Occurrence of nosocomial multi-drug resistant Klebsiella pneumoniae in India: A systemic review and meta-analysis

Introduction

The rapidly rise of Multi-Drug resistant Klebsiella pneumoniae infections specifically associated to hospital-acquired infections, are one of the major concern in the clinical settings.1 Understanding the prevalence of nosocomial multi-drug resistant Klebsiella pneumoniae is essential for developing effective infection control strategies (Figure 1 ). As per report of Mohd Asri et al.2 the global pooled prevalence of hospital acquired multi drug resistant klebsiella pneumoniae infection was 32%. It is awkward situation for immunocompromised and patients who are suffering from major surgeries and organ transplantations. Due to highly capsule producer strain, infection of Klebsiella pneumoniae increases hospital stays with risk of morbidity and mortality rate. Klebsiella pneumoniae is the most leading opportunistic pathogen associated with multi-drug resistance where it resist to last line antibiotics such as Carbapenem, Colistin and Tigecycline. 3

Figure 1

Factors influencing for nosocomial infection by Klebsiella pneumoniae

Over use and mis-use of β-lactam antibiotics, β-lactamase enzymes are because of wide spread mobilized enzyme around plasmid. By introducing β-lactamase antibiotics, TEM-1 and SHV-1 enzymes are arise which led to Extended spectrum β-lactamase antibiotics cefotaxime and ceftazidime that unfold to new β-lactamase that can hydrolyse the both new available antibiotics. ESBL are endemic enzyme belongs to serine β-lactamase and is widely seen in Enterobacterales & Ps. aeruginosa. All new β-lactamase variants are originated from TEM-1 and SHV-1 enzymes. So the rise of ESBL producing gram negative bacteria is found in both community and hospital settings. To overcome from ESBL producers, Carbapenems class of antibiotics became empirical antimicrobial therapy in majority of health care settings. This transformation of antimicrobial therapy gradual results into increase the report of carbapenem resistance. For better outcome there is necessary to evaluate data of prevalence rate of ESBL producing strains, their detection methods and other therapeutic options. 4

TEM and SHV are predominant ESBL families. TEM types -3 ESBL are more prevalent in France and rare in USA. TEM type -26 are isolated from all over globally. 5 While SHV type β-lactamase first originated from chromosome of K.pneumoniae and also it is most commonly found in clinical isolate K.pneumoniae. ESBL variant, SHV- type 5 and SHV- type 12 are most commonly observed globally out of 228 SHV variant.6 blaTEM and blaSHV are most commonly observed virulence gene among blaOXA, qnrB1, oqxA, sul2 and dfrA12.

Figure 2

Screening and confirmatory test procedure of ESBL as per CLSI Guideline.

A Nosocomial infection occurs during the time of health treatment receiving from 48 hours of hospitalization. It is usually absent at the time of hospital admission. It appear during implant of invasive devices, long term stay & ambulatory. It is transmitted from patient to all health care workers of settings. 7

This study represents a systematic review with meta-analysis of relevant literature to deliver a descriptive overview of the occurrence of multi drug resistant nosocomial Klebsiella pneumoniae.

Materials and Methods

A systematic and meta-analysis review was initiated by identification through searching several electronic based data containing Pub Med and Google scholar. Articles published from 2011 to 2023. Occurrence of Nosocomial Multi Drug resistant Klebsiella pneumoniae in India was considered for inclusion. The search terms used included "nosocomial infections," "Klebsiella pneumoniae," "Multi-drug resistant," and “prevalence in India." Total 35 articles screened and out of them 10 articles were covering global prevalence while 7 articles found duplicate so it excluded from study. After screening titles, abstracts, and full texts, relevant studies were included for data extraction 11 articles were finalized. All Articles were analysed through Preferred reporting Items for Systematic Reviews and meta-analysis (PRISMA) guideline & SPSS- 25 software used for Data analysis (Figure 3).

