Single dose abacavir pharmacokinetics and safety in neonates exposed to human immunodeficiency virus (HIV)

CITATION: Bekker, A. et al. 2020. Single Dose Abacavir Pharmacokinetics and Safety in Neonates Exposed to Human Immunodeficiency Virus (HIV). Clinical Infectious Diseases, 72 (11): 2032–2034. doi:10.1093/cid/ciaa1026The original publication is available at https://academic.oup.com/cid/Abacavir is a potential option for prophylaxis and early treatment of human immunodeficiency virus (HIV), but no data are available in neonates. Ten neonates administered a single abacavir dose of 8 mg/kg before 15 days of life had substantially higher exposures than those reported in infants and children, with no reported adverse events.https://academic.oup.com/cid/article/72/11/2032/5874909?login=truePublishers versio

Optimizing Dosing and Fixed-Dose Combinations of Rifampicin, Isoniazid, and Pyrazinamide in Pediatric Patients With Tuberculosis: A Prospective Population Pharmacokinetic Study

BackgroundIn 2010, the World Health Organization (WHO) revised dosing guidelines for treatment of childhood tuberculosis. Our aim was to investigate first-line antituberculosis drug exposures under these guidelines, explore dose optimization using the current dispersible fixed-dose combination (FDC) tablet of rifampicin/isoniazid/pyrazinamide; 75/50/150 mg, and suggest a new FDC with revised weight bands.MethodsChildren with drug-susceptible tuberculosis in Malawi and South Africa underwent pharmacokinetic sampling while receiving first-line tuberculosis drugs as single formulations according the 2010 WHO recommended doses. Nonlinear mixed-effects modeling and simulation was used to design the optimal FDC and weight-band dosing strategy for achieving the pharmacokinetic targets based on literature-derived adult AUC0-24h for rifampicin (38.7-72.9), isoniazid (11.6-26.3), and pyrazinamide (233-429 mg ∙ h/L).ResultsIn total, 180 children (42% female; 13.9% living with human immunodeficiency virus [HIV]; median [range] age 1.9 [0.22-12] years; weight 10.7 [3.20-28.8] kg) were administered 1, 2, 3, or 4 FDC tablets (rifampicin/isoniazid/pyrazinamide 75/50/150 mg) daily for 4-8, 8-12, 12-16, and 16-25 kg weight bands, respectively. Rifampicin exposure (for weight and age) was up to 50% lower than in adults. Increasing the tablet number resulted in adequate rifampicin but relatively high isoniazid and pyrazinamide exposures. Administering 1, 2, 3, or 4 optimized FDC tablets (rifampicin/isoniazid/pyrazinamide 120/35/130 mg) to children ConclusionsCurrent pediatric FDC doses resulted in low rifampicin exposures. Optimal dosing of all drugs cannot be achieved with the current FDCs. We propose a new FDC formulation and revised weight bands

Challenges in the implementation of the NeoOBS study, a global pragmatic observational cohort study, to investigate the aetiology and management of neonatal sepsis in the hospital setting

Neonatal sepsis is a significant cause of mortality and morbidity in low- and middle-income countries. To deliver high-quality data studies and inform future trials, it is crucial to understand the challenges encountered when managing global multi-centre research studies and to identify solutions that can feasibly be implemented in these settings. This paper provides an overview of the complexities faced by diverse research teams in different countries and regions, together with actions implemented to achieve pragmatic study management of a large multi-centre observational study of neonatal sepsis. We discuss specific considerations for enrolling sites with different approval processes and varied research experience, structures, and training. Implementing a flexible recruitment strategy and providing ongoing training were necessary to overcome these challenges. We emphasize the attention that must be given to designing the database and monitoring plans. Extensive data collection tools, complex databases, tight timelines, and stringent monitoring arrangements can be problematic and might put the study at risk. Finally, we discuss the complexities added when collecting and shipping isolates and the importance of having a robust central management team and interdisciplinary collaborators able to adapt easily and make swift decisions to deliver the study on time and to target. With pragmatic approaches, appropriate training, and good communication, these challenges can be overcome to deliver high-quality data from a complex study in challenging settings through a collaborative research network

