ORIGINAL ARTICLE |
https://doi.org/10.5005/jp-journals-10081-1445 |
Understanding the Factors Contributing to a Deadly Klebsiella pneumoniae Outbreak in a Neonatal Intensive Care Unit in India
1–6Department of Pediatrics, Postgraduate Institute Yashwantrao Chavan Memorial Hospital, Pune, Maharashtra, India
7Department of Microbiology, Postgraduate Institute Yashwantrao Chavan Memorial Hospital, Pune, Maharashtra, India
Corresponding Author: Deepali A Ambike, Department of Pediatrics, Postgraduate Institute Yashwantrao Chavan Memorial Hospital, Pune, Maharashtra, India, Phone: +91 9373002072, e-mail: ambikedeepa@gmail.com
Received: 30 April 2024; Accepted: 15 September 2024; Published on: 05 November 2024
ABSTRACT
Background: Klebsiella is an important causative organism of neonatal sepsis (NS), particularly in developing countries. This study aimed to analyze the demographic and clinical laboratory features of a fatal outbreak of Klebsiella spp. that occurred in a neonatal intensive care unit (NICU), identify the source of the infections, and propose infection control measures to prevent future occurrences.
Methods: We performed a retrospective analysis of the medical records and investigative reports of sepsis cases caused by Klebsiella pneumoniae admitted to the neonatal units of a tertiary care teaching hospital in western India from May to August 2022.
Results: Among the 26 neonates with Klebsiella sepsis, those born at <28 weeks and 28–32 weeks of gestation were the most affected group. The mortality rate was high (n = 21, 80%). The C-reactive protein (CRP) level was used to assess the severity and prognosis of the infection. The platelet count (PLT) decreased significantly from day 1 to 15 (p < 0.001) as the condition worsened. Elevated CRP levels (>100 mg/L) were also observed on the 5th day of admission (p < 0.001). We found unsatisfactory hand hygiene practices, and K. pneumoniae grew on surface swab sampling of wash basins and overhead water tanks. Thorough decontamination of the source of infection and strengthening of infection control practices was performed.
Conclusion: Carbapenem-resistant Klebsiella strains led to substantial morbidity and mortality during an outbreak in neonates.
Keywords: Epidemiology, Klebsiella, Multidrug-resistant, Neonates, Outbreak, Sepsis
How to cite this article: Patil VK, Kulkarni RK, Haribhakta SV, et al. Understanding the Factors Contributing to a Deadly Klebsiella pneumoniae Outbreak in a Neonatal Intensive Care Unit in India. Pediatr Inf Dis 2024;6(4):124–130.
Source of support: Nil
Conflict of interest: None
INTRODUCTION
Gram-negative microorganisms are the primary causative agents of neonatal sepsis (NS) in developing countries.1,2 The factors that increase the chances of NS are low birth weight, premature delivery, and prolonged hospital stay. Klebsiella pneumoniae is the primary microorganism in this category. The occurrence of hospital-acquired infections caused by strains of K. pneumoniae that generate extended-spectrum beta-lactamases (ESBL) has increased.3 The mortality rate associated with these infections ranges from 18 to 68%. The widespread application of broad-spectrum antibiotics in intensive care units (ICUs) has accelerated the emergence of multidrug-resistant (MDR) microorganisms.4 Moreover, it has also been reported that resistance to third-generation cephalosporins mediated by plasmids, and the effortless transmission of these resistant plasmids across different genera, poses a significant challenge in controlling the spread of these resistant microorganisms. This phenomenon is the primary cause of multiple outbreaks of hospital-acquired infection.5
The archived outbreaks vary in severity from colonization detected through routine or active surveillance cultures to clinical infections, resulting in high fatality rates. The identification and investigation of an outbreak caused by a specific pathogen depends on several factors, such as regular surveillance practices during nonoutbreak periods, healthcare workers’ clinical knowledge in identifying neonatal infections, hospital laboratory potential to conduct culture examinations, antimicrobial susceptibility assessments, and molecular strain typing.