Exclusion criteria

Beta-lactams containing six classes of antibiotics are penicillins, β-lactamase/penicillins inhibitors, cephalosporins, cephalosporins-β-lactamase inhibitor, Monobactams & carbapenems. Here trimethoprim, chloramphenicol, fosfomycin, rifampin, and nitrofurantoin etc classes of antibiotics were not included as the study only focused nosocomial MDR K. pneumoniae occurrence cases.

Figure 3

PRISMA frame work

Results & Discussion

The systematic review yielded a total of 11 studies from various geographic regions of India. A meta-analysis was carried out to estimate the overall occurrences of nosocomial multi-drug resistant Klebsiella pneumoniae.

Figure 4

Geographic distribution of nosocomial associated multi-drug resistant K. pneumoniae in India

11 studies included total 7265 patients and from them 2497 patient were identified as Multi drug resistant Klebsiella pneumoniae infection while 2330 patient recorded as ESBL producer strains. Patient’s infection type and their antibiotic sensitivity pattern were analysed. There was 82.76%, 78.6%, 268.32% and 39.80% prevalence from East, West, North, south and Central India respectively (Figure 4).

Meta-analysis report reveals that prevalence of multi-drug resistant Klebsiella pneumoniae among hospital acquired is 34.37 % and pooled prevalence rate of nosocomial associated multi drug resistant k.pneumoniae infections found 2 % (97.5 % CI, 2.5) with 0.01 p-values (Figure 5).

Figure 5

The pooled prevalence rate of nosocomial associated multi drug resistant k. pneumoniae infection

Since the collected data is not uniform according to methodology to characterized ESBL Klebsiella pneumoniae, each unique study discussed separately.

In East India study of Das and Dasgupta et al. (2015) carried out prospective observational study to identify risk factors & rate of infection associated with nosocomial and found that 11.98% infection rate associated and from them 0.71% patient get infected from pneumoniae by Klebsiella pneumoniae infection including mortality and morbidity. 7

While Chandramouli Bhattacharya et al. (2019) studied 78 patients of cirrhosis and out of them 18 infected with Klebsiella pneumoniae. 15 patients were Multi Drug resistant Klebsiella pneumoniae, among them 13 patients infected with Urinary tract infection followed by pneumonia. 27.7 % community acquired, 52.9% health care associated and 19.3% were nosocomial infection include mortality and morbidity rate. 8

Figure 6 reveals that contribution of antibiotics resistant rates which involves drastic shift of Amikacin from community acquired (57%) to health care associated (74%). cephalosporins and cephalosporins inhibitors like Amikacin, were shown changing trends of their resistant patterns. So it is alarming situation for public health care setting especially immunocompromised and ICUs patients. There are antibiotic resistant Genes (ARGs) also contribute to transmit infection from patient to health care workers. Shakti Rath et al. (2014) studied rate of nosocomial and health care associated for three years and found that occurrence of multi drug resistant k.pneumoniae was 74 % (200 isolates) out of 270 positive samples. 9, 4

Figure 6

Characterization of Antibiotic Susceptibility testing of community acquired and health care associated infection. 9

In report of Abhishek Sharma et al. (2023) found that there was significantly rise of antibiotic resistant from 7.5% to 21.4% from 2018 to 2022.while patient who are in ventilator, their antibiotic resistant trend increase from 62.5% to 71% in 2022 10 (Figure 8).

Figure 7

Antibiotic resistance profile among nosocomial multi-drug resistant K.pneumoniae infection.

Archana sikarwar et al. (2011) found that highly resistant k. Pneumoniae ESBL and SHV, TEM strains associated with nosocomial infections. Their rapidly rise of infection leads to increase morbidity and mortality (Figure 8). 11

Figure 8

Prevalence of ESBL gene

Figure 9

Forest plot of occurrence of nosocomial ESBL & Multi Drug resistant K. Pneumoniae (Table 1).

Nosocomial infections are foremost cause of prolong stays of patient in hospital with high mortality associated with it. Study reveals that prevalence of multi-drug resistant Klebsiella pneumoniae among hospital acquired is 34.37 % while pooled prevalence is 2%. It was found that high mortality rate also associated with it. 8 We report the occurrence of nosocomial multi-drug resistant Klebsiella pneumoniae in India (Table 1).

