New Delhi Metallo β-lactamases (NDM) production has been progressively identified in carbapenem-resistant Gram-negative bacteria on all continents, representing a significant challenge for clinical management and public health worldwide.1,2 Since 2013, the increase of NDM-positive strains in Brazil has been described in different species of Gram-negative bacilli (GNB) recovered from human, animal, and environmental sources.2-5 The transmission of NDM-positive strains in health care settings is related to close contact, with hospitalized patients being the most vulnerable for colonization and infection. Although, in general the same infection control measures should be applied to any carbapenem-resistant organisms regardless of the resistance mechanisms,6 NDM- and Klebsiella pneumoniae carbapenemase (KPC)-producing isolates apparently present relevant epidemiological differences.1,2 While KPC-producing isolates have been widely described internationally belonging to a major well-adapted K. pneumoniae clonal complex (258),7 NDM-producing isolates are commonly described in multiple GNB8 with apparently no sustained global spread of specific high-risk clades.1

Recently, the increased use of antibiotics may have been intensified by the COVID-19 pandemic worldwide9,10 raising concerns about the real impact of the pandemic on antimicrobial management programs and long-term antimicrobial resistance (AMR) rates,9 particularly strategies directed to COVID-19. The impact of the COVID-19 pandemic in Brazil and in São Paulo has posed significant threats to all, and in particular to the public hospital system10 in terms of allocated resources and quality of care. Most public hospitals have dedicated specific units (wards and intensive care units - ICU) for accommodating suspected and confirmed COVID-19 patients. In the study institution, the first case of carbapenemase detection (KPC) occurred in 2009 and spread in the postoperative ICU followed by some outbreaks of an endemic cluster of Klebsiella pneumoniae clonal complex 258 in the hospital environment.11,12 In this report, we describe the increase of another type of carbapenemase designated as NDM-1 producing Enterobacterales in COVID-19 units of a Brazilian high complexity tertiary hospital.

A total of 13,004 active surveillance cultures were performed between January 2017 to April 2021. Nine hundred twenty-nine (7.1%) were positive for multidrug-resistant (MDR) bacteria: 616 (66%) CRE, 176 (28.5%) VRE, and 137 (22%) BGN-NF. Among CRE samples, there were 42 (6.9%) NDM-producing Enterobacterales isolated in 39 patients: 36 Klebsiella pneumoniae, two Enterobacter cloacae, two Proteus mirabilis, one Morganella morganii and one Providencia rettgeri. Three patients carried more than one NDM-producing in different species of Enterobacterales. From the 39 patients identified with at least one NDM-producing GNB during the study period, all were considered colonized (rectal or inguinal sites) during the hospital stay and 4/39 patients presented central line-associated bloodstream infection (CLABSI). The time between colonization and infection ranged from four to seven days. Table 1A shows patient characteristics.

All 42 NDM-producing Enterobacterales had no remaining carbapenemase genes evaluated and showed high-level of resistance to broad-spectrum cephalosporins, carbapenems, ciprofloxacin, gentamicin and piperacillin-tazobactam, according to CLSI and BrCAST guidelines.14,15 All K. pneumoniae samples (n = 36) were susceptible to polymyxin B (MIC ≤ 0.5 µg/mL) according to BrCAST or EUCAST guidelines.15,16

Table 1B shows the PFGE method performed only on the Klebsiella pneumoniae isolates (n = 36) (one sample per patient). The dendrogram analysis revealed 17 PFGE patterns (“A” to “Q”). Five clusters (F, H, J, L and N) were detected with more than 80% of similarity by the Dice coefficient (Table 1B). The most prevalent cluster “N” was detected in 12 patients with 87.6% of similarity. Three of 12 K. pneumoniae strains cluster “N” was detected before the COVID pandemic period (year 2019), and nine strains were detected during the COVID pandemic period (after March 2020) and within COVID units. Cluster “H” was found in three patients in COVID units at the same period with 100% similarity. Cluster “L” was detected in three patients in non-COVID units.

Fig. 1A shows the rate of NDM cases (colonizations or infections) per total surveillance cultures from 2017 to 2021, with the respective total amounts and chi-squared test for trend (p < 0.0001), and 1B the rate of NDM cases (colonizations or infections) per total surveillance cultures per COVID or Non-COVID units, with the respective total amounts and Fisher's exact test (p < 0.0001).

