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The etiology and outcomes of blood stream infections (BSI) among pediatric patients is not well described in resource-limited countries including Georgia.
Patients with positive blood cultures at the largest pediatric hospital in the country of Georgia were identified by review of medical and laboratory records for patients who had blood cultures obtained between 01/2004-06/2006.
Of 1,693 blood cultures obtained during the study period, 338 (20%) were positive; 299 were included in our analysis. The median age was 14 days (range 2 days -14 years) and 178 (60%) were male; 53% of patients with a positive culture were admitted to Neonatal Intensive Care Unit (NICU). Gram-negative bacilli (GNB) were representing 165 (55%) of 299 cultures. Further speciation of 135 (82%) of 165 GNR was not possible because of lack of laboratory capacity. Overall mortality was 30% (90 of 299). Among the 90 children who died, 80 (89%) were neonates and 68 (76%) had BSI caused by Gram-negative organism. In multivariate analysis, independent risk factors for in-hospital mortality included age <30 days (OR=4.00, 95% CI 1.89-8.46) and having a positive blood culture for a Gram-negative BSI (OR=2.38, 95% CI 1.32-4.29).
A high mortality was seen among children, particularly neonates, with positive blood cultures at the largest pediatric hospital in Georgia. Because of limited laboratory capacity microbiological identification of common organisms known to cause BSI in children was not possible and susceptibility testing was not performed. Improving the infrastructure of diagnostic microbiology laboratories in resource limited countries is critical in order to improve patient care and clinical outcomes and from a public health standpoint to improve surveillance activities.
Georgia gained independence from the Soviet Union in 1991. Following independence there was a collapse of the public health and medical infrastructure. During the early 1990s an increase in infant mortality and decreased immunization rates in Georgia were observed, both of which are markers of a health care system in crisis [1,2]. Georgia is currently a lower middle income country and, despite many advancements, it remains a country in economic transition. The health care system in Georgia is currently undergoing many changes, moving from a centralized system based on the former Soviet model to a decentralized, market driven system .
Rates of blood stream infections among pediatric and adult patients in resource limited areas are generally poorly described. This is in part due to lack of laboratory infrastructure and surveillance capacity. There are limited data in Georgia regarding pediatric blood stream infections and outcomes among patients with positive blood cultures. We therefore carried out a study designed to determine the etiology of and outcomes of pediatric patients with positive blood cultures in country of Georgia. The study was initiated to obtain baseline data in an effort to establish a surveillance system for invasive bacterial infections in children and to aid in developing guidelines for empiric antibiotic use in suspected bacterial infections.
The study was conducted at Central Children's Hospital (CCH) in Tbilisi, Georgia. CCH is a 363-bedded referral hospital for the entire country of Georgia and the largest pediatric hospital in Georgia. The population of Georgia is 4.7 million with 17.3% below the age of 14 . The CCH microbiology laboratory processes an average of 30 specimens per day and 9,100 specimens per year. The study was approved by Emory University Institutional Review Board (IRB) and the CCH Ethics Committee.
A retrospective study was performed. All patients with at least one positive blood culture between January 2004 to June 2006 were identified by review of medical and laboratory records. Data were collected using a standard data collection form. For each patient the following demographic and clinical information was collected: date of birth, gender, internal displacement status (i.e. persons who were internally displaced as a result of a civil war in 1992-1993), admitting hospital department, date of blood culture collection, date of hospital admission, number of sets obtained for culture (e.g., 1 or 2), blood culture results, white blood cell count, temperature on admission, in-hospital mortality. Neonatal bloodstream infections (BSI) were defined as positive blood culture(s) in an infant with age ≤30 days. Nosocomial blood stream infections were defined as neonatal BSIs and all cultures in children with age >30 days that were positive >48 hours after admission to the hospital Information on previous admissions to the hospital and treatment was not available.
Blood cultures were collected by the nursing staff after cleaning the skin with chlorhexidine or alcohol. A total of 2 -3 ml of blood was drawn and placed in 2 aerobic blood culture bottles using a sterile needle. The microbiology laboratory did not have the capacity to perform anaerobic cultures. Blood culture bottles were incubated at 37°C. Subcultures were performed from all blood culture bottles irrespective of positive (turbid) or negative by appearance. These “blind” subcultures were performed at 24 hours, 48 hours and 7 days after collection. All the subcultures were plated onto blood agar, chocolate agar, and MacConkey agar plates. Agar was made in the CCH microbiology laboratory as no commercially prepared media was available in Georgia during the study period. Human (5%) rather than sheep's blood was used for preparation of culture media. Since incubators are available for growing cultures at the proper temperatures, plates are incubated for 18-24 hours as follows: blood and chocolate agar plates kept in a candle jar at 35°C, MacConkey agar plates aerobically at 35°C. Gram stains are performed routinely on all positive subcultures identified. All blood culture bottles were discarded after the 7th day of incubation. Some of the identifications were not carried out beyond Gram staining the positive culture due to lack of available equipment.
