Microorganisms killed at least 33,000 people in the country in 2019
Klebsiella pneumoniae bacteria culture prepared by biomedical scientist Thais Rezende at UNIFESP’s Special Laboratory for Clinical Microbiology
Léo Ramos Chaves / Pesquisa Fapesp
On November 6, Nazareno Scaccia put on a pair of gloves, tied a sterilized steel bucket to the end of a rope, then lowered it to the bottom of a sewer tunnel in central São Caetano, part of the São Paulo Metropolitan Area. He then hoisted it back up, full of slightly cloudy, yellowy-brown water with an unpleasant odor. He poured the liquid into a large plastic bottle and used a syringe attached to a filter to fill a small vial. “We do this to separate the microorganisms and prevent degradation of the chemical compounds present in the water,” explained the Italian microbiologist, who is doing a postdoctoral fellowship at the University of São Paulo’s School of Medicine (FM-USP). Some bacteria are capable of digesting the active ingredients of antibiotics, making it difficult to detect these compounds in water.
Later that morning, Scaccia and biologists Miriam Lopes da Silva and Francisca Peternella traveled to eight other locations in the city to repeat the procedure. The water collected from taps, streams, common sewage, and hospital sewage was then taken to a laboratory at USP’s School of Public Health (FSP) to test for the presence of antibiotic-resistant bacteria. The task was part of an international project—coordinated in Brazil by infectious disease specialist Anna Sara Levin from FM-USP—that is studying whether more appropriate prescription and use of these medications could reduce the emergence and spread of microorganisms against which antibiotics no longer produce the desired effect.
The spread of bacteria and other microorganisms resistant to almost all available antimicrobials is a global challenge. It has been a problem since antibiotics first came into use and it is progressing rapidly, keeping specialists up at night worrying about a threat to one of the greatest achievements of modern medicine: the ability to combat infections. Without effective antibiotics, it would be almost impossible to safely perform surgery, transplants, and chemotherapy. Common problems, such as a deep cut or a respiratory infection, would become life-threatening.
“Few interventions have increased human longevity as much as the treatment of drinking water and the development of vaccines and antibiotics,” says Arnaldo Lopes Colombo, an expert in infectious diseases from the Federal University of São Paulo (UNIFESP) who heads the Paulista Institute of Antimicrobial Resistance, one of the Research, Innovation, and Dissemination Centers (RIDCs) funded by FAPESP. Some estimates suggest that the use of antibiotics to treat infections has increased the average human lifespan by about 20 years.
Antibiotics are chemical compounds that kill or inhibit the growth of bacteria. They only act against these microorganisms—they do not work against viruses, for example. Technically, the term is used to define compounds of natural origin (produced by fungi or other bacteria) that eliminate pathogenic bacteria. The term is more commonly used, however, to describe synthetic or semisynthetic molecules that exterminate these microorganisms. There are roughly 12 classes of antibiotics. Each acts at a different point in the structure or functioning of bacteria (see infographic on page 16).
Alexandre Affonso/Pesquisa FAPESP
When exposed to the appropriate concentration of antibiotics for a sufficient amount of time, bacteria are easily killed. If the dosage and duration of the treatment are lower than needed to kill them, some can survive and multiply, accumulating changes in their genetic material that allow them to escape the action of the drugs.
Bacteria are everywhere: in water, soil, air, and on surfaces, including in our bodies. Due to the heavy use of antibiotics to treat human illness, to induce weight gain in livestock, and to protect animals from disease, bacteria are continually exposed to these drugs. This continuous contact leads to the selection of resistant strains.
“We are seeing the emergence of bacteria for which there are no longer any effective medications,” reports Brazilian infectious disease specialist Fernanda Lessa, head of the International Infection Control Branch at the USA’s Centers for Disease Control and Prevention (CDC). She edited a special supplement on the subject that was published in the journal Clinical Infectious Diseases in July 2023, stating: “Luckily, infections caused by these microorganisms are still relatively rare in the community and are almost entirely limited to hospital settings.”
