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Objectives Neonatal sepsis, a major cause of death amongst infants in sub‑Saharan Africa, is often gut derived. Gut colonisation by Enterobacteriaceae producing extended spectrum beta‑lactamase (ESBL) or carbapenemase enzymes can lead to antimicrobial‑resistant (AMR) or untreatable infections. We sought to explore the rates of colonisation by ESBL or carbapenemase producers in two neonatal units (NNUs) in West and East Africa. Methods Stool and rectal swab samples were taken at multiple timepoints from newborns admitted to the NNUs at the University College Hospital, Ibadan, Nigeria and the Jaramogi Oginga Odinga Teaching and Referral Hospital, Kisumu, western Kenya. Samples were tested for ESBL and carbapenemase genes using a previously validated qPCR assay. Kaplan–Meier survival analysis was used to examine colonisation rates at both sites. Results In total 119 stool and rectal swab samples were taken from 42 infants admitted to the two NNUs. Coloni‑ sation with ESBL (37 infants, 89%) was more common than with carbapenemase producers (26, 62.4%; P = 0.093). Median survival time before colonisation with ESBL organisms was 7 days and with carbapenemase producers 16 days (P = 0.035). The majority of ESBL genes detected belonged to the CTX‑M ‑1 (36/38; 95%), and CTX ‑M ‑9 (2/36; 5%) groups, and the most prevalent carbapenemase was bla (27/29, 93%). NDM Conclusions Gut colonisation of neonates by AMR organisms was common and occurred rapidly in NNUs in Kenya and Nigeria. Active surveillance of colonisation will improve the understanding of AMR in these settings and guide infection control and antibiotic prescribing practice to improve clinical outcomes. Keywords Carbapenemase, ESBL, Neonatal sepsis, Molecular diagnostics, Surveillance *Correspondence: Department of Public Health, School of Public Health and Community Thomas Edwards Development, Maseno University, Maseno, Kenya firstname.lastname@example.org College of Medicine, University of Ibadan, Ibadan, Nigeria 1 5 Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK Liverpool, UK Jaramogi Oginga Odinga Teaching and Referral Hospital, Jomo Kenyatta Highway Kaloleni Kisumu KE Central, Maseno, Kenya © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. 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Antimicrobial Resistance & Infection Control (2023) 12:14 Page 2 of 8 Introduction Methods Sepsis is a major cause of neonatal morbidity and mor- Study sites tality, with an estimated 1.7 million cases globally in The study was facilitated by the Neonatal Nutrition 2010, and 203,000 sepsis-attributable deaths . Neo- Network for sSA established in 2018 with the goal of natal sepsis has a higher incidence and mortality in building research capacity and establishing an environ- sub-Saharan Africa (sSA) than in other regions [1, 2]. ment for future trials of neonatal nutritional and other It is often gut derived, with compromised immunity interventions . Of the 7 secondary/tertiary NNUs and an impaired gut barrier allowing colonisation by in Nigeria and Kenya engaged in the network, the study opportunistic pathogens such as Enterobacteriaceae sites were the NNUs at the University College Hospi- to progress to blood stream infection . Preterm and tal, Ibadan, Nigeria and the Jaramogi Oginga Odinga low birth weight infants are at the greatest risk. Colo- Teaching and Referral Hospital (JOOTRH), Kisumu, nisation by antimicrobial resistant organisms (AROs) western Kenya. is particularly problematic and can lead to infections Over a 6-month period between August 2018 and that are difficult or impossible to treat. May 2019, the Ibadan NNU admitted 488 babies aged Infections with extended spectrum beta-lactamases less than 48 h. Amongst those with available data, (ESBL)-producing Enterobacteriaceae or carbap- 94/444 (21.2%) were very low birth weight (< 1500 g) enemase producing organisms (CPOs), which con- and 117/482 (24.3%) were very or extremely preterm rd fer resistance to 3 generation cephalosporins and (gestational age < 28 weeks). The Kisumu NNU admit - carbapenems respectively, are associated with poor ted 584 babies aged less than 48 h of which 100/579 clinical outcomes due to the increased likelihood of (17.3%) were very low birth weight and 88/550 (16.0%) treatment failure . Globally, organisms that produce were very or extremely preterm. either ESBL or carbapenemase enzymes, particularly Klebsiella pneumoniae, are