Challenges in the Implementation of the NeoOBS Study, a Global Pragmatic Observational Cohort Study, to Investigate the Aetiology and Management of Neonatal Sepsis in the Hospital Setting

Neonatal sepsis is a significant cause of mortality and morbidity in low- and middle-income countries. To deliver high-quality data studies and inform future trials, it is crucial to understand the challenges encountered when managing global multi-centre research studies and to identify solutions that can feasibly be implemented in these settings. This paper provides an overview of the complexities faced by diverse research teams in different countries and regions, together with actions implemented to achieve pragmatic study management of a large multi-centre observational study of neonatal sepsis. We discuss specific considerations for enrolling sites with different approval processes and varied research experience, structures, and training. Implementing a flexible recruitment strategy and providing ongoing training were necessary to overcome these challenges. We emphasize the attention that must be given to designing the database and monitoring plans. Extensive data collection tools, complex databases, tight timelines, and stringent monitoring arrangements can be problematic and might put the study at risk. Finally, we discuss the complexities added when collecting and shipping isolates and the importance of having a robust central management team and interdisciplinary collaborators able to adapt easily and make swift decisions to deliver the study on time and to target. With pragmatic approaches, appropriate training, and good communication, these challenges can be overcome to deliver high-quality data from a complex study in challenging settings through a collaborative research network

Patterns of antibiotic use, pathogens, and prediction of mortality in hospitalized neonates and young infants with sepsis: A global neonatal sepsis observational cohort study (NeoOBS)

BACKGROUND: There is limited data on antibiotic treatment in hospitalized neonates in low- and middle-income countries (LMICs). We aimed to describe patterns of antibiotic use, pathogens, and clinical outcomes, and to develop a severity score predicting mortality in neonatal sepsis to inform future clinical trial design. METHODS AND FINDINGS: Hospitalized infants <60 days with clinical sepsis were enrolled during 2018 to 2020 by 19 sites in 11 countries (mainly Asia and Africa). Prospective daily observational data was collected on clinical signs, supportive care, antibiotic treatment, microbiology, and 28-day mortality. Two prediction models were developed for (1) 28-day mortality from baseline variables (baseline NeoSep Severity Score); and (2) daily risk of death on IV antibiotics from daily updated assessments (NeoSep Recovery Score). Multivariable Cox regression models included a randomly selected 85% of infants, with 15% for validation. A total of 3,204 infants were enrolled, with median birth weight of 2,500 g (IQR 1,400 to 3,000) and postnatal age of 5 days (IQR 1 to 15). 206 different empiric antibiotic combinations were started in 3,141 infants, which were structured into 5 groups based on the World Health Organization (WHO) AWaRe classification. Approximately 25.9% (n = 814) of infants started WHO first line regimens (Group 1-Access) and 13.8% (n = 432) started WHO second-line cephalosporins (cefotaxime/ceftriaxone) (Group 2-"Low" Watch). The largest group (34.0%, n = 1,068) started a regimen providing partial extended-spectrum beta-lactamase (ESBL)/pseudomonal coverage (piperacillin-tazobactam, ceftazidime, or fluoroquinolone-based) (Group 3-"Medium" Watch), 18.0% (n = 566) started a carbapenem (Group 4-"High" Watch), and 1.8% (n = 57) a Reserve antibiotic (Group 5, largely colistin-based), and 728/2,880 (25.3%) of initial regimens in Groups 1 to 4 were escalated, mainly to carbapenems, usually for clinical deterioration (n = 480; 65.9%). A total of 564/3,195 infants (17.7%) were blood culture pathogen positive, of whom 62.9% (n = 355) had a gram-negative organism, predominantly Klebsiella pneumoniae (n = 132) or Acinetobacter spp. (n = 72). Both were commonly resistant to WHO-recommended regimens and to carbapenems in 43 (32.6%) and 50 (71.4%) of cases, respectively. MRSA accounted for 33 (61.1%) of 54 Staphylococcus aureus isolates. Overall, 350/3,204 infants died (11.3%; 95% CI 10.2% to 12.5%), 17.7% if blood cultures were positive for pathogens (95% CI 14.7% to 21.1%, n = 99/564). A baseline NeoSep Severity Score had a C-index of 0.76 (0.69 to 0.82) in the validation sample, with mortality of 1.6% (3/189; 95% CI: 0.5% to 4.6%), 11.0% (27/245; 7.7% to 15.6%), and 27.3% (12/44; 16.3% to 41.8%) in low (score 0 to 4), medium (5 to 8), and high (9 to 16) risk groups, respectively, with similar performance across subgroups. A related NeoSep Recovery Score had an area under the receiver operating curve for predicting death the next day between 0.8 and 0.9 over the first week. There was significant variation in outcomes between sites and external validation would strengthen score applicability. CONCLUSION: Antibiotic regimens used in neonatal sepsis commonly diverge from WHO guidelines, and trials of novel empiric regimens are urgently needed in the context of increasing antimicrobial resistance (AMR). The baseline NeoSep Severity Score identifies high mortality risk criteria for trial entry, while the NeoSep Recovery Score can help guide decisions on regimen change. NeoOBS data informed the NeoSep1 antibiotic trial (ISRCTN48721236), which aims to identify novel first- and second-line empiric antibiotic regimens for neonatal sepsis. TRIAL REGISTRATION: ClinicalTrials.gov, (NCT03721302)