Data was entered in Microsoft Excel 2000 (Microsoft Corp., Redmond, WA) and analyzed using SAS software, version 9.1 (SAS Institute, Cary NC). The Mantel-Haenszel odds ratios (OR) and corresponding 95% confidence intervals (CI) were calculated for dichotomous variables. Multivariate analysis was done using unconditional logistic regression model. A P value of ≤.05 was defined as statistically significant.
During the study period, 1,693 blood cultures were obtained from pediatric patients (mean of 94 blood cultures per month). Of these, 338 (20%) children had a least one positive culture, and 39 (12%) of the 338 were excluded from further analysis because 30 had incomplete or missing medical records and 9 had fungemia.
The median age of the 299 children included in analysis was 14 days and the mean age was 186 days (range 2 days -14 years); 178 (60%) were male. A total of 203 (68%) of 299 patients were neonates; 62 (21%) were internally displaced persons (IDP). The majority of patients were admitted to the CCH Neonatal Intensive Care Unit (NICU) (156 [53%] of 297 children), 75 (25%) were admitted to general neonatal departments, 7 (2%) to the neurology neonatal department; 31 (10%) to the Pediatric Intensive Care Units (ICU), 17 (6%) to general pediatric departments, 8 (3%) infectious diseases unit, and 2 (0.7%) were seen in the Emergency Department not admitted to a hospital ward. At the time of patients admission or presentation the hospital median body temperature was 36.6°C (range 34.0-39.8°C); 13 (4%) of 299 children had hypothermia <36°C. Median white blood count was 11.0/mm3 (range 1.8-57.5/mm3). Two sets of blood for cultures were obtained from 14 of 299 (5%) children and 285 (95%) had only one blood sample obtained for culture. Among 96 children aged >30 days 30 (31.3%) had cultures performed in >48 hours of admission to the hospital; total of 233 (78%) of 299 children had nosocomial infection.
Pathogens recovered from blood cultures are shown in Table 1. Gram-negative rod (GNR) bacteria (165 [55%] of 299) and coagulase-negative Staphylococcus (CNS) (109 [36%] of 299) accounted for the majority of recovered pathogens. Further identification of the majority (135 of 165 [82%]) GNR bacteria was not possible due to lack of laboratory capacity. The significance of a positive culture for CNS was difficult to assess because only a single blood culture was obtained in nearly all cases. No H. influenzae or S. pneumoniae were identified in blood cultures. Neonates were more likely to have a positive culture for a Gram negative bacteria compared to children >30 days (69% versus 25%, respectively, OR=6.77, 95% CI 3.91-11.74).
Mortality among those with a positive blood culture was 30% (90 of 299 children died). Among 90 children who died, 68 (76%) had a positive blood culture from which Gram-negative organisms were recovered (59 had GNR not identified, 5 had Pseudomonas spp, and 4 had Klebsiella spp), and 22 (24%) had had positive blood culture from which Gram-positive organisms were recovered (17 CNS, 2 Enterococcus spp, 1 Listeria monocytogenes, 1 S. aureus, and 1 had an unidentified Gram-positive rod organism). Mortality was significantly higher in neonates compared to infants/children >30 days (OR=5.59, 95% CI 2.74-1.41), children with body temperature at admission <37°C (OR=14.74, 95% CI 5.21-41.69), and those with a positive blood culture for a Gram-negative organism (OR=3.61, 95% CI 2.08-6.27). Internally displaced persons had significantly lower mortality (OR=0.38, 95% CI 0.18-0.78) than other patients with a positive blood culture; among IDPs 45% were newborn, and among non-IDPs 74% were newborn infants. In multivariate analysis, independent risk factors for mortality were a positive blood culture in a neonate (<30 days of age) (OR=4.00, 95% CI 1.89-8.46), and having a positive culture for a Gram-negative organism (OR=2.38, 95% CI 1.32-4.29).
This study is one of the first studies to assess the etiology and mortality among pediatric patients with positive blood cultures in Georgia. Most (68%) positive blood cultures occurred among neonates (age <30 days), and Gram-negative bacteria and CNS were most commonly recovered from blood cultures (82%). Unspecified GNR accounted for 45% of all positive blood cultures; further identification of these GNR to the genus and species level was limited due to lack of laboratory capacity. We suspect that E.coli may have accounted for many of these Gram-negative infections given that neonates were the most common pediatric patients to have these organisms recovered. Neonatal infections due to Gram-negative pathogens have also been reported from other resource limited countries in neonatal surveillance [5-8].
The second most commonly recovered organism was CNS. CNS is one of the most common cause of nosocomial blood stream infections but also the most common blood culture contaminant [5,8,9,10]. Because almost all of patients had only a single blood culture obtained, it was not feasible to assess whether patients that had CNS recovered had a true bacteremia or if recovery was due to skin contamination. However, it is important to note that a substantial proportion of children with positive blood cultures for CNS (17 [16%] of 109) died. It is also possible that recovery of CNS could be a marker for other factors such as a central venous catheter, prolonged hospital stay, underlying co-morbidities, or intracranial shunts. Guidelines are needed in Georgian hospitals to help ensure that two sets of blood cultures are obtained which will help distinguish true CNS bacteremia from contamination and that staff obtaining blood cultures receive ongoing training on aseptic technique when drawing blood cultures [11,12]. Surprisingly, there was no Staphylococcus aureus identified which could point poor quality control for coagulation.
