Klebsiella pneumonia is a Gram negative rod belonging to Enterobacteriaceae family. Carbapenem resistance in Klebsiella pneumonia is mainly associated with K. pneumoniae carbapenemase.1–3 It is a carbapenem hydrolizing beta-lactamase encoded by transmissible plasmids, which facilitate spread of the enzyme among bacterial species.4 During the last decade, infections due to carbapenem resistant Klebsiella pneumoniae (CRKP) has been reported throughout the world, spreading from the United States in 2001.2 Outbreaks of CRKP has been reported in several countries.5,6 Rapid and global dissemination of CRKP is of great concern in health care facilities. It can cause diverse infections including primary bacteremia, urinary tract infections, pneumonia, intra-abdominal infections, and wound infections. Crude mortality rate of CRKP infections ranges from 30% to 44%.7–9 It increases strikingly to 71.9%, when in the case of bacteremia.10 CRKP strains have higher mortality rate compared to strains susceptible to carbapenem.7,10

Prompt initiation of appropriate antibiotic therapy for CRKP infections is crucial for patient survival.8,11,12 However, appropriate antibiotics like colistin are not administered routinely to these patients until the cultures yield CRKP isolate. Knowing that a patient is colonized by CRKP may be beneficial in deciding to start empirical CRKP active treatment in suspicion of a Gram negative infection.

Risk factors for acquisition of CRKP colonization have been mainly assessed in studies involving adult patients and were identified as antibiotic exposure, especially carabapenem, intensive care unit stay, prolonged hospitalization, poor functional status, invasive devices.7,8,13–15 CRKP colonization of the host is a major predisposing factor for developing subsequent CRKP infection.7,16 The studies which evaluate the frequency and risk factors of CRKP infection occurrence in patients rectally colonized with CRKP are limited in the pediatric population. Therefore, the present study was planned to determine the frequency distribution and description of CRKP infections in rectally colonized patients, who were admitted in pediatric and neonatal intensive care units over five years, as well as to identify associated risk factors for developing subsequent CRKP infection.

Between January 2010 and December 2014, 2805 patients were admitted to the intensive care units of our institution (PICU: 1134 patients, NICU: 1671 patients). Throughout the study period, a total of 85 patients (3.03%) were rectally colonized with CRKP. Out of those 85 patients carrying CRKP, 44 patients were admitted at the NICU (2.6% of all patients admitted to NICU) and 41 patients were admitted at the PICU (3.6% of all patients admitted to PICU). No significant difference was found between PICU and NICU regarding CRKP colonization rate (p>0.05).

Patients’ ages ranged from 1 to 205 months (median: 3 months; mean: 30.7±5.7 months) and 54.1% were male. On the basis of criteria described in Section “Materials and methods”, the majority of patients acquired CRKP by cross-transmission (n=75, 88.2%), and 9 patients (10.5%) had imported CRKP. There was only one undetermined case.

Occurrence of CRKP infection

For all patients, frequency of subsequent CRKP infection among CRKP carriers was 28.2% (24 out of 85). In the NICU, 8 patients out of 44 (18.1%) developed subsequent CRKP infection, compared 16 patients out of 41 (39%) in the PICU (p=0.03). On average, patients developed CRKP infection 35.50±28.78 days (median: 33 days, range: 6–143 days) after admission and 10.6±1.9 days (median: 7 days, range: 2–38 days) after detection of CRKP colonization. The yearly distribution of CRKP-C and CRKP-I cases among all admitted patients to PICU and NICU in that particular year is presented in Figs. 1 and 2, respectively.

Fig. 1.

The percantage of CRKP-C and CRKP-I cases among all admitted patients to the pediatric intensive care unit from 2010 to 2014.

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Fig. 2.

The percantage of CRKP-C and CRKP-I cases among all admitted patients to the neonatal intensive care unit from 2010 to 2014.

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Types of CRKP infection included primary bacteremia in 15 patients (62.5%), ventilator-associated pneumonia in 4 patients (16.6%), ventriculitis in 2 patients (8.3%), intraabdominal infections in 2 patients (8.3%), and urinary tract infection in 1 patient (4.1%). Two of the primary bacteremia were catheter associated. Ventriculitis developed in 2 premature newborns with extraventricular drainage catheter inserted for hydrocephalus.

In daily practice, we are experiencing increasingly rates of CRKP infection. Treatment of these infections is more challenging for pediatricians due to limited appropriate antibiotic use groups in pediatrics. This real life problem in addition to the scarcity of pediatric studies on this issue prompted us to investigate the risk of subsequent CRKP infection of our CRKP colonized patients admitted to pediatric and neonatal intensive care units.