Prevention and treatment of perinatal and infant tuberculosis in the HIV era

Thesis (PhD)--Stellenbosch University, 2016ENGLISH ABSTRACT : Infants (<12 months) born to women with tuberculosis are at high risk of Mycobacterium tuberculosis (M. tuberculosis) exposure, infection and disease early in life. In settings with high prevalence of human immunodeficiency virus (HIV) and tuberculosis, tuberculosis disproportionately affects women of childbearing age. The aim of this dissertation was to comprehensively investigate prevention and treatment strategies for perinatal and infant tuberculosis in a high HIV-prevalence setting. Research objectives included: 1) defining clinical and epidemiological aspects of maternal-infant tuberculosis at a large referral hospital; 2) identifying barriers and solutions to isoniazid preventive therapy (IPT) delivery in tuberculosis-exposed newborns; and 3) obtaining rigorous pharmacokinetic data to guide the dosing of firstline antituberculosis drugs in newborns and infants for the prevention and treatment of tuberculosis. In the first retrospective study, 70 newborns (42 HIV-exposed) were investigated for tuberculosis at Tygerberg Hospital, a large provincial referral hospital in Cape Town. Newborns were mainly screened for tuberculosis because of maternal tuberculosis. Isoniazid preventive therapy (IPT) was initiated in 36/50 (72%) newborns, because of maternal tuberculosis infectious risk and exposure of infants. Few of the newborns who received IPT were traceable at one-year, and of those traced, less than half completed IPT. To generate more rigorous clinical and epidemiological data on maternal-infant tuberculosis, a prospective cohort study was conducted in pregnant and postpartum women receiving tuberculosis treatment at Tygerberg Hospital. Over a one-year period, 74 pregnant and postpartum women, 53 (72%) HIV-infected, were consecutively enrolled. Nearly half of the women, 35 (47%) were diagnosed with tuberculosis only at delivery or postpartum, and a third of women with tuberculosis reported prior tuberculosis treatment. Tuberculosis-exposed newborns were often premature and of low birth weight (LBW; <2500 grams). All deaths occurred in HIVinfected women (n=5) and all stillbirths (n=4) and newborn deaths (n=6) were from HIV-infected women. Favourable maternal tuberculosis treatment outcomes (cure and tuberculosis treatment completion) were documented only in 41/74 (55%) women, while 33 (45%) had unfavourable treatment outcomes (death, treatment failure and loss to follow-up). These poor observed outcomes highlight the need for earlier diagnosis and treatment of tuberculosis during pregnancy, and close follow-up to ensure maternal tuberculosis treatment completion. Improved care for pregnant women with tuberculosis, with and without HIV infection, will likely reduce morbidity and mortality in mothers and tuberculosis-exposed newborns. Delayed maternal tuberculosis diagnosis led to IPT initiation in a large number of newborns. Forty-four newborns on IPT were followed to 6 months. A hospital-based tuberculosis linkage to care intervention, led to 29/44 (66%) newborns completing IPT without a study team intervention. A further 8 infants completed IPT after studyteam intervention. Appropriate tuberculosis referral and linkage to care from hospital to local tuberculosis clinic substantially improved IPT completion among tuberculosis-exposed newborns. More pharmacokinetic data regarding the appropriate use of antituberculosis drugs are required in neonates and infants, who undergo