Use of the WHO Access, Watch, and Reserve classification to define patterns of hospital antibiotic use (AWaRe): an analysis of paediatric survey data from 56 countries

BACKGROUND: Improving the quality of hospital antibiotic use is a major goal of WHO's global action plan to combat antimicrobial resistance. The WHO Essential Medicines List Access, Watch, and Reserve (AWaRe) classification could facilitate simple stewardship interventions that are widely applicable globally. We aimed to present data on patterns of paediatric AWaRe antibiotic use that could be used for local and national stewardship interventions. METHODS: 1-day point prevalence survey antibiotic prescription data were combined from two independent global networks: the Global Antimicrobial Resistance, Prescribing, and Efficacy in Neonates and Children and the Global Point Prevalence Survey on Antimicrobial Consumption and Resistance networks. We included hospital inpatients aged younger than 19 years receiving at least one antibiotic on the day of the survey. The WHO AWaRe classification was used to describe overall antibiotic use as assessed by the variation between use of Access, Watch, and Reserve antibiotics, for neonates and children and for the commonest clinical indications. FINDINGS: Of the 23 572 patients included from 56 countries, 18 305 were children (77·7%) and 5267 were neonates (22·3%). Access antibiotic use in children ranged from 7·8% (China) to 61·2% (Slovenia) of all antibiotic prescriptions. The use of Watch antibiotics in children was highest in Iran (77·3%) and lowest in Finland (23·0%). In neonates, Access antibiotic use was highest in Singapore (100·0%) and lowest in China (24·2%). Reserve antibiotic use was low in all countries. Major differences in clinical syndrome-specific patterns of AWaRe antibiotic use in lower respiratory tract infection and neonatal sepsis were observed between WHO regions and countries. INTERPRETATION: There is substantial global variation in the proportion of AWaRe antibiotics used in hospitalised neonates and children. The AWaRe classification could potentially be used as a simple traffic light metric of appropriate antibiotic use. Future efforts should focus on developing and evaluating paediatric antibiotic stewardship programmes on the basis of the AWaRe index. FUNDING: GARPEC was funded by the PENTA Foundation. GARPEC-China data collection was funded by the Sanming Project of Medicine in Shenzhen (SZSM2015120330). bioMérieux provided unrestricted funding support for the Global-PPS

Effects of gestational age and prenatal and perinatal events on the coagulation status in premature infants

Objective: To study prospectively the effects of prematurity and perinatal events on the coagulation status of premature infants. Patients and main outcome measures: Blood samples from premature infants born before 37 gestational weeks were taken for analysis of coagulation factors II, V, VII, and X and platelet count. Results: A total of 125 premature infants, 71 boys, were studied at the median postnatal age of 40 minutes (range 12–100). The lowest median activities of coagulation factors II, V, VII, and X and the platelet count were observed, as expected, in infants (n = 21) born at 24–27 weeks gestation. Twin B (n = 14) had lower median activities of coagulation factors II, V, VII, and X than twin A. Infants with evidence of mild asphyxia (Apgar score at 5 minutes < 7 or cord pH < 7.26) had significantly (p < 0.05) lower levels of coagulation factors II, V, VII, and X and platelet counts than infants without asphyxia. Infants who were small for gestational age (SGA) had significantly (p < 0.05) lower levels of coagulation factors V and VII and platelet counts than infants of appropriate size for gestational age. Other prenatal and perinatal variables examined (sex, maternal hypertension and/or pre-eclampsia, antenatal steroid use, mode of delivery, Apgar scores) did not show any significant associations with coagulation status, which may be explained by the small number of infants studied. Conclusions: The data strongly suggest that there are distinct differences in specific coagulation tests in different patient populations, which could assist in the identification of extremely preterm, SGA, or asphyxiated preterm infants who may be susceptible to haemorrhagic problems perinatally

Interlaboratory variation in the detection of HPA-specific alloantibodies and in molecular HPA typing

