Does Second Place Count? Lessons from a Major Discrepancy Between Carbapenem-Resistant Klebsiella pneumoniae and Carbapenem-Resistant Enterobacter cloacae in a One-Year Follow-Up Study

To the Editor—Carbapenem-resistant Enterobacteriaceae (CREs) have become one of the most prevalent agents in nosocomial infections, and they are associated with poor outcomes. ¹ In many Brazilian hospitals, Klebsiella pneumoniae carbapenemase (KPC)–producing K. pneumoniae (Kp), a main representative of the CRE group, has reached endemic levels and has been responsible for high morbidity and mortality rates. ^{2 , 3}

Since the emergence of KPC Kp, practically no other microorganism has managed to achieve prevalence levels as severe as those achieved by KPC Kp. ^{2 , 4 , 5} Some studies have shown the emergence of Enterobacter spp, especially Enterobacter cloacae and Enterobacter aerogenes, as a reflection of an increased prevalence rate, and they implicate CREs as one of the main bacteria with the ability to acquire and develop antimicrobial resistance, including carbapenem agents. ^{6 , 7}

In the past few years, the emergence of Enterobacter spp has been considered a second epidemic subsequent to the epidemic wave of KPC-producing microorganisms. However, in Brazil, few data are available to reveal how this microorganism has evolved over time, despite its recognized clinical and epidemiological status.

To verify the crude prevalence rate of CREs and to recognize a possible second potential CRE agent and assess its differences in relation to the most prevalent CRE, a retrospective survey from January 1 to December 26, 2016, was conducted at a tertiary hospital in Porto Alegre, Southern Brazil.

Identification of bacterial species as well as an antimicrobial susceptibility profile were initially performed using an automated broth microdilution system (MicroScan, Beckman Coulter, Brea, CA); the results were confirmed using the disk diffusion method. Determination of the resistance mechanism attributable to carbapenem agents was performed by applying a synergistic test with phenyl-boronic acid and ethylenediamine tetra-acetic acid for detecting KPC and metallo-betalactamase enzymes, respectively, and by enzymatic inhibition using clavulanic acid and cloxacillin for detecting extended-spectrum β-lactamases (ESBLs) and AmpC enzymes, in that order, as previously described. ²

During the study period, 472 CRE isolates were recovered from clinical sites. Among them, 445 (94.3%) were KPC producers and the remaining 27 isolates (5.7%) were noncarbapenemase producers (nCPs).

Among the KPC-producing isolates, K. pneumoniae (98.9%; 440 of 445) was by far the most prevalent microorganism, followed by Escherichia coli (0.7%; 3 of 445) and Citrobacter freundii (0.4%; 2 of 445). Among the nCP isolates, Enterobacter cloacae (63%; 17 of 27) was the most common agent, and the remaining isolates were E. aerogenes and Serratia marcescens (14.8%; 4 isolates each), and K. pneumoniae and Escherichia coli (3.7%; 1 isolate each).

The crude prevalence rates for all CRE isolates found in this study, not including the carbapenem-resistance mechanism involved (as described above), are illustrated in Figure 1(A). Although the nCP E. cloacae was the second most prevalent CRE, its recovery rate was extremely low compared to KPC Kp (3.6% vs 93.3%, respectively). In addition, the prevalence of nCP E. cloacae decreased over the study period, contrary to the trend observed in other countries. ^{6 , 8}

FIGURE 1 (A) Crude prevalence of all CRE isolates found in this study and (B) cumulative prevalence of KPC-Kp and nCP-E. cloacae (the 2 most prevalent agents) recovered from some clinical specimens during the study period.

In past few years, K. pneumoniae and E. cloacae have proven to be challenging microorganisms regarding their pathogenesis, transmission, and ability to acquire antimicrobial resistance. Therefore, these organisms are highlighted in a faction of agents termed by the Infectious Diseases Society of America as the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, K. pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp), ⁹ and their prevalence rates are not constantly monitored. Likewise, it is important that the differences among them be evaluated to produce a better strategy to combat their spread.

This study produced several conclusions: (1) nCP E. cloacae is the second most prevalent CRE in our institution, and it is far less prevalent than KPC Kp. (2) Different gender and/or species may reflect a better ability to become established in a nosocomial environment. Moreover, 440 of 1,099 of all K. pneumoniae isolates (40%) recovered during the study period were KPC producers, whereas only 17 of 144 of all E. cloacae (11.8%) recovered in the same period were carbapenem-resistant isolates. (3) The type of resistance mechanism (ie, those that confer resistance to broad-spectrum activity agents, such as carbapenems) is as important as gender and/or species differences. Furthermore, the KPC resistance mechanism seems to be more dangerous than any other, such as ESBL or AmpC β-lactamases, efflux pumps, outer membrane impermeability or even a sum of them.

Why does a microorganism with relatively minor virulence and resistance remain a second potential CRE agent? Although this question is still under investigation, a reasonable explanation would be the fact that E. cloacae, like K. pneumoniae, has a greater ability to become resistant to polymyxins, which are currently widely used. ^{6 , 8}

In conclusion, the results of this study confirm KPC Kp as the most prevalent CRE, far more prevalent than an nCP E. cloacae isolate, which was the second most common CRE pathogen identified in this survey. The presence of the bla _KPC gene seems to be mandatory for this major difference between species. However, a well-structured and well-coordinated surveillance plan must be implemented together with a strict program of antimicrobial use to prevent the spread of the most prevalent CRE as well as the less prevalent CREs.