considerable physiological changes in the first year of life. An intensive isoniazid (INH) pharmacokinetic study was therefore designed and implemented in premature and LBW infants (n=20). Relatively high median INH peak concentrations of 5.63 μg/ml were achieved in LBW infants (at an INH dose of 10 mg/kg), compared to the adult proposed target value of > 3 μg/ml. INH exposures were higher with longer half-lives in smaller infants, and among genotypically determined N-acetyltransferase-2 (NAT2) slow acetylators, suggesting reduced clearance of INH. This first study of isoniazid use in LBW and premature neonates showed that the INH dose in premature and LBW infants should probably not exceed 10 mg/kg/day. The final study evaluated whether the revised higher 2009 World Health Organization (WHO)-recommended paediatric doses for rifampicin (RMP), INH, pyrazinamide (PZA) and ethambutol (EMB) achieved adequate drug concentrations in infants, compared to current adult pharmacokinetic target concentrations. All 39 infants enrolled achieved the minimum proposed adult target peak concentrations of > 3 μg/ml for INH at a mean dose of 12.8 mg/kg (10.3 - 15.4 mg/kg), and the minimum adult target of > 20 μg/ml for PZA at a mean dose of 33.3 mg/kg (28.5 – 38.5 mg/kg). RMP administered at mean dose of 15.4 mg/kg (10.1 - 20.5 mg/kg) resulted in very low RMP peak concentrations for both RMP formulations used during the study. None of the infants achieved the minimum proposed adult RMP target concentration of > 8 μg/ml. Given the findings of this study, higher doses of RMP in infants should be considered especially given emerging data from adult RMP doseescalation studies showing better efficacy at higher doses with limited toxicity for short-term use. For EMB, only 1 of 16 infants achieved the recommended adult target concentration of > 2 μg/ml when given at a mean dose of 20.2 mg/kg (15.4-24.1 mg/kg). EMB dose-dependent ocular toxicity however poses a concern regarding the recommendation of higher EMB doses in infants where vision testing is challenging. This is the largest pharmacokinetic study of first-line antituberculosis drugs performed in infants to date, which has generated valuable pharmacokinetic data to inform the effective and safe dosing of first-line antituberculosis drugs in infants. Pregnant women in settings with a high burden of tuberculosis and HIV and their infants face a considerable burden of tuberculosis disease in HIV-endemic settings. Maternal-infant tuberculosis care can be improved by health systems strengthening interventions. Data generated from pharmacokinetic studies of antituberculosis drugs in tuberculosis-exposed infants will inform much needed dosing guidelines of firstline antituberculosis drugs for newborns and infants, who have a high risk of tuberculosis and are prone to develop severe forms of tuberculosis.AFRIKAANSE OPSOMMING : Babas (<12 maande) van vroue met tuberkulose het ’n hoë risiko vir Mikobacterium tuberculosis (M. tuberculosis) blootstelling na geboorte, wat kan lei tot infeksie en die ontwikkeling van tuberkulose siekte. In gebiede met ’n hoë voorkoms van menslike immuungebrek virus (MIV) word vroue van kinderdraende ouderdom tot ’n groot mate aangetas deur tuberkulose. Die doel van hierdie verhandeling was om die voorkoming en behandelingstrategieë vir tuberkulose in die perinatale en baba tydperk omvattend te ondersoek binne die konteks van ‘n omgewing met ‘n hoë voorkoms van MIV. Navorsingsdoelwitte het die volgende ingesluit: 1) die definïering van kliniese en epidemiologiese aspekte