Electron microscope image of Staphylococcus aureus (yellow), which causes approximately 120,000 deaths per year as a result of hospital infections in the AmericasFrank DeLeo / NIAID
Even so, infections by multidrug-resistant bacteria—also called superbugs—can cause enormous damage. A survey led by epidemiologist Ramanan Laxminarayan of Princeton University, USA, estimated that there are 136 million hospital infections caused by these microorganisms worldwide every year. According to the results, published in the journal PLOS Medicine in June 2023, China is by far the most affected nation, with 52 million cases. Brazil placed fifth, with four million cases.
Worldwide, superbugs were directly responsible for 1.27 million deaths in 2019. If cases where the individual had another disease in addition to the infection are included, the number is 4.95 million, close to the total number of COVID-19 deaths recorded in the three-year pandemic and well above the combined annual deaths caused by malaria, AIDS, and tuberculosis.
These figures were calculated by an international group of researchers, including Brazilians, based on data from 204 countries. Published in The Lancet in 2022, the study found that almost 80% of deaths resulted from infections of the lower respiratory tract (bronchitis and pneumonia), the circulatory system, or the abdominal cavity.
Six superbug species were responsible for at least 70% of deaths: Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. All of them are on the list of priority pathogens for which new antibiotics are needed, published by the World Health Organization (WHO) in 2017.
Alexandre Affonso/Pesquisa FAPESP
Home to 14% of the world’s population, the 35 countries in the Americas account for approximately 11% of deaths from antibiotic-resistant bacterial infections. In 2019, superbugs were directly responsible for 141,000 deaths and associated with 569,000 more, according to a study published in The Lancet Regional Health – Americas in August 2023. Once again, the vast majority (80%) were caused by the six aforementioned pathogens. In absolute numbers, most cases occur in the most populous nations: the USA and Brazil. In the latter, there were 33,200 deaths (around 90 per day) directly caused by superbugs in 2019 and 138,000 more in which they played an indirect role. “The groups most likely to be affected are the very young and the elderly—newborns aged less than one month and people aged over 65,” says Eitan Berezin, a pediatrician from the Santa Casa School of Medicine in São Paulo and one of the authors of the paper (see graph below).
“I suspect that today, the number of deaths in Brazil and worldwide would be even higher,” said the CDC’s Lessa in an interview in September. “These studies used data from 2019, but the use of antibiotics increased during the COVID-19 pandemic,” she pointed out.
Alexandre Affonso/Pesquisa FAPESP
Two studies that she led, both published in Clinical Infectious Diseases in July, supported this theory. In one, Lessa and colleagues analyzed drug dispensary records in six hospitals—two in Brazil, two in Chile, and two in Argentina—from two periods: between March 2018 and February 2020, and in the first year of the pandemic. With the increase in hospital admissions following the emergence of the novel coronavirus, the use of antibiotics increased in all six hospitals (by up to 35%), something that was also observed in the USA. In Brazil, antibiotic prescriptions to treat respiratory infections at home have also increased. Between January 2019 and March 2020, 19.9 million courses of antibiotics were prescribed, while 27.5 million were prescribed in the first year of the pandemic, according to the second study.
Even before the emergence of the novel coronavirus, there were already signs that consumption of antibiotics was growing around the world. Princeton’s Laxminarayan and colleagues tracked antibiotic sales in 76 countries between 2000 and 2015 and identified two trends. The first was a 65% increase in the quantity consumed, from 21.1 billion daily doses to 34.8 billion, according to a 2018 paper in the journal PNAS. The second was that the proportion of people using this type of medication grew by almost 40%: from 11.3 daily doses per 1,000 inhabitants in 2000 to 15.7 per 1,000 in 2015. The increase was driven largely by economic improvement in and low- and middle-income countries. Despite the rise, it is estimated that globally, six million people die every year due to lack of access to antibiotics.
The combination of the increased use of these drugs—especially during the pandemic—and overcrowding in hospitals appears to have facilitated the spread of genes that allow bacteria to escape the action of the drugs.
