Sepsis related mortality of extremely low gestational age newborns after the introduction of colonization screening for multi-drug resistant organisms

Neonatal sepsis has a major impact on mortality and long-term morbidity. There is an urgent need for new strategies to prevent sepsis, particularly in preterm infants who are highly vulnerable to be involved in healthcare-associated infection outbreaks [1‐7]. Endogenous risk factors of sepsis in preterm infants include immaturity of barriers (skin, mucosa) and systemic immune responses while the colonizing microbiota is also considered to play a key role. As a consequence of several infection outbreaks in German NICUs being a topic in the public media [8‐10] the German Commission on Hospital Hygiene and Infection Prevention (KRINKO) at the Robert-Koch Institute, Berlin, decided to update the recommendations for infection surveillance in neonatal intensive care units (NICUs) [11]. The 2013 update recommended weekly colonization screening followed by proactive hygiene interventions based on screening results to be mandatory for German NICUs. This strategy aimed to (a) adjust empirical anti-infective therapy in colonized patients when sepsis is suspected, (b) to assess local epidemiology of multi-drug resistant organisms (MDRO) and to recognize an outbreak as early as possible and (c) to prevent spreading of MDRO or pathogens with high epidemic potential by extended hygiene measures [12]. The scientific evidence of this recommendation is limited. Whether colonization is related to sepsis risk with the same pathogen is still a matter of controversial discussion [13‐15]. While other European countries have not officially adopted the colonization screening strategy in guidelines of neonatal societies, several units have voluntarily implemented this approach for infection control [16‐19]. The German Neonatal Network (GNN) is a population-based, prospective study including 62 tertiary (highest) care level NICUs, i.e. data from > 30% of extremely preterm infants born in Germany. The updated KRINKO recommendations were implemented in all GNN sites at the same time. We aimed to evaluate the sepsis incidence and pathogen specific fatality rates before and after the guideline update.

A total of 12.823 extremely preterm infants born in GNN centers were included in this study, 3.920 infants before publication of updated guidelines (treatment 2011–2013) and 8.903 infants after introduction of mandatory colonization screening (treatment 2014–2018). There were no differences in clinical characteristics in both groups (Table 1).

The GNN collaboration offers a great opportunity to compile data about interventions taken and to evaluate clinical practice. We found a temporal decline of clinical sepsis, total culture-proven sepsis and late-onset sepsis incidence. However, introduction of weekly colonization screening had no effects on sepsis-related mortality and sepsis with MDRO or highly epidemic pathogens. While the exposure rate to cefotaxime declined, the use of meropenem increased. Recent survey data indicate that the compliance to KRINKO recommendations is high among German NICUs (> 90% for MDRO screening) [21, 22], hence our cohort is a representative sample of the population of extremely preterm infants in Germany.

The advances in neonatology and participation in our network led to declining mortality during the observational period. In comparison to other network studies, the survival rate of infants is relatively high, i.e. 75% in infants born at 24 weeks of gestation vs. 84% (Japan), 71% (Finland), 70% (Sweden) and 58% (USA) [2, 23, 24]. After respiratory failure, sepsis remains the second most important cause of death, e.g. 17% deaths in a recent GNN sample in infants < 29 weeks [2]. Notably, the incidence of clinical or culture-proven (late-onset) sepsis has been continuously decreasing which is mainly explained by a decline in the frequency of infections with Coagulase negative staphylococci but not with a reduced number of Gram-negative infections. In that aspect, weekly colonization screening has no specific impact but might be considered as part of an increased “sepsis awareness” bundle in NICUs which has surrogate positive effects on sepsis-related outcome. Whether improved sepsis outcome is related to extended hygiene precautions and whether the screening strategy is a cost-effective measure remains a matter of discussion.

No difference was observed for pathogen-specific fatality rates before and after guideline update. The sepsis pathogens have different habitats and pathogenicity factors which lead to variable clinical courses. In this study, every second infant with Pseudomonas aeruginosa infection died which is in line with previous reports [25, 26]. The case-fatality rates for Candida albicans (24%), E. coli (11%), Klebsiella spp. (11%) and Group B Streptococcus (9%) were also significant. In a recent Italian area-based, retrospective study culture-proven late-onset sepsis occurred in 12% of preterm ELBWI and case fatality rate was 13% [27] which is also comparable to Swiss data (12%) [7].