van tuberkulose in moeders en babas by ’n groot verwysingshospitaal, 2) die identifisering van struikelblokke en oplossings vir die gebruik van isoniasied voorkomende behandeling in babas met blootstelling aan M. tuberculosis; en 3) die verkryging van betroubare farmakokinetiese data wat doseringsriglyne kan verskaf vir eerste-linie antituberkulose middels vir die voorkoming en behandeling van tuberkulose in pasgeborenes en babas. In die eerste studie is 70 pasgeborenes (waarvan 42 blootgestel was aan MIV) retrospektiewelik ondersoek vir tuberkulose by Tygerberg Hospitaal. Tygerberg Hospitaal is ‘n groot provinsiale verwysingshospitaal in Kaapstad. Pasgeborenes was hoofsaaklik vir tuberkulose ondersoek as gevolg van moederlike tuberkulose. Vanweë potensiële tuberkulose blootstelling aan pasgeborenes en die risiko dat tuberkulose moeders nog aansteeklik was, is isoniasied voorkomende behandeling gegee in 36/50 (72%) pasgeborenes. Min van die pasgeborenes wat isoniasied voorkomende behandeling ontvang het kon opgespoor word na een jaar, en minder as die helfte van die babas wat opgespoor is, het isoniasied voorkomende behandeling voltooi. ’n Prospektiewe kohortstudie is onderneem in swanger en postpartum vroue op behandeling vir tuberkulose by Tygerberg Hospitaal. Die doel van hierdie studie was om meer omvattende kliniese en epidemiologiese inligting te versamel in moeders met tuberkulose en hulle babas. Gedurende die verloop van een jaar is 74 swanger en postpartum vroue, 53 (72%) met MIV-infeksie, ingesluit in die studie. Ongeveer die helfte van die vroue, 35 (47%) was eers gediagnoseer met tuberkulose tydens verlossing of in die postpartum periode. ’n Derde van vroue met tuberkulose het ’n geskiedenis gehad van vorige tuberkulose behandeling. Tuberkulose-blootgestelde pasgeborenes was dikwels prematuur en/of gebore met ’n lae geboorte gewig (LGG; <2500 gram). Alle moederlike sterftegevalle het voorgekom in moeders met MIVinfeksie (n=5) en alle stilgeboortes (n=4) en babasterftes (n=6) was in babas van moeders met MIV-infeksie. Gunstige uitkomste van moederlike tuberkulose behandeling (genesing en voltooiïng van TB behandeling) was gedokumenteer in slegs 41/74 (55%) vroue, terwyl 33 (45%) ongunstige behandelingsuitkomste gehad het (sterfte, onsuksesvolle behandeling en verlore tydens opvolg). Hierdie ongunstige uitkomste beklemtoon die behoefte aan ‘n vroeër diagnose en behandeling van tuberkulose tydens swangerskap, asook noukeurige opvolg gedurende tuberkulose behandeling ten einde voltooiïng te verseker. Verbeterde sorg vir swanger vroue met tuberkulose, ongeag van MIV-infeksie, behoort die morbiditeit en mortaliteit in moeders en hulle tuberkulose-blootgestelde pasgeborenes te verminder. Die laat diagnose van moederlike tuberkulose tydens swangerskap het daartoe aanleiding gegee dat ‘n groot aantal pasgeborenes isoniasied voorkomende behandeling benodig het. Vier-en-veertig pasgeborens wat isoniasied voorkomende behandeling ontvang het, is vir ‘n tydperk van 6 maande opgevolg. ’n Hospitaal-gebaseerde strategie wat die koppeling van hospitaal na plaaslike TB klinieke ingesluit het, het aanleiding gegee tot die voltooiïng van isoniasied voorkomende behandeling in 29/44 (66%) pasgeborenes. Hierdie voltooiïng van isoniasied voorkomende behandeling is bewerkstellig sonder die ingryping van die studiespan. Na ingryping deur die studiespan het ‘n verdere 8 pasgeborenes isoniasied voorkomende behandeling voltooi. Toepaslike tuberkulose verwysing, wat die koppeling vanaf hospitaal na plaaslike TB klinieke verbeter het, het ‘n beduidende bydrae gelewer tot die voltooiïng van isoniasied voorkomende behandeling in pasgeborenes blootgestel aan M. tuberculosis. Verdere farmakokinetiese inligting word benodig vir effektiewe antituberkulose behandeling in pasgeborenes en babas wat aansienlike fisiologiese veranderinge in die eerste lewensjaar ondergaan. ’n Intensiewe isoniasied (INH) farmakokinetiese studie is beplan en uitgevoer in premature en LGG babas (n=20). LGG babas wat ‘n dosis van 10 mg/kg INH ontvang het, het relatiewe hoë mediane INH piek konsentrasies van 5.63 μg/ml bereik, in vergelyking met die die voorgestelde teiken waarde vir volwassenes van > 3 μg/ml. INH konsentrasies was hoër met ‘n langer half-leeftyd in kleiner babas, asook in genotipies-vasgestelde N-asetieltransferase-2 (NAT-2) stadige asetileerders, wat daarop aandui dat daar verminderde INH opruiming was. Hierdie eerste studie van isoniasied in LGG en premature pasgeborenes het aangedui dat die dosering van INH na alle waarskynlikheid nie 10 mg/kg/dag behoort te oorskry nie. Die finale studie het die gewysigde hoër 2009 Wêreld Gesondheidsheidsorganisasie (WGO)-aanbevole pediatriese doserings vir rifampisien (RMP), INH, pirasinamied (PZA) en etambutol (EMB) ondersoek, om te bevestig of voldoende geneesmiddelkonsentrasies in babas bereik word, in vergelyking met die huidige teikenkonsentrasies in volwassenes. Al 39 babas op die studie het die minimum voorgestelde volwasse teikenkonsentrasies van > 3 μg/ml vir INH bereik met die toediening van ‘n gemiddelde dosering van 12.8 mg/kg (10.3 - 15.4 mg/kg), en die minimum volwasse teikenkonsentrasie van > 20 μg/ml vir PZA met die toediening van ‘n gemidddelde dosering van 33.3 mg/kg (28.5 - 38.5 mg/kg). Rifampisien was toegedien teen ’n gemiddelde dosering van 15.4 mg/kg (10.1 - 20.5 mg/kg) en het baie lae RMP-konsentrasies tot gevolg gehad vir beide RMP formulerings wat in die studie gebruik is. Die voorgestelde volwasse RMP teikenkonsentrasie van > 8μg/ml is nie waargeneem in enige van die babas nie. Gegewe die bevindinge van hierdie studie behoort hoër doserings van RMP in babas oorweeg te word. Hoër RMP doserings is veral noodsaaklik in die lig van onlangse studies in volwassenes waar dit meer doeltreffend blyk te wees, en ook ‘n beperkte toksisiteit getoon het met korttermyn toediening. Vir EMB het slegs 1 uit 16 babas die vereiste aanbeveelde volwasse teiken konsentrasie van > 2 μg/ml bereik, met ‘n gemiddelde EMB toediening van 20.2 mg/kg (15.4 - 24.1 mg/kg). ‘n Dosis-afhanklike risiko vir oog-toksisiteit met EMB is rede tot kommer ingevolge die gebruik van hoër EMB dosisse in babas, aangesien die bepaling van sig moeilik is in babas. Hierdie is die grootste farmakokinetiese studie van eerste-linie antituberkulose geneesmiddels wat al in babas uitgevoer is en het waardevolle farmakokinetiese inligting verskaf wat bydra tot die effektiewe en veilige doserings van hierdie geneesmiddels in babas. Swanger vrouens, asook hulle babas, is baie vatbaar vir blootstelling aan M. tuberculosis infeksie en die ontwikkeling van tuberkulose in gebiede met ‘n hoë voorkoms van tuberkulose en HIV. Die sorg van moeders en babas met tuberkulose kan verbeter word deur die versterking van bestaande gesondheidssisteem strukture. Inligting verskaf van farmakokinetika studies in eerste-linie antituberkulose geneesmiddels wat in pasgeborenes en babas met tuberkulose gedoen word, sal help om die nodige doseringsriglyne te verskaf vir babas, wat n hoë risiko het vir die ontwikkeling van tuberkulose, insluitende ernstige vorms van tuberkulose