Platelet immunology quality assurance exercises have been organized by National Institute for Biological Standards and Control since 1991 and, as of 2006, 35 laboratories participate in the serology section. Molecular human platelet antigen (HPA) typing has been included in the exercises since 1998 and, as of 2006, 29 laboratories participate in this part of the exercise. This report details the performance of laboratories in these two areas. Every 6 months laboratories are sent up to four coded serum/plasma samples for testing in their in-house assays for HPA antibody detection/identification and four coded whole blood samples to be typed for HPA-1, -2, -3 -5 and (since 2003) -15 by their molecular typing assays ('genotyping'). Fifty-two sera containing HPA-specific alloantibodies and 13 sera that were inert, contained only human leucocyte antigen (HLA) class I or high-titre anti-A+B antibodies were distributed; 15 sera were issued in more than one exercise. The percentage of participating laboratories that were able to detect HPA-specific alloantibodies ranged from 15.0 to 100%; the percentage that were able to correctly determine the specificities also ranged from 15.0 to 100%. Over the 20 serology exercises the percentage of laboratories classified as poor performers ranged from 3.1 to 36.7%. A total of 12 780 individual HPA genotyping results were assessed. The overall error rate was 0.7% but there was considerable variation between HPA alleles. Over 11 exercises the percentage of laboratories classified as poor performers varied from 6.3 to 26.3%. The ability to detect and to identify platelet-specific alloantibodies varied widely between laboratories and between various examples of antibodies issued. An increase in the number of laboratories screening for HPA-15 antibodies was seen, although detection and identification of these antibodies was problematic. The majority of examples of HPA-3a antibodies and some examples of HPA-1a and -5b were also difficult to detect and identify. In addition, this scheme has shown that despite the apparent reliability of molecular typing techniques, mistakes do occur, particularly with certain systems. Approximately one in five laboratories participating in the serology exercises and one in seven participating in the genotyping exercises were classified as poor performer at one point or more during the series of exercise

Sensitivity of assays for the detection of HPA-1a antibodies: results of an international workshop demonstrating the impact of cation chelation from integrin αIIbβ3 on three widely used assays

HPA-1a antibodies account for 70-80% of cases of fetal-neonatal alloimmune thrombocytopenia (FNAIT) in Caucasians. However, numerous workshops have demonstrated variability in their detection. We recently showed that exposure of αIIbβ3 to ethylene diamine tetraacetic acid (EDTA) affected binding of many anti-αIIbβ3 monoclonal, and HPA-1a allo-, antibodies; this adversely affected sensitivity of the monoclonal antibody-specific immobilization of platelet antigens (MAIPA) assay and indirect platelet immunofluorescence test (PIFT). This study presents results from an international workshop studying the impact of cation chelation on HPA-1a antibody detection in routine diagnostic laboratories. Serum and EDTA-anticoagulated plasma samples containing anti-HPA-1a were distributed to 39 laboratories. Participants were asked to detect and identify any HPA antibodies present. 2/39 (5·1%) participants were able to detect and identify anti-HPA-1a in the serum, but not in the plasma sample. EDTA plasma reduced MAIPA assay sensitivity by ≥20% in 17/24 (70·8%) laboratories and by ≥50% in 9/24 (37·5%) when using HPA-1a1a platelets (mean: 27·7%, range 0-85·1%); when using HPA-1a1b platelets 3/4 (75%), participants reported ≥50% loss of sensitivity (mean 65·6%, range 0-96·6%). A small but significant increase in optical densities was observed in antigen capture ELISA assays when using plasma (mean difference: 0·081, P < 0·01). Insufficient PIFT data were returned to draw firm conclusions. Use of EDTA plasma significantly affects the sensitivity of the MAIPA assay and can affect detection of even potent, FNAIT-causing examples of anti-HPA-1a. These data highlight the importance of use of αIIbβ3 in an appropriate conformation for the sensitive detection of anti-HPA-1

Collaborative studies to establish the first World Health Organization International Standard for detection of human antibody against human platelet antigen-3a

The platelet-specific antibody anti-human platelet antigen-3a (anti-HPA-3a) is involved in neonatal alloimmune thrombocytopenia, post-transfusion purpura, and platelet refractoriness. However, HPA-3a antibodies are often difficult to detect, probably because the antigen is labile. This report describes the production of a freeze-dried preparation of pooled human plasma, coded 03/190, containing IgG antibodies against the HPA-3a. The material is intended for use as a minimum sensitivity reagent in glycoprotein-specific assays currently used for anti-HPA-3a detection. Laboratories can use it to assess the sensitivity of their 'in-house' assays for anti-HPA-3a and to calibrate local controls for routine use in each batch of tests. Plasma containing anti-HPA-3a was obtained from a mother of two babies both born with severe thrombocytopenia, and following dilution it was freeze dried in glass ampoules. Two collaborative studies demonstrated that the candidate material contained anti-HPA-3a and human leucocyte antigen (HLA) class I antibodies, but no other HPA antibodies that might confuse the detection of the anti-HPA-3a. The minimum dilution that should give a positive result was determined to be 1 : 8 by two further international collaborative studies involving a total of 49 laboratories in 23 countries. The material also contains HLA antibodies and is suitable for use only in techniques that are glycoprotein specific (i.e. monoclonal antibody immobilization of platelet antigens and enzyme-linked immunosorbent assay) where only HPA antibodies will be detected. This standard will allow laboratories to measure their sensitivity of detection of anti-HPA-3a and will also allow those laboratories with relatively insensitive techniques to monitor their performance as they improve their methodolog