Overall, the rate of subsequent a nosocomial CRKP infection in colonized patients was 28.2%, and PICU had significantly higher infection rate than NICU (39% and 18.1%, respectively). This discrepancy can be explained by the higher frequency of more complicated patients with severe underlying diseases at the PICU compared to NICU, which mainly cares for premature neonates in their way to thrive. To date, there is no published study that has investigated the prevalance of neonatal colonization and subsequent infection with CRKP. In a pediatric study from Turkey, evaluating all pediatric units for a period of 7 months, a much higher colonization rate (29.5%), but a lower infection rate (3.4%) in colonized patients was found.19 In that Low infection rate in that study reflects the fact that it did not include only high risk patients, in contrary to our studied sample. Adult studies have reported a wide range of CRKP infection rates among colonizers (8.8–42%).20,21 These differences observed in colonization and subsequent infection rates among studies may be linked to inclusion of different patient populations, variations in infrastructural properties, and implementation of infection control programs. High colonization rates may indicate poor infection control measures inadequate to prevent horizontal transmisson.16 On the other hand, high infection rates may be associated with patient complexity requiring more invasive procedures and longer ICU stay under high colonization pressure.

Yearly distribution of colonization/infection rates gives the impression of a gradually increasing trend, especially at the PICU. In 2013–2014, a substantial increase both in colonization and infection was observed at the PICU. Because these cases were not clustered in time, but dispersed throughout the year, it was not considered as an outbreak. No change has occurred in physical conditions and staff structure in that year. It might have been a reflection of a considerably increasing frequency of carbapenem resistance in Klebsiella isolates in our country also, which has been shown recently in an adult study.22

Literature review reveals primarily adult studies, which defined several risk factors for development of CRKP infection in colonized patients.7,8,13–15,20 Serious underlying diseases like diabetes mellitus, malignancies, or renal disease have been previously reported risk factors for emergence of infections due to resistant microorganisms.9,13–16,20 In this study, underlying neurological and metabolic diseases were more frequently seen in CRKP-I group and the former was found to be an independent risk factor for subsequentCRKP infection. Metabolic diseases, which are predominatly diseases of the childhood, was first reported to be an independent risk factor for CRKP infection, which may be due to the scarcity of pediatric studies on this issue. Neutropenia was determined as another risk factor for CRKP infection in colonized patients. It is a rarely studied risk factor in similarly designed studies.

In the current study, urinary catheterizaton, tracheostomy, and previous surgical procedure were found to be more frequently performed in patients with CRKP-I. On multivariate analysis, previous surgical procedure was found as an independent risk factor. Surgery is a well known risk factor for infection with resistant microrganisms like CRKP, as shown in other published studies as well.15,21 Both colonization and infection have been linked to the use of invasive procedures.9,14,16,20 They facilitate the entry of the microrganism to the host. However, for this entry to occur, the microrganism should already exist in the natural or man-made environment. So, because invasive procedures are not avoidable in ICU patients most of the time, implementation and good compliance of infection control measures to prevent colonization of the environment and the patient are always key points for reducing nosocomial infections with resistant microorganisms.

Although it is generally accepted that there is a link between antibiotic usage and emergence of resistant microorganisms, literature review on this issue reveals conflicting results. As there are studies reporting antibiotic exposure as an independent risk factor for CRKP infection,7,14,19,20,23 there are also some other studies revealing no correlation between antimicrobials and isolation of CRKP.15,16,21,24 The current work found no difference in total duration of antibiotic usage between the CRKP-C and CRKP-I groups, because virtually all patients admitted to an ICU were heavily treated with antibiotics before CRKP detection. However, when individual antibotic groups were evaluated, carbapenem exposure was found to be a risk factor for subsequent CRKP-I. This finding is in accordance with other studies that have reported strong association of exposure to carbapenem agents and CRKP infection.7,14,19,25 Carbapenem use may cause selective pressure on persistence of the resistant microrganism, thereby increasing infection risk. Although there are studies indicating no effect of change in antimicrobial use in reducing CRKP infections,26 we think thata the use of carbapenem agents should be minimized, together with implementation of appropriate and strict infection control programs to combat emergence and spread of CRKP strains.

This study has several limitations. First, we could not determine types of carbapenameses harbored by CRKP strains, because this was a retrospective study and molecular analysis were not routinely performed in our institution. Second, being a study with a retrospective design, it lacks enough strength to establish a casual relationship between possible risk factors for CRKP infection. Besides, there may be additional unmeasured variables associated with CRKP infection. Third, we could not implement a comorbidity index, which would measure the severity of comorbid conditions and minimize any selection bias, due to difficulties resulting from the retrospective nature of the study design. Fourth, we did not have data about compliance of health care workers to infection control measures. It is obviously an impotant risk factor for acquisiton of CRKP, but its role in infection occurrence in patients who are already colonized, which is the focus of our study, remains to be answered in prospectively designed studies. Data are limited regarding CRKP infection development in critically ill pediatric and neonatal patients colonized with CRKP. Nonetheless, despite its limitations, this study provides important information regarding infection control in this population.

In conclusion, our data highlights the importance of CRKP colonization, which resulted in infection in nearly half of the patients admitted to the PICU and one fifth of the patients in the NICU. We demonstrated several independent risk factors for developing CRKP infection in patients initially colonized with CRKP, including underlying metabolic disease, neutropenia, previous surgical procedure, and previous carbapenem use. Patients with CRKP colonization especially those having these clinical factors should be targeted for interventions to reduce the risk of subsequent clinical infection. They should also be carefully followed up regarding signs and symptoms of infection in order to timely initiation of empirical active treatment against CRKP.

The authors declare no conflicts of interest.