Acquired neonatal bronchial stenosis after selective intubation : successful managed with balloon dilatation

CITATION: Goussard, P., et al. 2019. Acquired neonatal bronchial stenosis after selective intubation : successful managed with balloon dilatation. Clinical Case Reports, 7(5):917-919, doi:10.1002/ccr3.2112.The original publication is available at https://onlinelibrary.wiley.comENGLISH ABSTRACT: Premature babies are prone to airway‐related complications. Selective intubation for the management of pulmonary interstitial emphysema may cause acquired bronchial stenosis. Balloon dilatation under fluoroscopy is a safe minimal invasive and successful intervention for acquired bronchial stenosis. Follow‐up bronchoscopy is needed due to risk of restenosis.https://onlinelibrary.wiley.com/doi/10.1002/ccr3.2112Publisher's versio

A retrospective analysis of pathogen profile, antimicrobial resistance and mortality in neonatal hospital-acquired bloodstream infections from 2009-2018 at Tygerberg Hospital, South Africa.

BackgroundAnalysis of hospital-acquired bloodstream infection (HA-BSI) trends is important to monitor emerging antimicrobial resistance (AMR) threats and guide empiric antibiotic choices.MethodsA retrospective 10-year review of neonatal HA-BSI was performed at Tygerberg Hospital's neonatal unit in Cape Town, South Africa. Neonatal clinical and laboratory data from 2014 to 2018 (Period 2) was compared with published data from 2009 to 2013 (Period 1).ResultsThe neonatal unit's HA-BSI rate declined between periods from 3.9/1000 inpatient-days in Period 1 to 3.3/1000 inpatient-days in Period 2 (p = 0.002). Pathogen yield and blood culture contamination rate were unchanged (11.0% to 10.4%, p = 0.233; 5.1% to 5.3%, p = 0.636 respectively). Gram-negative pathogens predominated (1047/1636; 64.0%); Klebsiella species, Staphylococcus aureus, Serratia marcescens, Enterococcus species and Acinetobacter baumannii were the most frequent pathogens. Extended spectrum beta-lactamase production was observed in 319/432 (73.8%) of Klebsiella species, methicillin resistance in 171/246 (69.5%) of Staphylococcus aureus and extensive drug resistance in 115/137 (83.9%) of Acinetobacter species (2009-2018). The crude mortality rate of neonatal HA-BSI episodes increased from Period 1 to Period 2 from 139/717 (19.4%) to 179/718 (24.9%) (p = 0.014), but HA-BSI attributable mortality remained unchanged (97/139 [69.8%] vs 118/179 [65.9%], p = 0.542). The in-vitro activity of piperacillin-tazobactam and amikacin declined during Period 2 (74.6% to 61.4%; pConclusionAlthough HA-BSI rates declined in the neonatal unit, antimicrobial resistance rates in BSI pathogens remained high. Continuous BSI surveillance is a valuable tool to detect changes in pathogen and AMR profiles and inform empiric antibiotic recommendations for neonatal units in resource-limited settings

Early versus late onset sepsis in neonates - Time to shift the paradigm?