Fig. 1.

Ratio of NDM cases (colonizations or infections) per total surveillance cultures (in Log scale). (A) Per year, from 2017 to 2021, with total amounts and the chi2 test for trend. (B) Per unit, COVID-19 or non-COVID-19, with total amounts and the Fisher exact test.

(0.18MB).

The COVID-19 pandemic posed a significant threat, not yet overcome, on health systems worldwide, and despite relevant public responses, public hospitals have faced important secondary impacts on their structure, particularly on increased density of inpatients, extenuated health care workers, and increased antimicrobial consumption.10,17,18 In the pandemic scenario (March 2020 to December 2021), to enable hospitalization of COVID-19 cases, the IDPC reduced the number of elective cardiovascular surgeries, setting up 30 ICU beds and 40 designated beds for COVID-19 patients. There was a 20% reduction in hospitalizations compared to previous years. Elective surgeries were suspended during part of this period, hence leading to a 30% reduction in the number of procedures. However, even with the reduction of hospitalizations, there was still an increase in the consumption of antimicrobials, according to hospital pharmacy information. In the period of January to December 2020, ceftriaxone consumption increased by 22%, piperacillin-tazobactam by 14%, and azithromycin by 70%. In a cohort of 52 critically ill patients with SARS CoV-2 pneumonia in hospital care in Wuhan city, the rate of broad-spectrum antibiotics use was 94%, although the reported incidence of secondary infections was lower than 15%.19

In the present study, we report five years of surveillance to multidrug resistant GNB in a complex hospital, with a significant increase in NDM-producing bacteria over time. There was a significant increase detected by chi-squared test for trend on NDM-producing GNB (p < 0.0001) between 2017 and April 2021, specially in COVID-19 units (p < 0.0001) (Fig. 1). All isolates were highly resistant to the antimicrobial agents tested, and unfortunately, polymyxin B was considered the last resort to treat these patients. The emergence of such antimicrobial resistance pattern (including readily transmissible mobile genetic elements) in most of the cases is caused by suboptimal and/or excessive use of antimicrobials inside and outside hospital settings. Suboptimal antimicrobial usage often stems from the absence of or inappropriate interpretation of microbiological diagnosis.20

The PFGE analysis showed the emergence of different clusters after March 2020, which coincides with the beginning of COVID-19 pandemic. Different clusters were identified during these periods, one of them (Cluster H) exclusively in COVID-19 units and another (Cluster L) exclusively in non-COVID-19 units (Table 1B). Among 17 patients admitted in COVID-19 units, nine were colonized by the same NDM-producing K. pneumoniae cluster “N” and three were colonized by cluster H. These findings are reasonable evidence of horizontal NDM-producing K. pneumoniae transfer occurring between patients admitted in COVID-19 units, which may be attributed to the pandemic pressures of higher patient density, new and young healthcare employees at COVID-19 units, work overload even though the infection control team have performed several trainings to all professionals, including HAI infection prevention and isolation precautions.

The diversity of NDM-producing Enterobacterales species and K. pneumoniae clones observed in the present study brings up an interesting question. As previously shown, NDM-producing isolates are commonly described in multiple GNB8 with apparently no sustained spread of specific high-risk clades.1 In addition, blaNDM genes have also been detected in hospital sewage of several countries, which may reflect intestinal carriage of NDM-producing strains among the population of health care settings.1 Thus, it seems reasonable to hypothesize that the cluster diversity and the major differences in clones detected pre- and post-March 2020 may have been associated to other factors, not only related to patient density and horizontal transmission. In this scenario, antimicrobial consumption might have provided the necessary selective pressure for the emergence of colonization by multidrug-resistant pathogens carrying extended-spectrum beta-lactamase genes, including carbapenemase genes. Further studies should be carried out to clarify these findings.

This work was supported by AFIP – Associação Fundo de Incentivo a Pesquisa.

The study was approved by the Ethical Committee of Instituto Dante Pazzanese de Cardiologia (São Paulo, Brazil) [n° 5162].