As discussed in the previous section, the infectious disease burden, greatest in low- and middle-income countries, is significantly complicated by increasing antimicrobial resistance. And while bacterial resistance to antibiotics is of chief concern, strains of resistant parasites, viruses, and fungi also represent clear public health threats.
In the past, conditions such as pneumonia, diarrhea, malaria, sexually transmitted infections (STIs), and others were readily managed with available therapies. But as resistance to common medications increases, such conditions are becoming more difficult and costly to treat.
Tuberculosis, malaria, and hospital-acquired infections (also known as nosocomial infections), which can be difficult to treat even with effective first-line agents, have become huge burdens on health systems as resistance has increased.
After completing this session, learners will be able to briefly describe how resistance is affecting the control of the following diseases of major public health importance:
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- Bacteria: TB, pneumonia, gonorrhea, methicillin-resistant Staphylococcus aureus (MRSA) and others
- Parasites: Malaria
- Viruses: HIV
- Fungi: Candida
Glossary term
Bacterium: Tuberculosis
Overall global incidence of tuberculosis (TB) is holding steady at an estimated 10 million people per year, but TB still claims the lives of approximately 1.5 million people each year. The 2020 milestones of decreasing incidence by 20% and the number of deaths by 35% are still far away.
In an attempt to slow the development of resistance, patients are treated with multiple drugs over the course of generally six months. The long duration of treatment, plus medication side effects and other factors, make it difficult for patients to adhere to a full course of treatment. WHO’s End TB strategy recommends counseling and social support for treatment adherence, through directly observed treatment when necessary.
An estimated 3.5% of new TB cases and 18% of previously treated cases have been found to have multidrug-resistant TB (MDR-TB). Thirty countries are classified as having a high MDR-TB burden; the countries with the highest incidence rates of MDR-TB are located in the former Soviet Union.
Treatment of MDR-TB can last up to 20 months, can cost up to 250 times more than treatment of susceptible TB, has more side effects, and yields lower cure rates. About one in three patients with MDR-TB access treatment, and of those who do, about 56% are cured.
Worryingly, cases of extensively drug-resistant TB (XDR-TB) have also occurred. XDR-TB has been reported in 128 countries and territories. An estimated 6% of people with MDR-TB had XDR-TB in 2019. The treatment success rate is only 34%. In some cases, these strains of TB are virtually untreatable.
Source
Sources: KFF 2020; WHO 2015b; WHO 2018a; WHO 2018b; WHO 2019b WHO 2020e.
Did you know?
In recent years, two drugs, bedaquiline and delamanid emerged as effective new treatments for MDR-TB. At the end of 2020, 109 countries reported having introduced bedaquiline in an effort to improve the effectiveness of MDR-TB treatment regimens. In 2019, the TB Alliance announced the approval of pretomanid for use in combination with other drugs for stubborn cases of MDR-TB as well as XDR-TB.
Sources: TB Alliance 2019; WHO 2020c.
Source
Source: Adapted from WHO’s Personal Stories from TB Survivors—My Journey Fighting TB.
Highlight
Other personal stories of TB patients can be found on WHO and U.S. Centers of Disease Control and Prevention (including Spanish-language versions) websites.
Bacterium: Pneumonia
Pneumonia can be caused by multiple types of pathogens, including bacteria, viruses, and fungi. In children, the most common cause of pneumonia is the bacterium Streptococcus pneumoniae (S. pneumoniae).
The CDC has classified drug-resistant S. pneumoniae as a serious threat that requires prompt and sustained action.
For many years, pneumonia was cured inexpensively with penicillin. However, resistant strains were identified only four years after penicillin’s introduction. WHO data from 22 countries showed that resistance to penicillin ranged from zero to 51%. Penicillin-resistant strains are also more likely to be resistant to other antibiotics.
Between 20 and 40% of the isolates are resistant to macrolide antibiotics, around 22% to clindamycin, and about 35% to trimethoprim-sulfamethoxazole.