The mortality rate in patients with blood stream infections was very high and most of those who died were neonates. Utilizing antimicrobial agents with in vitro activity against the pathogen recovered could improve patient outcomes and survival . However, the lack of laboratory capacity at this institution and many hospitals in resource limited areas hampers effective care of patients with bacteremia. The hospital's clinical laboratory did not have the capacity to fully identify many of the pathogens recovered to the genus and species level and did not have the capacity to perform susceptibility testing. Surveillance data (e.g., antibiogram) is also important in assisting in appropriate empiric antibiotic choices. On an individual level a positive blood culture should directly impact patient care if the physician incorporates the result into decision making, i.e. improving the link between the microbiology laboratory and clinical practice will lead to improved patient care. The lack of laboratory capacity appears to also impact suboptimal clinical practices. Anecdotal evidence suggested that antibiotics are often given for several days prior to blood being obtained for culture and because of lack of laboratory capacity we suspect that sometimes they are not obtained by clinicians when bacteremia or sepsis is suspected.
The laboratory at this childrens' hospital, as health care facilities in other former Soviet republics, is currently facing many problems relating to aging infrastructure, depreciated and obsolete equipment, and severe financial constraints which all lead to limited laboratory capacity. Staff training and acceptance of modern medical practices are also barriers in this transitioning health care system. In the microbiology laboratory routine supplies are sometimes difficult to obtain and culture plates are glass and are reused after sterilization. Funds are not sufficient to obtain commercially manufactured media and all media are made in the hospital without the use of a vacuum hood. A system for automated blood cultures is currently cost prohibitive. The state of these laboratories is a public health emergency and need to address as Georgia and other countries reform and modernize their health care system .
In our study, there was no recovery of either S. pneumoniae or H. influenzae in blood cultures. These pathogens are commonly causes of invasive bacterial infections in an unvaccinated pediatric population [14-17]. WHO estimates that H. influenzae is the leading cause of bacterial meningitis in children under 5 years of age and the second leading cause of deaths to due bacterial pneumonia in resource limited areas where vaccination is not carried out as is the current situation in Georgia [18-20]. S. pneumoniae is possibly the most important pathogen of infancy, especially in developing countries . However, it is possible that many cases of invasive pneumococcal or H. influenzae infections in Georgia go undiagnosed due to the laboratory's limited resources, especially considering the estimated prevalence of these two pathogens in other developing countries. There is a possibility that lab-prepared culture media (with human blood) might inhibit or not support the growth of strains of S. pneumoniae or H. influenzae. It is unclear if such fastidious organisms can be recovered by current practice without appropriate control materials such as ATCC strains of S. pneumoniae or H. influenzae. Good quality control and quality assurance program for laboratory practice are necessary in the laboratory that commercially prepared culture media are not available. [18,19]. Another possible explanation for the lack of recovery of these two organisms is that antibiotics were given prior to collection of blood cultures (either as an inpatient or as an outpatient prior to admission). Antibiotics are readily available at pharmacies in Georgia without the need of a prescription. It is clear that a laboratory surveillance system for S. pneumoniae and H. influenzae will be an important first step for surveillance activities on the prevalence and incidence of invasive pneumococcal and H. influenzae infections and to measure the impact of the introduction of vaccination for both pathogens. As noted, measures to build laboratory capacity to ultimately improve diagnostic and surveillance capabilities and implementation of vaccines against important childhood bacterial infections in children is urgently needed.
This study is subject to several serious limitations. The lack of laboratory capacity impacted the ability to identify many Gram-negative bacteria to the genus and species level. Also due to lack of laboratory capacity, susceptibility testing was not performed. Because only a single blood culture was obtained in the large majority of cases, we could not evaluate if CNS was a contaminant or a true pathogen. Some patients had fungemia; although these were likely true pathogens, we limited our study to patients with bacterial BSI. No data on previous admissions to the hospital and treatment during current hospitalization was available. In addition, because of the lack of ability to distinguish between true bacteremias and contaminants we were not able to readily assess if mortality was due to the bacteremia. However, a high mortalilty was seen among those who had a positive blood culture.
In summary, a high mortality (30%) was seen among patients with positive blood stream infections at the largest children's hospital in Georgia. Microbiological identification of common organisms known to cause blood stream infections in children is difficult in the Republic of Georgia due to limited resources and laboratory capacity in the clinical microbiology laboratory. Improving the infrastructure and capacity of diagnostic microbiology laboratories in resource limited countries is a major public health need and critical to improve patient care and clinical outcomes as well as establishing and conducting appropriate microbiological surveillance including that for vaccine preventable diseases.
This study was supported in part by funding from the National Institutes of Health/Fogarty International Center [D43 TW007124 and D43 TW01042].
There was no conflict of interest for all authors.