In Brazil, this trend was observed by infectious disease specialist Carlos Kiffer of UNIFESP and colleagues from the Pontifical Catholic University of Paraná (PUC-PR) and the Oswaldo Cruz Foundation (FIOCRUZ). The team analyzed genetic data from more than 80,000 bacterial samples collected in hospitals across the country between 2017 and 2022. They found that during the pandemic, there was a significant increase (from 4 to 21 percentage points) in the frequency of genes that give eight species of bacteria resistance to carbapenems, antibiotics considered the last resort in treating serious hospital infections. Klebsiella pneumoniae, Escherichia coli and Acinetobacter baumannii were among the microorganisms affected, according to the results, published in Clinical Infectious Diseases in July. “There was evidence that some of these genes were becoming more common in the country. We helped determine the scale of the problem,” says Kiffer.
For Anna Levin, an infectious disease specialist from USP and head of the monitoring project mentioned at the beginning of this report, hospital infections caused by antibiotic-resistant bacteria reflect the quality of care. “When the system is at its limit, with too many patients and not enough health professionals to care for them, infection rates increase,” says the researcher, who chairs the infection control committee at USP’s Hospital das Clínicas, the largest health complex in Brazil. During the pandemic, Levin’s group managed to control the spread of infections caused by multidrug-resistant bacteria in the hospital’s emergency room by testing patients for the pathogens and isolating anyone who was infected, treating them separately.
Although antibiotic resistance has long been a problem, the world has only recently started paying attention to it, primarily because of two documents: a 2014 WHO report that showed the global nature of the phenomenon and a study by economist James O’Neill, carried out for the UK government, that made catastrophic projections for 2050. If nothing is done, antibiotic-resistant infections are expected to cause 10 million deaths per year by the middle of the century, resulting in economic losses of up to US$100 trillion.
The 2016 edition of Brock Biology of Microorganisms, a book often used as a reference in health courses, reports that at least 10,000 tons of antibiotics are produced globally per year for use in human and animal healthcare. One consequence is that these products, even when used correctly, contaminate the environment, leading to the emergence of resistant bacteria. “In Brazil, there is no rule that hospital sewage must be treated to eliminate bacteria from the urine and feces of patients or the hospital environment. We do not have a good surveillance system for monitoring the frequency of resistant microorganisms in hospitals and their spread in the community and the environment,” says Ana Gales, an infectious disease specialist from UNIFESP who studies the subject.
Collection of sewage water from São Caetano to test for the presence of antibiotic-resistant bacteria (above) and preparation for filtrationLéo Ramos Chaves / Pesquisa Fapesp
In recent years, a number of studies have provided evidence that the problem, which was thought to be predominantly hospital-based, is becoming more pronounced in the wider environment. A team led by biochemical pharmacist Eliana Stehling of USP’s Ribeirão Preto School of Pharmaceutical Sciences is monitoring the spread of multidrug-resistant bacteria in almost 50 towns in the north of São Paulo State. They have detected the microorganisms in soil samples from agricultural areas and in water from rivers, streams, and creeks. “In the environment, especially in water, these drugs can lead to the emergence of superbugs, accelerating the spread of antimicrobial resistance, since these microorganisms go on to exchange genetic material with each other,” says João Pedro Furlan, a pharmacist who is part of the Ribeirão Preto group.
At USP’s São Paulo campus, Chilean microbiologist Nilton Lincopan and his team have identified resistant bacteria in every place imaginable, including in the Tietê and Pinheiros rivers that cross the capital and in turtles, penguins, whales, dolphins, and seabirds off the Brazilian coast. “We have recorded around 30 cases in the last four years,” says the researcher.
They were also found in dogs and cats treated at veterinary clinics and hospitals in the city, and in samples of fresh lettuce, arugula, and cabbage sold by the biggest commercial distributor in São Paulo. “Some strains are resistant to acidic environments. This means that when someone eats a poorly washed vegetable, they can pass through the stomach and colonize the intestine,” explains Lincopan.