S. pneumoniae is the leading cause of death from pneumonia worldwide. It claimed the lives of an estimated 808,694 children under five years of age in 2017. It also causes a huge burden of disease in adults. In the US alone, pneumococcal pneumonia in adults leads to an estimated 150,000 hospitalizations each year.
Source
CDC 2019; Review on Antimicrobial Resistance 2016; WHO 2018c; WHO 2019c. Cherazard 2017.
Glossary term
Did you know?
Since the pneumococcal conjugate vaccine has been in wide use, resistant strains of S. pneumoniae have sharply fallen; for example, since the vaccine was introduced in the United States in 2000, the rates of antibiotic-resistant invasive pneumococcal infections caused by vaccine strains decreased by 97% among children younger than 5 years old and by more than 60% among adults.
Sources: CDC 2020; Review on Antimicrobial Resistance 2016.
Bacterium: Gonorrhea
Data from 2016 estimated that 87 million people were infected with gonorrhea in one year. If left untreated, it can cause serious complications, particularly in women.
Potential complications caused by gonorrhea include the following:
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- Infertility
- Eye (ophthalmic) infections in newborns
- Pelvic inflammatory disease Miscarriage
- Five-fold increase in HIV transmission
Once easily treatable, gonorrhea is now resistant to several antibiotics, including penicillin, tetracycline, fluoroquinolones (such as ciprofloxacin and ofloxacin), and older generations of cephalosporins.
Resistance to extended-spectrum cephalosporins such as cefixime—currently regarded as the “last-line” treatment—has also been documented in Australia, Japan, Norway, and other countries.
With no vaccine available and no new drugs in development, it is likely that gonorrhea may soon become untreatable.
Source
CDC 2019; Wi et al. 2017; WHO 2020a. WHO 2018d; Wi 2017.
Did you know?
A survey of gonococcal samples in 21 Asia Pacific countries or territories from 2011 to 2016 showed quickly increasing resistance to ceftriaxone and azithromycin. Samples of ceftriaxone meeting WHO's definition of decreased susceptibility increased from 14.3% to 35.3% and the percentage of locations reporting samples with azithromycin resistance increased from 14.3% to 38.9%.
Source: George CRR et al. 2019.
Bacterium: MRSA
Methicillin-resistant Staphylococcus aureus (MRSA) refers to a strain of S. aureus (a common cause of skin, wound, and blood infections) that has acquired genes that can withstand the effects of several types of antibiotics.
MRSA began emerging during the 1960s and was primarily seen in hospital-acquired infections. Today, instances of community-acquired MRSA have increased significantly in many countries. Livestock-associated MRSA has also been identified and is now a major concern in many parts of the world. Those who handle livestock have a significantly higher risk of getting colonized and infected by livestock-associated MRSA.
WHO’s first global report on antibiotic resistance, published in 2014, highlighted the global problem of MRSA. In some parts of the WHO Africa and Western Pacific regions, as many as 80% of staph infections were methicillin-resistant.
While the incidence of MRSA infections has overall been declining in recent years, progress to prevent MRSA bloodstream infections in healthcare has stalled, and as a result, serious health care-associated MRSA infections have not been declining.
People with MRSA are estimated to be 64% more likely to die than those with a non-resistant form of the infection.
Source
CDDEP 2017; CDC 2019; CDC 2019a; Chen 2020; Sadiq A. et al. 2020; WHO 2014; WHO 2020a.
Glossary term
Bacterium: Other bacteria of international concern
A host of additional bacteria that cause significant death and disability have been identified by the WHO as bacteria of international concern. These pathogens, along with others already discussed in this course (including S. pneumoniae, MRSA, and gonorrhea) are frequent causes of community or hospital-acquired infections.
Of particular concern is the growing resistance of several bacteria to a class of antibiotics known as cephalosporins and carbapenems, which, for many conditions, represent the last line of effective treatment. Some strains of carbapenem-resistant Enterobacterales (CRE) have developed resistance to most of the available antibiotics, resulting in mortality rates of 50%.