a common cause of out- Participants and data collection breaks in neonatal units (NNU) [5–7], often due to Parents of neonates admitted to the NNUs were pro- horizontal transmission from a colonised infant admit- vided with information about the study and asked to ted to the ward . Mortality rates of up to 64% have provide informed consent. Clinical details of enrolled been reported , driven by the lack of effective treat- neonates were extracted from case records and entered ment options. Outbreaks of ESBL/CPO K. pneumoniae into a case report form which was updated with patient have been described frequently in African neonatal outcomes upon discharge from the unit. Suspected sep- units  caused by contaminated intravenous fluids/ sis was based on clinical assessment that advised start- antibiotics , or associated with gut colonisation ing or changing antibiotic treatment. Confirmation of . Treatment options for neonatal infections with sepsis by laboratory analysis was rarely available. Anti- this resistance profile in sub-Saharan Africa (sSA) are biotic usage data for each participant was also available severely restricted, due to a lack of alternative antibi- from the Ibadan NNU. otics and contraindications in this age group [10, 13]. Data on the prevalence of gut colonisation in NNUs Sampling in sSA is limited due to a lack of routine surveillance. Samples of neonatal stool were taken by swabbing fae- Defining ARO epidemiology and colonisation rates in cal material from diapers or, if no stool was present, a NNUs in sSA is critical for guiding antimicrobial stew- rectal swab. Swabs were immediately frozen at − 20 °C ardship and to assess the impact of interventions . prior to DNA extraction. Sampling was scheduled to Typically, culture-based methods from rectal swabs occur on a weekly basis for six weeks post-admission. or stool samples  are used for detecting colonisa- However, in practice, samples were often taken at tion. However, increasingly, molecular tools are used opportunistically and at different timepoints due to to screen samples directly for the presence of AMR the high clinical workload for nursing staff, and some genes, foregoing a culture step, providing faster results babies were sampled throughout their stay (up to and increased throughput [16, 17]. 58 days). We sought to explore the frequency and rates of gut colonisation by AROs in two NNU’s, one in West and DNA extraction and molecular detection of AMR markers one in East Africa, using highly multiplexed molecular DNA was extracted from the stool samples and rectal diagnostics. swabs using a Qiagen Fast DNA stool mini kit (Qiagen, Germany), following the manufacturer’s instructions. DNA was shipped to the UK for molecular analysis. E dwards et al. Antimicrobial Resistance & Infection Control (2023) 12:14 Page 3 of 8 Antimicrobial resistance genes were detected using colonisation were analysed with Chi-Squared and Fishers a previously validated in-house high resolution melt Exact Tests using GraphPad Prism Version 5 (GraphPad (HRM) analysis qPCR assay  that detects the five Software Inc, United States). A p-value < 0·05 was consid- main carbapenemase genes (bla , bla , bla , ered significant. VIM IMP−1 KPC bla , bla ) and ESBL genes (CTX-M groups 1 NDM OXA−48 and 9). Briefly, the 12.5 µl reactions contained 6.25 µl Results 2 × Type-It HRM mix (Qiagen, Germany), 1 µl primer Demographics and clinical characteristics mix (final primer concentrations range from 100 to A total of 42 neonates were enrolled in the study, includ- 500 nM), 2.75 µl molecular grade water and 2.5 µl ing 24 in Ibadan and 18 in Kisumu (Table 1). Overall, 24 DNA. Reactions were carried out using a Rotor-Gene (57.1%) were female, and 6 (14.3%) were extremely pre- Q (Qiagen, Germany), with end point detection car- term (gestational age < 28 weeks). Suspected sepsis based ried out via HRM. Positive controls were DNA sam- on clinical assessment occurred in the majority of infants ples extracted from isolates carrying each AMR gene as (30/42; 71.4%). detailed previously . Sampling Statistical analysis A total of 58 samples were obtained from the 24 neonates A patient was defined as CPO or ESBL colonised on the in Ibadan between 1- and 56-days post admission. The date that a carbapenemase or ESBL gene was detected average number of infants sampled per day between days by the HRM analysis qPCR assay. Patients were assumed 1–15, 16–30 and 31–45 were 1.9, 1.3 and 0.4, respec- not to be