Healthcare workers and infection control specialists must understand the epidemiology of hospital-acquired infections, particularly during outbreaks, to prevent infections in susceptible neonates.6 C-reactive protein (CRP) is a commonly used biomarker in critically ill patients with sepsis. Elevated CRP levels have been linked to persistent infection, organ failure, and ICU mortality.7 Timely administration of antimicrobial therapy and control of infection sources have been demonstrated to improve outcomes in patients with sepsis. CRP levels may decrease in patients with well-controlled sepsis, indicating improvement.8
Platelets are vital for blood clotting and coagulation. Platelets can discharge cytokines that stimulate inflammation, aid in creating microthrombi, and interact with endothelial cells, eventually leading to multiple organ failures. Numerous investigations have confirmed that platelets play a role in the onset of sepsis and contribute to its pathogenesis.9 Additionally, the CRP-to-(platelet count) PLT ratio (CPR) is a metric that employs both CRP levels and PLT counts to assess both inflammatory and coagulation status.10
Consequently, monitoring variations in biochemical indicators can assist in predicting the response to treatment and prognosis in patients with sepsis. However, the predictive value of these indicators remains unclear. Several studies have indicated that changes in CRP levels and PLTs can be used to predict sepsis outcomes. A dynamic approach to assess biomarkers may provide additional insights into patient outcomes in sepsis.
Upon the admission of neonates to the neonatal intensive care unit (NICU), biochemical markers are often assessed to anticipate the effectiveness of treatment, severity of infection, and patient prognosis. Nevertheless, there is still an ongoing debate regarding the prognostic significance of these biochemical markers. In the present article, we describe the features of a hospital-acquired outbreak of NS in our hospital NICU.
METHODS
This descriptive study was conducted in the NICU of a tertiary care teaching hospital in western India from May to August 2022. This study was approved by the Institutional Review Committee. The study analyzed the medical records of infants who were Klebsiella culture positive during the 4 month study period (May to August 2022), including demographic, laboratory, and clinical data. The recorded maternal data included information on maternal hypertension, mode of delivery, and risk factors for infection, such as premature rupture of membranes, foul-smelling amniotic fluid, and maternal fever.
The neonatal data record included gestational age, birth weight, whether the infant was small for gestational age (SGA), defined as a birth weight below the tenth percentile for gestational age), whether the infant had a very low birth weight (VLBW, expressed as a birth weight below 1,500), sex, the day of onset, duration of thrombocytopenia, length of hospital stay, and neonatal mortality. Hematological parameters were also recorded for each neonate, including the initial PLT at the onset of clinical sepsis and the lowest PLT during the sepsis episode.
Samples were collected for culture from the laryngoscope blades, ventilators, stethoscopes, equipment trolleys, incubators, central lines, endotracheal tube tips, suction tubes, tap water, floor, and door handles. These cultures were collected every 2 weeks and sent to the department of microbiology laboratory for analysis. Detailed inspections were conducted in the NICU to identify the potential sources of infection.
All laboratory investigation results were analyzed. We investigated the PLT in all studied patients on days 1, 5, and 15. We also evaluated all occurrences in which CRP levels exceeded 90–100 mg/L in neonates admitted to the unit within 15 days of birth, without any exclusion based on gestational age. We defined an “episode” as a period during which CRP levels increased above 90–100 mg/L, and we considered the start of an episode as the day when CRP levels initially exceeded 90–100 mg/L. We counted a new episode if (1) CRP levels dropped below 100 mg/L but increased again, resulting in the infant undergoing additional culturing or (2) CRP levels fell but then rose again in another distinct diagnosis, such as necrotizing enterocolitis (NEC).
Owing to monetary constraints, only one sample was sent for the Xpert Carba-R resistance assay, through seminested real-time polymerase chain reaction (PCR). This assay detects imipenemase (IMP), New Delhi metallo-beta-lactamase (NDM), Verona integrin-mediated metallo-β-lactamase (VIM), K. pneumoniae carbapenemase (KPC), and OXA-48 genes in gram-negative bacilli.
Statistical Analysis
Statistical analysis was performed using two-way analysis of variance (ANOVA), post hoc Tukey test, and t-test using GraphPad Instant software (GraphPad Software, Inc.).
RESULTS
Patient Characteristics
A total of 1,007 patients were admitted, of which 26 (May–August) were included in this study as they were positive for Klebsiella species. Of the 26 patients, 21 could not survive due to severe infection, 4 were discharged and 1 patient was left against medical advice (Fig. 1). The NICU mortality during the study period was 26.7% (admissions = 281, deaths = 75), while mortality among K. pneumoniae culture positive babies was 80.71%.