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Bacteria |
Example of illness caused |
Showing resistance to |
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Enterococci |
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Escherichia coli (E.coli) |
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Klebsiella pneumoniae (K. pneumoniae) |
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Nontyphoidal Salmonella |
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Pseudomonas aeruginosa |
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Salmonella typhi |
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Shigella species |
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The following is a list of antibiotic-resistant bacteria that cause many hospital-acquired infections:
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- Carbapenem-resistant Enterobacterales
- Methicillin-resistant Staphylococcus aureus
- Extended-spectrum β-lactamase-producing Enterobacterales Vancomycin-resistant Enterococci
- Multidrug-resistant Pseudomonas aeruginosa
- Multidrug-resistant Acinetobacter
In Europe from 2007 to 2015, the median number of deaths attributed to carbapenem-resistant P. aeruginosa, K. pneumoniae, and E. coli increased by a factor of 3.29, 6.16, and 4.76, respectively. Colistin is the last resort treatment for CRE. Resistance to colistin (a crucial antimicrobial agent for some multidrug resistant infections) has recently been detected in several countries and regions, making those infections untreatable. Both CDC and WHO have classified CRE as one of the most critical MDR pathogens of public health significance.
Source
Cassini et al. 2019; CDC 2019; WHO 2017b; WHO 2014; Wang M. et al. 2019; WHO 2020a.
Glossary term
Highlight
To read more about how antimicrobial resistance has affected people, visit this page of patient stories from the Infectious Disease Society of America.
Parasite: Malaria
Substantial decreases in the number of both malaria cases and deaths have been observed in recent years, largely due to effective prevention and treatment strategies using:
Antimalarial medicines Vector control Insecticide-treated nets
For example, the global number of cases decreased to 228 million in 2018 from 251 million in 2010. However, in 2018, nearly half of the world’s population still remained at risk for malaria and 405,000 people died from the disease.
Chloroquine, once widely effective in eliminating one of the main malaria-causing parasites, Plasmodium falciparum, is now no longer effective across much of Africa (where the disease burden is greatest).
Chloroquine was replaced by sulfadoxine-pyrimethamine (SP), which also showed signs of resistance within a few years of mainstream use.
Artemisinin-based combination therapies (ACTs) are the standard for malaria treatment. However, it is worrisome that parasite resistance to and treatment failure with ACTs are being reported from countries in Asia’s Greater Mekong Subregion, the same region where chloroquine resistance first emerged. Recent studies suggest a failure rate for dihydroartemisinin-piperaquine (DHA-PPQ) of up to 62% in western Cambodia; 53% in southwestern Vietnam, and 87% in northeastern Thailand. Of great concern are the new findings of emerging artemisinin resistance of Plasmodium falciparum in Africa.
Chloroquine is still effective as the first-line treatment for P. vivax in many countries; however, resistance or high treatment failure rates are being seen in some countries, such as Ethiopia, Madagascar, Myanmar, and Timor-Leste.
The rise of drug-resistant malaria strains has occurred largely as a consequence of the irrational (i.e., inappropriate) use of antimalarial medicines, including poor treatment practices, poor patient adherence, and the availability of substandard and falsified medicines.
The use of oral artemisinin and its derivatives, such as artesunate, as a monotherapy, is an example of irrational use that contributes to ACT resistance. In addition, the indiscriminate use of chloroquine/hydroxychloroquine as a potential (and later proved ineffective) treatment for COVID-19 caused drug shortages and potentially increased chloroquine resistance, which is still the drug of choice for Plasmodium species other than P. falciparum.
The spread of ACT-resistant malaria to other parts of the world, particularly sub-Saharan Africa, could pose a major health security risk, because no alternative antimalarial medicine has the same level of efficacy and tolerability as ACTs.
Source
Abena et al. 2020; Mellon 2019; Kozlov 2021; The Lancet 2019; WHO 2019d. WHO 2019e; WHO 2020d.