Survivors of sepsis have a major risk for long-term morbidity of several organ systems including CNS, lung and gut [1]. Given the lack of reliable biomarkers to discriminate between infection and other causes of systemic inflammation, empirical broad-spectrum antibiotics are administered when sepsis is clinically suspected. The choice of empiric first line therapy is of critical importance in a patient colonized with an MDRO, as a therapeutic mismatch during the first 2 to 3 days of the infection (until culture results are reported) may be the most important reason for a complicated course of sepsis. On the other hand, the uncritical use of carbapenems which has been noted in timely association with public media reports on NICU infection outbreaks [10] should be avoided. In our setting, the active continuous surveillance did not influence Gram-negative/MDRO sepsis related outcomes but led to an increased prescription rate of meropenem. Hence there is a perceived threat posed by MDRO which is not supported by epidemiological data. The latter aspect and the increasing exposure of extremely preterm infants to antifungal drugs need to become major targets for anti-infective stewardship programs which have recently been implemented in several GNN NICUs. The effectiveness of network feedback and benchmarking on drug prescriptions has been shown for the use of cefotaxime. The prescription rate of cefotaxime declined during the observational period in this study, after continued education on the risks of cefotaxime, e.g. of selection of MDR enterobacteria has been provided during GNN meetings. In line with that, we noted a 3.4% reduction in the total antibiotic treatment rate. i.e. after guideline update 225 more extremely preterm infants were not exposed to antibiotics at all.

Interpretation of surveillance data is an interdisciplinary task involving experts in neonatology, infectious diseases, microbiology, hospital hygiene and pharmacy. Continuous surveillance allows a characterization of the local epidemiology in longer time periods, the investigation of the epidemic potential of specific pathogens and an evaluation of outbreaks including a root-cause analysis. We provide the first robust data that the availability of screening data is associated with declining sepsis rates probably due to an increased risk awareness. Routine screening followed by extended barrier precautions for colonized babies is time consuming and does not necessarily have an effect on the frequency of invasive disease or mortality from sepsis with screening relevant pathogens. This needs to be put in into the perspective of an increased use of third-line anti-infective drugs, staff intensity, costs and decisions to the disadvantage of other priorities of care (e.g. avoidance of co-bedding of twins with different screening results). It has also been debated whether the care of MDRO colonized babies in isolation rooms with closed doors without permanent presence of a nurse might actually increase the risk, e.g. to suffer from prolonged apnoea, specifically in times of overcrowding and understaffing.

Our study has limitations. The observational design does not allow to account for all confounding factors that might have an impact on change over time (i.e. number of infants enrolled/year, center-specific effects, different local guidelines before mandatory implementation of guidelines). In addition, although none of the NICUs had introduced a generalized screening that was postulated by the KRINKO, some NICUs used selective screening approaches at least in outbreak situations which might have influenced the results reported in ours study. Second, we were not able to determine the compliance rate to extended hygiene precautions based on screening results in our study. Finally, the treatment rate with antibiotics is a rather crude estimation of the actual exposure, i.e. the documentation of defined daily doses of antibiotics is needed for future evaluations.

In conclusion, the introduction of weekly screening and extended hygiene measures is associated with reduced sepsis rates, but has no effects on sepsis-related mortality and sepsis with screening-relevant pathogens. Every effort should be made to prevent colonization and nosocomial transmission with potentially life-threatening bacteria. Colonized infants represent the most important reservoir for subsequent nosocomial transmission. Continuous surveillance is regarded as an important tool for hospital hygiene management but has not yet been proven to be effective to reduce sepsis-related outcome in highly preterm infants. Additional assessments (genotyping) need to be performed to evaluate the identity of colonizing and invasive strains in outbreak situations. Unwanted effects of screening need to be actively addressed by antibiotic stewardship programs with impactful interventions [28]. Future studies should focus on protective measures like modulation of the local microbiome promoting gut eubiosis in order to control drug-resistant or highly epidemic enterobacteria.