Fig. 1: The representative illustration shows the total cases, fatality rate and mortality percentage from January to December 2022
The proportion of male neonates with susceptibility to sepsis was higher (54%). Regarding the gestational age distribution, 28–32 weeks, neonates are frequently affected followed by 33–37 weeks. Of the studied neonates, 38% weighed 1000–1500 gm weight, 31% weighed 1500–1999 gm, and only 4% weighed 2500 gm (Figs 2A and B).
Figs 2A and B: The distribution of neonates with Klebsiella sepsis according to their (A) gestational age and (B) birth weight (n = 26)
Gestational age distribution was as follows:
| Gestation (weeks) | Number |
|---|---|
| ≤28 | 1 |
| 28+1 to ≤32 | 16 |
| 32+1 to ≤37 | 8 |
| ≥37 | 1 |
| Weight (in gm) | Number |
|---|---|
| ≤1000 | 6 |
| 1001 to ≤1500 | 10 |
| 1501 to ≤2500 | 9 |
| ≥2500 | 1 |
Of all the babies included in the study, 69% (n = 18) were appropriately grown for gestational age (AGA) and 31% (n = 8) were SGA.
Sixteen neonates had a peripherally inserted central catheter (PICC) line inserted, three had an umbilical venous catheter (UVC) inserted, and the average duration of central venous catheterization was 8 days. Of the 26 neonates, 21 required mechanical ventilation, and none of them survived. Surfactants were administered to six neonates.
Neonates other than Klebsiella sepsis also had hypoxic-ischemic encephalopathy (n = 3), NEC (n = 6), respiratory distress syndrome (n = 6), pulmonary hemorrhage (n = 8), pneumothorax (n = 2), acute renal failure (n = 3), and meningitis (n = 4), of which two grew K. pneumoniae in cerebrospinal fluid (CSF) culture.
The clinical suspicion of sepsis was observed on average on the 3rd day of life, while on average, sepsis was confirmed on the 7th day of life. The average duration of hospital stay for neonates who succumbed to sepsis was 22.3 days.
Consequences Related to Severe Sepsis
It was observed that with the increase in infection in the neonates, there was a significant decrease in PLT from day 1 to 15 (p < 0.001) (Fig. 3).
Fig. 3: PLT of neonates with Klebsiella sepsis is assessed during their stay in the NICU on days 1, 5, and 15. Data from 20 neonates shown as mean ± SD; *p < 0.05, **p < 0.01, and ***p < 0.001. One-way analysis of variance (ANOVA) with the Bonferroni post hoc test
Our study found that the CRP level significantly increased from the 5th day of admission to day 15 in the neonates (p < 0.001), as shown in Figure 4.
Fig. 4: CRP level of neonates with Klebsiella sepsis is assessed during their stay in the NICU on days 5 and 15. Data from 20 neonates shown as mean ± SD; *p < 0.05, **p < 0.01, and ***p < 0.001. One-way analysis of variance (ANOVA) with the Bonferroni post hoc test
Although, increased CRP levels and thrombocytopenia are not unique and specific to Klebsiella sepsis, exceptionally high levels of CRP (> 90) and severe thrombocytopenia (PLT < 20,000) were observed early in neonates with Klebsiella sepsis. This observation helped during the outbreak to formulate a new antibiotic policy to escalate antibiotics empirically before culture reports were positive in babies who were clinically suspected of having sepsis.
Antimicrobial susceptibility testing (AST) was performed to determine the effectiveness of the antibiotics against Klebsiella sepsis. Table 1 shows the susceptibility (S) and resistance (R) patterns of 12 different antibiotics [Amikacin (AMK), Cefotaxime (CTX), Ceftazidime (CAZ), Ciprofloxacin (CIP), Colistin (COL), Gentamycin (GEN), Imipenem (IPM), Meropenem (MEM), Piperacillin + Tazobactam (TZP), Polymyxin B (POL), Tetracycline (TCY), and Trimethoprim + Sulfamethoxazole (SXT)] against K. pneumoniae sepsis (Table 1).
