Drug abuse and crowded ICUs in pandemic led to outbreak of resistant fungus, study says

A group of Brazilian researchers recorded the biggest outbreak ever caused by the same strain of Candida parapsilosis, a fungus that invades the bloodstream and can lead to death. The emergence of the strain, resistant or tolerant to two of the main classes of antifungal drugs, took place between 2020 and 2021 in an ICU (Intensive Care Unit) in Salvador, Bahia, during one of the peaks of the Covid-19 pandemic.

The study, published in the journal Emerging Microbes and Infections, warns of the possible emergence of new resistant strains in the future, as well as the need for practices that help prevent fungal infections in hospitals.

“In this study, 90% of patients infected with this species of Candida had drug-resistant or drug-tolerant strains representing the two main classes of antifungal drugs used to treat invasive candidiasis, fluconazole and echinocandins. Among these patients, almost 60% died”, reports Arnaldo Colombo, professor at the Escola Paulista de Medicina at the Federal University of São Paulo (EPM-Unifesp) and coordinator of the study, supported by Fapesp.

Sixty samples were isolated from Candida parapsilosis of 57 patients admitted to the ICU with severe Covid-19. Genetic analyzes showed that 51 (85%) of the fluconazole-resistant isolates belonged to the same cluster, that is, they had the same common ancestor. A part of them were still tolerant to echinocandins, a class of drug used against isolates of Candida fluconazole resistant.

The term resistance refers to the ability of the microorganism to multiply even in the presence of the administered drug. In turn, tolerance occurs when the antimicrobial acts by reducing the growth of the microorganism, but is not able to kill the pathogen.

“The circulation of the resistant strain was probably facilitated by a health professional, with poor hand hygiene, which ended up contaminating vascular catheters through which drugs and other infusions are applied directly into the bloodstream. This is the result of an ICU overcrowded and high demand for care”, explains João Nóbrega de Almeida Júnior, a researcher at the Hospital das Clínicas, Faculty of Medicine, University of São Paulo (FM-USP) supported by Fapesp and co-author of the study.

Almeida Júnior was part of the work with a research grant abroad, carried out at the Center for Discovery and Innovation at Hackensack Meridian Health, in the United States.

pandemic conditions

Resistance and tolerance probably occurred as a result of the indiscriminate use of antifungals in patients at risk, with a long hospital stay. The practice is common in critically ill patients who remain unstable.

“Since tests for the detection of microorganisms take time, in emergency situations doctors can use antibiotics and antifungals empirically, that is, based on the most likely agents of infection. The idea is to treat an eventual episode of sepsis. [infecção generalizada] by different microorganisms. The practice, however, must be rationalized, in order to avoid the development of resistance, toxicity and additional cost”, says Colombo, who is also a researcher and infectious disease specialist at Hospital São Paulo, linked to Unifesp.

In Brazil, most medical centers do not have tests to assess the susceptibility of fungi to antifungal agents, making early recognition of resistant strains more difficult. This can be a facilitator of dissemination in the health system. Likewise, if the agent is not well characterized before treating the infection, the patient may be treated with an ineffective drug. Therefore, the researchers emphasize the importance of an accurate diagnosis before administering antifungals.

For this, it is recommended to carry out more complete molecular tests for the characterization of resistant agents. The study showed that mutations in the ERG11 gene, normally used as an indicator of resistance to the group of antifungals in which fluconazole is found, were present in only 35.8% of the samples.

On the other hand, all resistant strains had a mutation in another gene, TAC1, which in turn increases the expression of CDR1. The latter is responsible for a resistance mechanism called an efflux pump. Basically, fluconazole manages to penetrate the fungal cell, but the resistant strain acquires the ability to pump the drug out, reducing its concentration and therapeutic potential.

When this genetic mutation appeared in strains of Candida parapsilosis originally sensitive to fluconazole, they started to demand concentrations up to eight times higher of the drug in order to have some inhibitory action. Other mutations were found in the FKS1 gene, in a region where such alterations are not so common.

“They are tolerant, they need higher doses to be killed. This implies that, soon, we will be able to find strains resistant to this class of drugs, which is currently recommended for fluconazole-resistant fungi”, warns Almeida Júnior.

recommendations

In the specific scenario of this outbreak, in addition to reinforcing the importance of carrying out tests for the characterization of resistance and tolerance of fungi in medical centers of reference, the researchers recommend the use of a third class of drugs when strains with these characteristics are found. It is liposomal amphotericin B, a drug with greater potential for toxicity to humans and more expensive than fluconazole and echinocandins, but effective in the treatment of Candida resistant or tolerant.

“It is necessary to establish decision-making algorithms and use biomarkers to use antibiotics and antifungals only when necessary, in the correct dose and time. This avoids the emergence of resistant strains”, attests Colombo, who works with Anvisa (National Health Surveillance Agency). ) to establish protocols for the SUS (Unified Health System) related to fungal infections.

The researcher also recalls that the indiscriminate use of antibiotics is also a risk factor for fungal infection, since, by killing microorganisms in the intestine, the treatment can make the intestinal wall more permeable and allow fungi of the genus Candida, which live in the human gastrointestinal tract, enter the bloodstream. Under normal conditions, these fungi do not cause harm.

Systemic infections caused by Candida occur mainly in the hospital environment, where there are patients with compromised immune systems and invasive procedures are used, such as hemodialysis, application of drugs in the vein and mechanical respiration, which can also lead to Candida to the bloodstream.

Among the patients in the study, 54% used a catheter when they had the infection diagnosed. Overall, the 30-day mortality was 59.6%.