, Vivekanandan P. Antibiotic Resistance and Epigenetics: More to It than Meets the Eye. Antimicrob Agents Chemother. 2020 Jan 27;64(2):e02225-19.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985748/
(5) Antibiotic resistance, the World Health Organization (WHO).
https://www.who.int/news-room/fact-sheets/detail/antibiotic-resistance
(6) Antimicrobial resistance, centers for disease control and prevention (CDC)
https://www.cdc.gov/drugresistance/about.html
(7) Ventola CL. The antibiotic resistance crisis: part 1: causes and threats. P T. 2015 Apr;40(4):277-83.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4378521/
(8) Larsson DGJ, Flach CF. Antibiotic resistance in the environment. Nat Rev Microbiol. 2022 May;20(5):257-269.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8567979/
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