| Antibiotics | AMK | CTX | CAZ | CIP | COL | GEN | IPM | MEM | TZP | POL | TCY | SXT |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | S | R | R | R | S | S | R | R | R | S | S | R |
| 2 | R | R | R | R | S | S | R | R | R | S | S | R |
| 3 | R | R | R | R | S | S | R | R | R | S | R | R |
| 4 | R | R | R | R | S | S | R | R | R | S | R | R |
| 5 | S | R | R | R | S | S | R | R | R | S | S | R |
| 6 | R | R | R | R | S | S | R | R | S | S | R | R |
| 7 | S | R | R | S | S | S | S | S | S | S | S | S |
| 8 | S | R | R | S | S | S | R | R | R | S | S | S |
| 9 | R | R | R | R | S | R | R | R | R | S | S | R |
| 10 | R | R | R | S | S | R | S | S | S | S | S | R |
| 11 | R | R | R | R | S | R | R | R | R | S | S | R |
| 12 | R | R | R | R | S | R | R | R | S | S | S | R |
| 13 | R | R | R | R | S | R | R | R | R | S | S | R |
| 14 | R | R | R | R | S | R | R | R | R | S | R | R |
| 15 | R | R | R | R | S | R | R | R | R | S | S | R |
| 16 | R | R | R | R | S | R | R | R | R | S | R | R |
| 17 | R | R | R | R | S | R | R | R | R | S | S | R |
| 18 | R | R | R | R | S | R | R | R | R | S | S | R |
| 19 | R | R | R | R | S | R | R | R | R | S | S | R |
| 20 | R | R | R | R | S | R | R | R | R | S | R | R |
| 21 | R | R | R | R | S | R | R | R | R | S | R | R |
| 22 | R | R | R | R | S | R | R | R | R | S | R | R |
| 23 | R | R | R | R | S | R | R | R | R | S | R | R |
| 24 | S | R | R | S | S | S | R | R | R | S | S | S |
| 25 | S | R | R | S | S | S | R | R | R | S | R | S |
| 26 | S | R | R | S | S | S | R | R | R | S | S | S |
The table contains data from 26 patients treated with 14 different antibiotics. The susceptibility or resistance of each bacterial strain to each antibiotic is indicated by an “S” or an “R” respectively. Antibiotics to which the microorganism is susceptible are chosen for treatment, whereas those to which it is resistant are avoided. The choice of antibiotics may also depend on factors such as the severity of the infection, patient’s age and medical history, and availability and cost of different antibiotics. It is important to note that the susceptibility and resistance patterns of microorganisms can change over time owing to factors such as the selective pressure of antibiotics, emergence of new resistance mechanisms, and spread of resistant strains.
Figure 5 shows the susceptibility and resistance rates of bacterial isolates to various antibiotics. The antibiotics listed in the figure were CTX, CAZ, CIP, COL, GEN, IMP, MEM, TZP, POL, TCY, and SXT. The values for each antibiotic indicate the number of isolates that were tested and categorized as either resistant (R) or susceptible (S). As shown in Figure 5, all isolates tested for AMK, CTX, CAZ, CIP, GEN, IMP, MEM, TZP, TCY, and SXT were classified as resistant (R). On the contrary, for these same antibiotics, COL and POL were classified as susceptible (S). This data suggests that the Klebsiella isolates tested in the present study are highly resistant to the following AMK, CTX, CAZ, CIP, GEN, IMP, MEM, TZP, TCY, and SXT antibiotics. However, there is some variability in susceptibility between different antibiotics, with some antibiotics showing slightly higher exposure than others. The high level of resistance to these antibiotics is concerning and indicates the need for further investigation and the development of alternative treatment options.
Fig. 5: The representative bar graph shows the AST of Klebsiella sepsis for 12 antibiotics showing susceptibility or resistance in 26 admitted neonates
Furthermore, a seminested real-time PCR was used to investigate the resistance to various antibiotics in one patient, and it was observed that the patient was positive for the carbapenemase gene NDM in a blood isolate of K. pneumoniae, indicating that the bacterial strain was resistant to carbapenem antibiotics.