The high occurrence of nosocomial multi-drug resistant K. pneumoniae globally is a cause for concern. The factors contributing to the spread of this MDRO include inadequate infection control practices, excessive and inappropriate antibiotic use, and the frequent transfer of patients between healthcare facilities. The variability in prevalence among regions can be attributed to differences in healthcare systems, antibiotic prescribing practices, and local epidemiology.

In India, due to high population and poor sanitation practices contribute to the rapid transmission of antibiotic Resistant Genes (ARGs). To understand this issue, A NICU outbreak report of India, 2023 where total 6 out of 7 neonates infected with blood stream infection of Klebsiella pneumoniae and they all were resistant to carbapenems & Colistin antibiotics. Their genomic analysis of clinical samples found that 3 different sequence of isolates namely ST-101, ST-11 and ST-16. Their environmental analysis report reveals that k.pneumoniae ST-101 isolated from incubator water sample which contains ESBL genes bla_CTX-M, Carbapenem gene bla_NDM-5, bla _OXA-232 genes. No mcr gene for Colistin detected. So infection control strategies should apply to prevent spread of highly infectious genes of multi-drug resistant organisms to the community. 3 There is high prevalence of occurrence of ventilator associated pneumonia in intubated patient after 48 hours of patient admission in ICU. So Infectious Disease Society of America (IDSA) recommends to preparing of antibiogram for optimal selection of antibiotics. As per IDSA, A good regimen should work maximum 95% of patients like use of anti-pseudomonal as a empirical therapy. It should include piperacillin –tazobactam, carbapenems and cefoperazone salbactam. Second anti-pseudomonal regimen should include either aminoglycosides or fluoroquinolones. There is necessity to develop antibiogram to formulate regimen for empirical therapy to overcome and treat hospital acquired infection. To apply IDSA guideline, Nitin gupta et al., 2018 carried out prospective study on search of best effective regimen among nosocomial pneumonia patients and found that Ps.aeruginosa was most common isolate organism and effective regimen was cefoperazone-salbactam alone as well with combination of Amikacin.7, 15, 16, 17, 18, 19

Moreover, the widespread utilization of broad-spectrum antibiotics in this Indian health care practices promotes the natural selection and evolution of multi-drug resistant K.pneumoniae. On other side, notifiable results from comprehensive Infection control programs, Implement of antibiotic stewardship, and efficient surveillance systems are possible strategies to prevent Antibiotic Resistance regionally and globally.

Limitations of the included studies should be acknowledged. There was heterogeneity in the methodology used to define nosocomial infections and multi-drug resistance, making direct comparisons between studies challenging. Additionally, publication bias may be present as studies reporting higher prevalence rates are more likely to be published.

Conclusion

Nosocomial associated multi-drug resistant K. pneumoniae is a significant healthcare burden worldwide. Efforts to control and prevent the spread of this MDRO should focus on improving infection control practices, implementing effective antibiotic stewardship programs, and guide enhancing surveillance systems. Understanding the geographical variation in prevalence can targeted interventions tailored to specific regions. Further research is required to address the Gaps in knowledge and to develop evidence-based strategies to mitigate the impact of this MDRO.

By analysing different geographic regions of India, meta-analysis reveals prevalence of multi-drug resistant Klebsiella pneumoniae among hospital acquired is 34.37% and pooled prevalence of multi drug resistant k.pneumoniae among hospital acquired was found at 2%. It can be considered as moderate level. By analysing their antibiotic resistance pattern shown that high resistant to β-lactamase inhibitors (86%). While some studied recorded genomic analysis which has shown that majority of resistant genes, blaSHV encoded for β-lactamase responsible for transmission of disease from patient to health care workers. So accurate infection control protocol required to implementing in health care settings and more community based data required to prevent antibiotic resistance specifically for virulent strain like k.pneumoniae.

Source of Funding

None.

Conflict of Interest

None.