Glossary term
Highlight
WHO approved the first malaria vaccine (RTS,S vaccine) in October 2021 and recommended its widespread use among children in sub-Saharan Africa.
Source: Maxmen 2021.
Virus: HIV
By the end of 2019, 38 million people were living with HIV. Antiretroviral treatment in low- and middle-income countries has expanded dramatically throughout the past decade, with over 25 million now receiving treatment.
As with any antimicrobial agent, with the widespread use of antiretrovirals (ARVs) comes the risk of the development and spread of resistance.
Surveys in 18 low- and middle-income countries between 2014 and 2018 showed that 12 of those 18 countries had a prevalence of resistance to non-nucleoside reverse transcriptase inhibitors (nevirapine/efavirenz) above 10% for patients who had never previously received antiretroviral treatment.
The burden was much higher in women, with an average prevalence of 11.8% compared with 7.8% for men across the 18 countries.
The extremely high rate at which HIV mutates, combined with the difficulties in maintaining optimal and lifelong adherence to ARV treatment, means that a drug- resistant strain can become the predominant circulating strain in just two to four weeks, underscoring the need for pharmacovigilance and other monitoring.
The WHO has identified resistance to antiretroviral agents as a major public health concern. Preventing drug-resistant HIV is one of the strategic objectives of the Global Action Plan on HIVDR: 2017-2021.
The high levels of pretreatment drug resistance that exceed the recommended threshold of 10% highlight the need to fast-track WHO’s recommendation in 2018 to adopt a dolutegravir-based regimen to help prevent the negative effects of resistance to nevirapine and efavirenz. In addition, countries need to improve practice quality indicators such as appropriate prescribing and retention on therapy at 12 months, which needs particular attention.
Source
WHO 2019f; WHO 2019i.
Highlight
The prevalence of resistance to nevirapine/efavirenz among women was over 30% in three countries—Cuba, Honduras, and Nicaragua—highlighting the urgency of changing first-line treatment there.
Source: WHO 2019f.
Did you know?
People with HIV are at an increased risk for TB. In fact, TB accounts for one-third of all AIDS deaths worldwide and is one of the most common causes of morbidity among people living with HIV/AIDS.
Source: WHO 2019g.
Fungi: Candida
Some infections, like candidiasis, are caused by fungi. Candidiasis frequently develops in patients receiving intensive antibacterial therapy and is caused by the yeast Candida, which is the most common cause of fungal infections worldwide.
Three primary antifungal classes of medicines exist to treat Candida and other fungal infections.
Some fungi have developed resistance and no longer respond to these medications—Candida auris and Candida glabrata, for example, can be resistant to all three classes:
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- Azoles (e.g., fluconazole)
- Echinocandins, (anidulafungin, caspofungin, and micafungin) Polyene (e.g., amphotericin B)
- Global rates of fluconazole and echinocandins resistance appear to be rising. However, resistance varies widely depending on the Candida species. In addition to clinical use, the increasing use of these compounds in agricultural pesticides may also contribute to resistance.
For patients who develop Candida infections that are multidrug resistant, there are few remaining treatment options, some of which can be toxic for patients who are already extremely sick. An average of one in four patients with Candida bloodstream infections die.
Sources
Hendrickson JA et al. 2019; Ostrowsky B 2019; Toda M et al. 2019; Whaley SG et al., 2017.
Session summary
Antimicrobial resistance is not only a concern for one disease or due to one type of microorganism. This session described how antimicrobial resistance has wide-ranging effects across disease-causing bacteria, viruses, parasites, and fungi of major public health importance. As the case study of Thandiwe showed, becoming infected with a resistant organism (or multiple resistant organisms) can have severe and lasting effects on an individual’s health and wellbeing.
In the next session, we will discuss the impact AMR has on individuals, health systems, societies, and global public health goals, as well as identify some of the key international responses to AMR.
These materials were adapted from the Global Health eLearning Center, U.S. Agency for International Development.
Image credits
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