Identification of the Source of the Infection
An infection control investigation round was conducted by the faculty of the microbiology department. The observation was made that the hand hygiene facility was limited where bar soap was being used, for which a dedicated container was not available, and it was lying in the basin. The sink was shallow and was not equipped with an elbow-operated tap. The hand hygiene basin was visibly dirty. Compliance with hand hygiene practices was unsatisfactory for the resident doctors. Cleaning of the floor and various surfaces was not satisfactory. Dry brooming was practiced in the NICU and appropriate mops were not available. It was also observed that single-use devices and drug vials were sometimes reused. On environmental surface swab sampling, swabs from the wash basin grew K. pneumoniae; hence, the overhead water tank culture was performed. In addition, the IV extension line and syringe attached to the suction tubing showed the growth of gram-negative bacilli.
DISCUSSION
Our study describes an outbreak of MDR K. pneumoniae sepsis in the NICU from May to August 2022. Twenty-six infants had culture-positive Klebsiella sepsis, of which 21 could not survive. All isolates were resistant to first- and second-line antibiotics, and despite using antibiotics that were sensitive in vitro on blood cultures, sepsis had very high mortality.
Neonatal sepsis is a severe and potentially fatal condition. Despite advances in diagnosis and treatment have been made, diagnosing NS remains difficult. K. pneumoniae is an important pathogen that can be acquired in hospitals and can potentially cause severe illness and death in children. Multiple instances of infection caused by drug-resistant K. pneumoniae have been extensively documented. Understanding the likely origin of ESBL-positive K. pneumoniae in a patient is crucial for managing infections, particularly in the NICU, where intensive care is provided.11 This bacterium typically resides in the gut and on the skin, and is most likely transmitted through the hands of medical staff. One major challenge is that the standard diagnostic method, blood culture, requires a long time in the laboratory to produce results, causing delays in diagnosis and effective treatment. Furthermore, the low positive rate of blood culture due to the use of antibiotics before hospitalization and insufficient blood volume, along with the multiple and nonspecific clinical signs of NS, makes the early diagnosis of the disease challenging. As a result, researchers are exploring the potential of circulating blood biomarkers for early detection of NS at an earlier stage.
Thrombocytopenia is a frequent issue in neonates with confirmed sepsis and affects, half of the cases. Nearly three-fourths (76.9%) of the neonates in our study exhibited very severe thrombocytopenia, with PLTs ≤20 × 10/L. When examining factors such as the incidence of cesarean section deliveries, high blood pressure in mothers, SGA babies, gram-negative sepsis, birth weight, and vascular thrombosis, there were noticeable differences between infants with and those without thrombocytopenia.12
Numerous outbreaks have been caused by K. pneumoniae isolates that are resistant to broad-spectrum cephalosporins and aminoglycosides.13-16Klebsiella can potentially cause severe infections like bacteremia, pneumonia, and UTIs, especially in immunodeficient or admitted patients. MDR strains, which carry a high risk of mortality, are often the culprit behind these infections. In NICUs, the use of mechanical ventilation, low birth weight, extended hospital stays, administration of third-generation cephalosporins, and invasive medical procedures are noteworthy risk factors associated with the development of healthcare-associated infections and higher rates of death among neonates.15 More than 65% of the newborns included in the study were born before 32 weeks of gestation and 61% had VLBW. Among the 26 neonates, 21 that grew Klebsiella died, four were discharged, and one patient went home on discharged against medical advice (DAMA). Similar observations were made by Amatya et al., where over 50% of the neonates in the study showed an increased prevalence of infection in those who had low birth weights and were born prematurely. In addition, Amatya et al. noted that out of 23 newborns, 18 required mechanical assistance with breathing and either central venous or arterial catheters. Eight out of 18 endotracheal tube-tip cultures showed the presence of Klebsiella, and six out of eight infants with Klebsiella in their endotracheal tip samples died. Furthermore, both of the 13 umbilical lines that showed Klebsiella growth led to the death of neonates.17
Previous research on the relationship between the type of Gram stain and thrombocytopenia in NS is contradictory. Manzoni discovered no difference in thrombocytopenia occurrence between gram-negative and gram-positive bacterial infections in very low birth weight neonates, although they used a different threshold for thrombocytopenia.18
