Antibiotic resistance is a major health problem, especially when it comes to the control of infections caused by microorganisms that were sensitive to antimicrobials. Many microorganisms, especially bacteria, have become resistant to almost all clinically important antimicrobials. The biggest problem is that the pharmaceutical industry does not have enough new drugs to complement the growth of resistance of these microorganisms, such as K. pneumoniae. The growing number of cases of antibiotic-resistant Klebsiella pneumoniae infections stands out as a worldwide health problem, presenting as a clinically important bacterium causing pneumonia in hospital environments [1].

The resistance of K. pneumoniae is a consequence of the presence of extended-spectrum β-lactamases (ESBLs), described as enzymes that, through plasmid mediation, confer resistance to penicillins and cephalosporins, including combinations of sulbactam, clavulanic acid, and monobactams. ESBLs are commonly detected in strains of Klebsiella pneumoniae, qualified as an opportunistic pathogen, the etiologic agent of serious infections in hospitalized patients, with emphasis on patients with compromised immunity to serious diseases. K. pneumoniae capable of producing β-lactamase was first detected in Germany in 1983, and there has been a steady increase worldwide in subsequent decades ^[1][2][1,2].

Nosocomial infections are usually caused by K. pneumoniae, Acinetobacter baumanie, and other gram-negative microorganisms. These bacteria used to cause a variety of serious health problems all over the world. Carbapenem-resistant Enterobacteriaceae (CRE) infections, in particular, have become a constant challenge for therapeutics ^[2][3][4][2,3,4].

Among the CRE, Citrobacter freundii, Escherichia coli, and carbapenem-resistant K. pneumoniae (CRKp) [5] stand out. According to the Clinical and Laboratory Standards Institute, CRKp are all K. pneumoniae isolates resistant to any carbapenems: meropenem, imipenem, or ertapenem, with this, CRKp emerges as a multidrug-resistant microorganism resistant to most antibiotics currently availablewith a great threat to human health ^[6][7][6,7].

CRKp infections are treated with restricted therapeutic options, such as aminoglycosides, tigecycline, colistin, and cetftazidime associated with avibactam. Resistance to carbapenems is a consequence of the presence of genes encoding carbapenemases, among the CRKp isolates, the blaKPC-2 and blaKPC-3 genes are the most common ^{[8][9][10][11]}[8,9,10,11].

CRKp is responsible for a high mortality rate, aggravated by the significant increase in the worldwide prevalence rate [11]. The rapidly increasing morbidity rate of the pathogen is a consequence of clonal and plasmid-interceded dissemination of strains not sensitive to carbapenems ^{[5][9][10][12][13]}[5,9,10,12,13]. Considering the high therapeutic and clinical costs associated with CRKp infections, in view of the mechanisms of resistance and unavailability of effective treatment, the World Health Organization (WHO) recognized CRKp as a critical priority level 1 bacterium for the development of new antibiotics ^[14][15][14,15].

Several infectious diseases are associated with adjacent diseases, increasing the risk of infection and complications. Epidemiological information shows that the increased incidence of nosocomial infections and some community-acquired infections is related to those patients with preexisting comorbidities, such as diabetes, immunosuppressant, lung diseases, and nephropathies ^[1][14][15][1,14,15].