colonised until a positive sample was obtained. tively. In Kisumu, 57 samples were obtained from the Rates of colonisation of both CPO and ESBL produc- 18 neonates (Fig.S1), taken between 1- and 46-days post ers were described using Kaplan–Meier survival curves admission. The average number of infants sampled per (GraphPad Prism), with patient’s data censored at the day between days 1–15, 16–30 and 31–45 were 2.1, 1.5 point of their last sample . All samples, includ- and 0.5, respectively. ing those taken beyond six week post admission, were included in the analysis. Antibiotic usage To calculate the proportion of the various AMR genes Antibiotic usage data was only available for the neonates for both the ESBL and CPO genotypes in the cohort, all in Ibadan NNU; antibiotics were used for both prophy- genes detected in an individual patients’ samples across laxis in newborns with risk factors for infection and all time points were included and collated. Genes that treatment of suspected sepsis. The antibiotics received were isolated in multiple samples in a single patient were by the cohort were amikacin (received by all neonates), only counted once and when first identified, as these ampicillin/sulbactam (95.2%), ceftazidime (42.9%), gen- were assumed to belong to the same colonising organ- tamycin (38.1%), levofloxacin (19.1%), metronidazole ism. Associations between clinical variables and ARO (14.3%), piperacillin/tazobactam (9.52%), clindamycin Table 1 Characteristics of the study participants, colonisation and mortality Characteristic Ibadan n (%) Kisumu n (%) Total n (%) Participants 24 (57.1) 18 (42.9) 42 (100.0) Female 14 (58.3) 10 (55.6) 24 (57.1) Very low birthweight (< 1500 g) 24 (100) 4 (22.2) 28 (66.7) Extremely preterm (gestational age < 28 completed weeks) 1 (4.2) 5 (27.8) 6 (14.3) Caesarean section delivery 13 (54.2) 6 (33.3) 19 (45.2) Mother HIV positive 0 (0.0) 3 (16.7) 3 (8.6) 1 or more episodes of suspected sepsis 12 (50) 18 (100.0) 30 (71.4) 1 or more episodes of necrotising enterocolitis 5 (20.8) 1 (5.5) 6 (14.3) ESBL colonised 22 (91.6) 14 (77.8) 36 (85.7) CPO colonised 20 (83.3) 8 (44.4) 28 (66.7) Uncolonized by antimicrobial‑resistant organism 0 (0.0) 2 (11.1) 2 (4.8) Mortality in neonatal unit 5 (20.8) 7 (38.9) 12 (28.6) ESBL extended spectrum beta-lactamase, CPO carbapenemase producing organism At any time during admission Edwards et al. Antimicrobial Resistance & Infection Control (2023) 12:14 Page 4 of 8 Fig. 1 A The percentage of participants at each site colonised by ESBL, CPO or both during the study period. B Number of participants at each site positive for various ESBL and carbapenemase genes identified during the study Molecular epidemiology of AMR genes (9.52%), cefotaxime (4.8%) ciprofloxacin (4.8%), vanco - In Kisumu, the majority of ESBL genes detected belonged mycin (4.8%), and meropenem (4.8%). to the CTX-M-1 family (14/16, 87.5.%), and CTX-M-9 (2/16, 12.5%) (Fig. 1B.). The most prevalent carbapen - Colonisation status emase was bla (7/8, 87.5%). A single bla gene was NDM VIM The overall colonisation rates among the study partici - also detected (1/8, 12.5%). In Ibadan, CTX-M-1 was again pants were 88.0% for ESBL and 64.3% for CPO organ- the dominant ESBL family (22/22, 100%), and bla the NDM isms. A total of 50.0% (9/18), 5.5% (1/18), and 33.3% dominant carbapenemase (20/21, 95.2%). One sample (6/18) of neonates in the Kisumu NNU were colonised by was positive for bla (1/22, 4.8%). We did not detect OXA-48 ESBL, CPO, or both ESBL/CPO, respectively at any point any of the carbapenemases bla or bla genes in KPC IMP during their admission (Fig. 1A). Colonisation rates were either site. higher in Ibadan, with 79.2% (19/24) of neonates colo- nised by both ESBL/CPO organisms during their admis- Discussion sion, 12.5% (3/24) ESBL only, 4.2% (1/24) CPO only, and Using a combination of longitudinal sampling and only 4.2% (1/24) uncolonised by either organism. Of molecular testing for a panel of AMR genes we were able the three infants who remained uncolonised across the to demonstrate rapid rates of colonisation of neonates two sites, all submitted a single sample on days one or admitted to two neonatal units by ESBL and carbapen- two, with one being discharged from the ward and the emase producing organisms. The prevalence of colonisa - remaining dying during the study. Colonisation accord- tion by ESBLs in infants admitted to both the Kisumu and ing the demographic and clinical variables