BACKGROUND: Neonatal sepsis is traditionally classified as early-onset sepsis (EOS) and late-onset sepsis (LOS) disease categories. This paradigm was based on observed epidemiological data from high income settings. However, increasing availability of microbiology results from diverse settings challenges these assumptions, necessitating re-examination of neonatal sepsis classifications. OBJECTIVES: To review the literature describing the aetiology of EOS and LOS in hospitalised neonates with stratification of pathogen spectrum by low- (LIC), middle- (MIC) and high-income (HIC) country settings, to critically re-examine the continued appropriateness of the 'EOS vs LOS' sepsis paradigm in all settings. SOURCES: PubMed was searched for peer-reviewed English full-text articles published from inception up until August 8th, 2022. CONTENT: Studies often report on either EOS, or LOS, rather than both. We identified only 49 original articles reporting on pathogen distribution of both EOS and LOS in the same hospital setting. Clear differences in sepsis aetiology were shown between LIC-, MIC-, and HIC-settings, with increasing importance of K. pneumoniae and decreasing importance of Group B Streptococcus (GBS) in the first 72 hours of life in LIC and MIC. IMPLICATIONS: The concept of 'EOS vs LOS' may be less useful for predicting the pathogen spectrum of neonatal sepsis in LIC and MIC, but the paradigm has shaped reporting of neonatal sepsis, and our understanding. Future neonatal sepsis reporting should utilise STROBE-NI reporting guidelines and clearly describe timing of infection by day, and variation in pathogen spectrum across the neonatal period. Data identified in this review challenge the generalisability of the prevailing EOS/LOS paradigm in LIC and MIC

Tuberculosis disease during pregnancy and treatment outcomes in HIV-infected and uninfected women at a referral hospital in Cape Town

CITATION: Bekker, A., et al. 2016. Tuberculosis disease during pregnancy and treatment outcomes in HIV-infected and uninfected women at a referral hospital in Cape Town. PLoS ONE, 11(11):e0164249, doi:10.1371/journal.pone.0164249.The original publication is available at http://journals.plos.org/plosoneBackground: Tuberculosis during pregnancy and treatment outcomes are poorly defined in high prevalence tuberculosis and HIV settings. Methods: A prospective cohort study of pregnant and postpartum women identified to be routinely on antituberculosis treatment was conducted at Tygerberg Hospital, Cape Town, South Africa, from January 2011 through December 2011. Maternal tuberculosis disease spectrum and tuberculosis-exposed newborns were characterized by maternal HIV status. Maternal tuberculosis treatment outcomes were documented and a multivariable regression model identified predictors of unfavourable tuberculosis treatment outcomes. Infant outcomes were also described. Results: Seventy-four women with tuberculosis, 53 (72%) HIV-infected, were consecutively enrolled; 35 (47%) were diagnosed at delivery or postpartum and 22 (30%) of women reported previous antituberculosis treatment. HIV-infected women were 5.67 times more likely to have extrapulmonary tuberculosis (95% CI 1.18–27.25, p = 0.03). All 5 maternal deaths were amongst HIV-infected women. Birth outcomes were available for 75 newborns (2 sets of twins, missing data for 1 stillbirth). Of the 75 newborns, 49 (65%) were premature and 44 (59%) were low birth weight (LBW; <2500 grams). All 6 infants who died and the 4 stillbirths were born to HIV-infected women. Unfavourable tuberculosis treatment outcomes were documented in 33/74 (45%) women. Unfavourable maternal tuberculosis outcome was associated with delivery of LBW infants (OR 3.83; 95% CI 1.40–10.53, p = 0.009). Conclusions: A large number of pregnant women with tuberculosis presented at a provincial referral hospital. All maternal and infant deaths occurred in HIV-infected women and their newborns. Maternal tuberculosis treatment outcomes were poor.http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0164249Publisher's versio