Conversely, other studies have reported similar results, indicating a higher incidence of thrombocytopenia in cases of gram-negative sepsis. However, our study focused primarily on populations of neonates with very low birth weight or who were born prematurely, along with cases spanning a broad range of gestational ages. CRP is a widely recognized and frequently used indicator that is strongly correlated with inflammation-related diseases. Elevated CRP levels detected on the 4th day after birth were mainly observed in premature neonates with confirmed infections, particularly those related to bloodstream infections associated with central lines. Elevated CRP levels during the first 3 days after birth were mainly observed in infants with conditions such as hypoxic-ischemic encephalopathy that required cooling or those affected by meconium aspiration7,8 and full-term neonates, without any apparent reason. Nonetheless, life-threatening bacterial infections were still observed in newborns, with significantly elevated CRP levels (>100 mg/dL) during the first 3 days after birth; thus, it is recommended that these infants be given empirical antibiotic treatment until an infection has been ruled out. The results of our study demonstrated that premature neonates had a surprisingly high incidence of CRP levels exceeding 100 mg/L during the first 15 days after birth. Our study observed that preterm infants are more prone to having significantly elevated CRP levels during the initial days after birth and are more susceptible to severe sepsis. In contrast to what was observed by Hofer and colleagues, out of 19 full-term infants with confirmed early onset sepsis, 10% of them had CRP levels exceeding 100 mg/L within the first 72 hours after birth. However, none of the 14 premature infants born before 37 weeks of gestation with culture-confirmed early onset sepsis had CRP levels ≥100 mg/L.
Based on the observations made by the Hospital Infection Control Committee (HICC), few recommendations were made to curtail the ongoing outbreak. The use of liquid soap was advised, and the practice of using bar soap should be discouraged. The hand hygiene basin should be deep, made of stainless steel, and an elbow-operated tap should be provided. Single-use paper towels should be used to dry hands. The basin should be cleaned with an appropriate disinfectant, such as 1% sodium hypochlorite19 after cleaning with soap and water. To eliminate the source of infection after thorough basin cleaning, the old overhead water tank was replaced with a new one.
Regular training programs on hand hygiene are advised. The reuse of single-use devices and multidose vials should be discouraged. It was advised that if multidose vials were used, they should not be used beyond 24 hours. The patient care items should be discarded immediately. NICU admissions were stopped for a duration of 10 days and all further admissions were strictly segregated from already admitted newborns.
Lastly, in our study, we utilized seminested real-time PCR to evaluate the antibiotic resistance to several antibiotics in one patient. The results showed that the patient tested positive for the presence of the carbapenemase gene NDM in a blood sample. This indicated that the bacterial strain was resistant to carbapenem antibiotics.
This resistance can pose a significant threat to patient health, as NDM carbapenemase enzyme is able to hydrolyze several available antibiotics and the gene for NDM carbapenemase can be horizontally passed on to various other gram-negative bacteria making it challenging to treat such infections effectively.16,20 High-dose carbapenem-containing treatments may show efficacy in instances where carbapenem minimum inhibitory concentration (MIC) levels are relatively low or moderately elevated, but they may not offer benefits for cases with extremely high carbapenem MICs.21 A meta-analysis of studies involving adults has demonstrated that utilizing combination therapy with a minimum of two agents decreases mortality rates from 38.7 to 27.4% compared to single-agent therapies.22
CONCLUSION
In conclusion, our study showed that the emergence of MDR K. pneumoniae poses a great challenge to clinicians with very high mortality despite treatment with antibiotics found to be sensitive in blood culture, limiting the treatment options. Prematurity and low birth weight were the significant predisposing factors. In our study, very high CRP levels and severe thrombocytopenia were always observed before the culture results were positive, underscoring the potential importance of these biomarkers in predicting the likelihood of severe gram-negative sepsis. Finally, strict adherence to hand hygiene practices and thorough environmental disinfection helped curtail the outbreak, underlining the importance of microbiological surveillance in identifying the potential source of infection.
ORCID
Vinay K Patil https://orcid.org/0009-0007-0273-8876
ACKNOWLEDGMENTS
We would like to thank the Department of Microbiology, Pathology, and Biochemistry for helping us with data collection and analysis.
AVAILABILITY OF DATA AND MATERIALS
Please contact the corresponding author for data requests.
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