is shown in Ibadan NNUs was higher than previously reported in sSA Additional file 1: Table S1. NNUs including Tanzania  and Kenya . A sys- tematic review of gut ESBL colonisation in sSA reported rates ranging from 25 to 74% , which are all below the Colonisation rates levels found in our study. Colonisation of infants with Longitudinal sampling revealed that colonisation ESBL producers was rapid, with mean time to colonisa- occurred rapidly (Fig. 2) and had often occurred by the tion of 8 days. This is comparable to studies in Asia  first sampling point (35/42; 83.3%). Median survival where the use of carbapenems and 3rd generation cepha- time to colonisation by ESBL organisms was 7 days with losporins is widespread. In a minority of infants, coloni- a maximum of 97% of colonisation by day 45 (Fig. 3). In sation was dynamic, with acquisition and loss of either contrast, the rate of CPO colonisation was significantly ESBL or CPO bacteria occurring during the study. Whilst lower (P = 0.035, Mantel-Cox Test), with a median sur- colonisation can last for months or even years , rapid vival time before colonisation of day 16, but also with acquisition and loss has been shown in travellers to areas a maximum of 97% by day 45. Colonisation was also with high ESBL prevalence . dynamic; in 13 (31%) cases either ESBL or CPO carriage Data on gut colonisation by CPOs in sSA is limited; was detected but then absent in a subsequent sample. however, this is assumed to be less common than ESBL colonisation, in part due to the lower usage of expensive E dwards et al. Antimicrobial Resistance & Infection Control (2023) 12:14 Page 5 of 8 Fig. 2 Longitudinal acquisition, carriage, and loss of ESBL and CPOs according to study site. Note: Each box represents a stool or rectal swab sample. Days are counted from the admission of each individual participant and do not run concurrently of hospital inpatients were colonised by CPOs, and high- lighted the circulation of bla and bla carbapen- NDM VIM emases . A country specific meta-analysis found the prevalence of carbapenem resistance amongst Entero- bacteriaceae to be 5% in Nigeria and 0.3% in Kenya . The proportion of neonates colonised by CPOs in Ibadan exceeds the highest proportions reported in previous meta-analysis studies  carried out in non-NNU hos- pital and community settings in Africa and highlights that NNUs could be a major reservoir of CPOs. The majority of CTX-M ESBL genes detected were Fig. 3 Kaplan–Meier survival analysis showing time to first in CTX-M group one, which includes bla and CTX-M−15 colonisation by ESBL and CPOs. Notes: Dotted line indicates time to bla enzymes . These are the most wide - 50% of infants colonised. ESBL extended spectrum beta‑lactamase, CTX-M−1 spread ESBL genes globally and have previously been CPO carbapenemase producing organism reported as the most prevalent genes in sSA . The discovery of bla as the most common carbapen- NDM carbapenem drugs in this setting . A recent study emase gene present in both the Ibadan and Kisumu from Nigeria, including patient isolates from the same tertiary NNUs is in agreement with previous studies; hospital involved in our study, reported 69.1% of a cohort A 2012–2014 survey found bla and bla genes NDM VIM Edwards et al. Antimicrobial Resistance & Infection Control (2023) 12:14 Page 6 of 8 to be the only reported carbapenemases in both Nige- also meant that sampling did not occur at regular inter- ria and Kenya . A high prevalence of bla was vals, and not all participants were sampled within their NDM−1 found in the Ibadan NNU despite only a single dose first week of admission to the NNU. This could affect the of carbapenem antibiotics being given over the study results, particularly the time-to-colonisation analysis. period. However, 95.2% of neonates in Ibadan received a β-lactam antibiotic, and 46.7% a 3rd generation Conclusion cephalosporin, and the use of these antibiotics could This report highlights that gut colonisation of infants potentially select for bacteria producing any circulating by AROs in NNUs in Kenya and Nigeria is common and enzyme capable of providing resistance, including car- occurs rapidly. The carbapenemase bla and group NDM−1 bapenemases. The frequent co-localisation of bla 1 bla genes were the most prevalent resistance NDM−1 CTX-M with other AMR genes on mobile genetic elements genes at both sites. The study demonstrates that active means that co-selection of bla can also occur surveillance of colonisation can be used to improve the NDM−1 during exposure to other antibiotic classes such as ami- understanding of AMR in NNUs in sSA, and these data noglycosides . could guide infection control and prescribing practice The transmission of AROs from the hospital environ - to improve clinical outcomes. ment to the neonatal gut has been well documented, with health care workers , sinks and taps , sur- Supplementary Information face environments  and maternal colonisation  The online version contains supplementary material available at https:// doi. org/ 10. 