Drug resistance also occurs among fungi, although it is more difficult to measure due to a lack of data. In 2022, the WHO released the first list of fungal pathogens that require public health interventions as a priority. It included the yeast Candida auris, of which there have been outbreaks in hospitals all over the world. “Infections caused by multidrug-resistant fungi are less common, but can be more lethal than bacterial infections,” says UNIFESP’s Colombo, who has been studying the problem.
Experts have recommended certain measures be taken. The simplest and most comprehensive, which should be adopted by everyone, are to practice good personal and food hygiene, and to vaccinate against microorganisms when possible, such as for the bacteria that cause pneumonia, tuberculosis, and meningitis. Another is to use medications optimally and rigorously. Doctors should prescribe antibiotics only for bacterial infections, with the help of testing, if possible, to determine which drug is most appropriate for each case, and antifungals for fungal infections. Patients should take the recommended dose for the indicated length of time, even if their condition improves sooner. Whenever possible, people should stay away from hospitals, and when unavoidable, they should spend as little time there as possible.
Projects 1. São Paulo Institute of Antimicrobial Resistance (Aries Project) (nº 21/10599-3); Grant Mechanism Research, Innovation, and Dissemination Centers (RIDC); Principal Investigator Arnaldo Lopes Colombo (UNIFESP); Investment R$15,021,964.28. 2. International multidisciplinary network to characterize microbiological aspects and the natural history of Invasive Fungal Infections (IFI) by species of the genus Candida (nº 17/02203-7); Grant Mechanism Thematic Project; Principal Investigator Arnaldo Lopes Colombo (UNIFESP); Investment R$1,328,821.49. 3. Screening and early isolation of patients colonized by carbapenem-resistant enterobacteriaceae admitted to the emergency department (nº 18/06016-0); Grant Mechanism Regular Research Grant; Principal Investigator Icaro Boszoczowski (FM-USP); Investment R$114,610.59. 4. Resistome, plasmidome, and virulome of Enterobacterales isolated from the environment carrying mcr-like genes (nº 21/01655-7); Grant Mechanism Regular Research Grant; Principal Investigator Eliana Guedes Stehling (USP-RP); Investment R$199,956.01. 5. Study of the resistance, virulence, and epidemiological profile of Escherichia coli isolated from the environment (nº 18/01890-3); Grant Mechanism Doctoral Fellowship; Supervisor Eliana Guedes Stehling (USP-RP); Beneficiary João Pedro Rueda Furlan; Investment R$150,141.19. 6. One Health Brazilian Resistance (OneBR): Integrated genomic base for surveillance, diagnosis, and treatment of antimicrobial resistance at the human-environment-animal interface in Brazil (nº 20/08224-9); Grant Mechanism Regular Research Grant; Principle Investigator Nilton Erbet Lincopan Huenuman (USP); Investment R$241,806.62. 7. Viruloma and pathogenicity of priority bacterial strains resistant to carbapenems and polymyxins in One Health (nº 19/15578-4); Grant Mechanism Doctoral Fellowship; Supervisor Nilton Erbet Lincopan Huenuman (USP); Beneficiary Fernanda Ribeiro dos Santos Esposito; Investment R$190,601.93. 8. Pan-resistome of Klebsiella pneumoniae and Escherichia coli beta-lactamase producers (KPC-2, CTX-M-8, CTX-M-15) endemic in Brazil (nº 16/08593-9); Grant Mechanism Regular Research Grant; Principal Investigator Nilton Erbet Lincopan Huenuman (USP); Investment R$214,075.41. 9. Comparative analysis of the Klebsiella pneumoniae XDR resistome (NDM-1/KPC-2), part of the endemic high-risk clonal complex (CC) CC258 (nº 15/21325-0); Grant Mechanism Doctoral Fellowship; Supervisor Nilton Erbet Lincopan Huenuman (USP); Beneficiary Louise Teixeira Cerdeira; Investment R$131,634.25.
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