2. Elevated Mortality Risk from CRKp Associated with Comorbidities

The presence of resistant bacteria stands out as a frequent problem in hospital environments. The emergence of multidrug-resistant species is related to the increase in resistance of members contained in the Enterobacteriaceae family. The main form of resistance among gram-negative bacteria is the ability to produce beta-lactamases which are responsible for bacterial resistance to beta-lactams. Beta-lactamases are enzymes responsible for the degradation of the beta-lactam ring, thus inactivating antimicrobials and preventing activity against the enzymes responsible for the synthesis of the bacterial cell wall. Among the bacteria producing beta-lactamases, the genus Klebsiella spp, Escherichia spp, Enterobacter spp, Salmonella spp, Serratia spp, Citrobacter spp, Proteus spp, and Morganella stand out. The genes responsible for encoding the most prevalent carbapenemases are from the blaKPC, blaVIM, blaIMP, blaOxa, and blaNdm groups [16]. K. pneumoniae is responsible for causing one-third of gram-negative infections such as urinary tract infections, pneumonia, cystitis, surgical wound infections, endocarditis, and septicemia. K. pneumoniae can also cause necrotizing pneumonia and pyogenic liver abscesses. This microorganism has been associated with high death rates, high treatment costs, and prolonged hospital stays. K. pneumoniae is a microorganism present in all environments; it is one of the opportunistic pathogens with high relevance, standing out for causing several infections in humans such as UTIs, surgical infections, and respiratory tract infections causing pneumonia. The development of resistance in K. pneumoniae isolates is a consequence of the production of extended-spectrum β-lactamases (ESBLs). K. pneumoniae strains that produce ESBL are found all over the world, causing numerous outbreaks of infections. Bloodstream infections caused by K. pneumoniae can occur because of ventilator-acquired pneumonia or through social contact, through the urinary system, intra-abdominal diseases, and central venous line infections ^{[16][17][18][19]}[16,17,18,19]. CRKP stands out as a major public health concern, as infections caused by these bacteria are highly associated with mortality ^[16][17][16,17]. Mortality in hospital settings can be explained by the fact that patients who become infected with CRKP are, in general, acutely ill and chronically ill (with comorbidities). Comorbidities can lead patients to longer exposure time in hospitals, hospitalizations, and prolonged use of antibiotics, which are relevant risk factors for CRKP infection [18]. The present meta-analysis confirms the strong association between the increase in mortality of patients with confirmed CRKP, the proportion of deaths, and the increase in risk. Patients with three or more comorbidities demonstrated an independent risk factor for CRKP infections and were associated with a higher rate of ICU admission, worse clinical outcomes, and mortality ^[16][19][16,19]. Patients with comorbidities are usually in a precarious physical condition, in addition to having an immune system with compromised function in certain situations and being more prone to infections with high severity because they do not have sufficient defenses against resistant infections. The multicenter study by Bahlis and collaborators [19] carried out in China, used the Charlson Comorbidity Index (ICC), which is applied to classify the severity based on comorbidities leading to a higher risk of death to the patient. In this study, 831 patients had CRKP infections, and the mean ICC found was 5, demonstrating a high risk of death in patients with CRKP ^[19][20][19,20]. The results of existing research point to the assertiveness of the present resysearchtematic review, however, the meta-analysis in question presents mortality results from CRKP and CSKP, contributing with relevant information about the current situation experienced in hospital environments, with an emphasis on ICUs. In the study by Wang and collaborators [11], 96 patients were evaluated, 48 of whom were infected with CRKp and the other 48 with CSKp. Among patients infected with CRKp, 23 (47.9%) died, while 2 (4.2%) patients in the CSKp infected group died, indicating assertiveness in the results obtained in the present meta-analysis where the increase in the risk of death by CRKp was higher than the risk of death by CSKp. Wang and collaborators [11] also presented that, among the factors associated with death from K. pneumoniae infection in both groups, the comorbidities found were cardiovascular disease—20 patients (80%); renal dysfunction—17 patients (68%); neurological disease and diabetes mellitus—12 patients each (48% each); Tumor—11 patients (44%); hepatobiliary disease—6 patients (24%); pulmonary disease—3 patients (12%); and autoimmune disease—2 patients (8%). Although the results by Wang et al. [11] demonstrate similarity to the results of the present research, the reliability of the new results is presented with greater weight, considering the larger sample number after combining the selected data. The data show the correlation between the higher risks of mortality in patients who have some comorbidity in CRKp infection compared to those who do not have comorbidities. It is believed that the colonization of K. pneumoniae in a community or even in the hospital environment may be related to the location, although there are several other factors. In the study by Ling et al. [21], it was found that the Chinese had a colonization rate of 66% compared to Malays (14.3%), Indians (7.9%), and other nationalities (11.8%). The reason why colonization differs between these populations is not clear, but it may be linked to environmental factors that provide greater exposure to the pathogen.

3. Conclusions

K. pneumoniae is associated with a high mortality rate, standing out as a global health problem. Hospitalized patients with comorbidities almost always present impairment or limitations of the immune system, favoring opportunistic microorganisms. The association between comorbidities and CRKp increased the proportion of deaths and increased the risk of death. This data indicates the need to prioritize the problem addressed.