1186/ s13756‑ 023‑ 01216‑0. all implicated as potential transmission sources. Molec- ular surveillance coupled with immediate patient isola- Additional file 1: Table S1. Occurrence of selected variables in partici‑ tion has been demonstrated to be an effective infection pants according to colonisation with ESBL and CPOs. control measure in intensive care units , and the Additional file 2: Fig. S1. Sample collection rates in Kisumu and Ibadan enhanced speed of molecular testing can be useful in NNUs. Days are counted from first day of life per participant. ensuring prompt intervention to prevent hospital or unit wide outbreaks . However, these interventions Acknowledgements require the infrastructure capacity for isolation units. We acknowledge the technical staff in the diagnostic microbiology labora‑ tories at Kenya Medical Research Institute, Centre for Global Health Research, Successful control measures that focus on prevent- Kisumu, Kenya and the University College Hospital, Ibadan, Nigeria. We thank ing colonisation include the use of disposable gloves the parents and NNU staff who very kindly supported this study. and gowns for single patient use , improved hand Author contributions hygiene, and intensive bio-cleaning of wards . The TE, OOT, HN, ERA and SA conceptualised the study. PA, WO, MO, GN, AA, and assay we used in this study has since been validated in OOT managed the clinical studies, including collecting patient information a dry-format, requiring only the addition of DNA and and samples. TE, CTW, OOT, HN, ERA and SA contributed to the experimental design and data analysis. TE, CTW and TR carried out laboratory experiments. nuclease-free water to resuspend the dried reagents TE, CW, AICA and SA wrote the first draft of the manuscript. All authors . This eliminates the need for a cold chain for ship - approved the final manuscript. ping and storage, making it more applicable to this set- Funding ting. By directly testing faecal samples or swabs without This work was supported by the MRC Confidence in Global Nutrition and a culture step, this method can be used to provide same Health Research Institutional “pump‑priming” award 2018‑2020 (MC_PC_MR/ day results. Although this approach does not identify R019789/1). the bacterial species, there are companion molecular Availability of data and materials assays that can be run alongside if this information is An anonymized database of the microbiological data related to study partici‑ desired . pants is available from the corresponding authors. Our study had several limitations. The small sample size limited our ability to explore associations between Declarations demographic and clinical variables and colonisation. Ethics approval and consent to participate Nevertheless, the very high proportions of ESBL and/ The study was approved by the Liverpool School of Tropical Medicine or CPO colonised infants provides important epidemio- Research Ethics Committee (study number 18‑021), the University of Ibadan/ University College Hospital Ethics Committee (UI/EC/18/0446) and the logical information to inform infection control strate- JOOTRH Ethics Review Committee (ERC.IB/VOL.1/510). gies. Whilst utilising molecular methods has several advantages, including the identification of specific AMR Consent for publication Not applicable. genes, this approach prevented the linkage of AMR genes to particular isolates, and therefore, we could not deter- Competing interests mine the species or sequence type of the AROs detected. The authors declare no competing interests. Our pragmatic approach to sampling around clinical care E dwards et al. 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Antimicrobial Resistance and Infection Control – Springer Journals
Published: Feb 22, 2023
Keywords: Carbapenemase; ESBL; Neonatal sepsis; Molecular diagnostics; Surveillance
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