A descriptive study of vancomycin use at Red Cross War Memorial Children's Hospital, Cape Town.

Background: Antimicrobial stewardship principles guide the clinical use of antimicrobials, including vancomycin, but paediatric vancomycin prescribing practices have not been evaluated in South Africa. Objectives: To document the use, prescribing practices and monitoring of intravenous vancomycin and the spectrum of bacteria isolated on microbiological culture in children treated with intravenous vancomycin during a 12-month period at Red Cross War Memorial Children's Hospital (RCWMCH). Method: A retrospective audit of intravenous vancomycin use in children admitted to RCWMCH during 2019 was performed. Results: All 158 vancomycin prescription episodes for 143 children were included. Overall usage of intravenous vancomycin was 63 days of therapy per 1000 patient days (interquartile range [IQR]: 38-72). The median starting dose was 15 mg/kg per dose (IQR: 14-15) and median daily dose was 45 mg/kg per day (IQR: 43-60). Vancomycin was prescribed as empiric (127/158, 80%) and directed (31/158, 20%) treatment. The median duration of treatment for the directed group (7 days) was longer than the empiric group (4 days) (p = 0.001). Vancomycin serum trough concentrations were performed in 65/98 (66%) episodes where vancomycin treatment exceeded 3 days, with only 16/65 (25%) of these samples obtained before the fourth dose. Prolonged antibiotic treatment of 14 days or more was not associated with Gram-positive bacteria on culture (odds ratio [OR]: 1.02, 95% confidence interval [CI]: 0.17-4.2). Conclusion: Dosing errors, prolonged empiric treatment and inappropriate vancomycin monitoring were problems associated with vancomycin prescriptions. Contribution: The study identified multiple opportunities for improved vancomycin prescribing and monitoring. Further research and implementation of improved prescribing practices could contribute to the preservation of vancomycin as an effective antibiotic.

Candida bloodstream infection among children hospitalised in three public-sector hospitals in the Metro West region of Cape Town, South Africa.

BACKGROUND: Candida bloodstream infection (BSI) causes appreciable mortality in neonates and children. There are few studies describing the epidemiology of Candida BSI in children living in sub-Saharan Africa. METHODS: A retrospective descriptive study was conducted at three public sector hospitals in Cape Town, South Africa. Demographic and clinical details, antifungal management and patient outcome data were obtained by medical record review. Candida species distribution and antifungal susceptibility testing results were obtained from the National Health Laboratory Service database. RESULTS: Of the 97 Candida BSI episodes identified during a five-year period, 48/97 (49%) were Candida albicans (C. albicans), and 49/97 (51%) were non-C. albicans species. The overall incidence risk was 0.8 Candida BSI episodes per 1000 admissions at Red Cross War Memorial Children's Hospital. Of the 77/97 (79%) Candida BSI episodes with available clinical information, the median age (interquartile range) at the time of BSI was 7 (1-25) months, 36/77 (47%) were associated with moderate or severe underweight-for-age and vasopressor therapy was administered to 22/77 (29%) study participants. Most of the Candida BSI episodes were healthcare-associated infections, 63/77 (82%). Fluconazole resistance was documented among 17%, 0% and 0% of C. parapsilosis, C. tropicalis and C. albicans isolates, respectively. All Candida isolates tested were susceptible to amphotericin B and the echinocandins. The mortality rate within 30 days of Candida BSI diagnosis was 13/75 (17%). On multivariable analysis, factors associated with mortality within 30 days of Candida BSI diagnosis included vasopressor therapy requirement during Candida BSI, adjusted Odds ratio (aOR) 53 (95% confidence interval 2-1029); hepatic dysfunction, aOR 13 (95% CI 1-146); and concomitant bacterial BSI, aOR 10 (95% CI 2-60). CONCLUSION: The study adds to the limited number of studies describing paediatric Candida BSI in sub-Saharan Africa. Non-C. Albicans BSI episodes occurred more frequently than C. albicans episodes, and vasopressor therapy requirement, hepatic dysfunction and concomitant bacterial BSI were associated with an increase in 30-day mortality.

Descriptive analysis of infections due to New Delhi metallo-ß-lactamase-producing Enterobacterales in children at Red Cross War Memorial Children's Hospital.

The increased incidence and absence of antibiotic treatment options for New Delhi metallo-ß-lactamase (NDM)-producing carbapenem-resistant Enterobacterales (CRE) infection are concerning. Recent reports have highlighted NDM-producing Serratia marcescens, as a specific concern, as it is an organism which is intrinsically resistant to colistin. In this study, a descriptive analysis of NDM-producing CRE infections was performed at the Red Cross War Memorial Children's Hospital.

Balamuthia mandrillaris Granulomatous Amoebic Encephalitis: The First African Experience.

We report the first case of Balamuthia mandrillaris granulomatous amoebic encephalitis definitively acquired in Africa. Our case emphasizes initial nonspecific dermatological features, delays in confirmation of the diagnosis, difficulties accessing recommended medication, and uncertainty about optimal treatment of a disease with a frequently fatal outcome.

Xpert MTB/RIF Ultra and mycobacterial culture in routine clinical care at a paediatric hospital.

Background: Microbiological confirmation of pulmonary tuberculosis (PTB) in children is a well-documented challenge. This study evaluated Xpert Mycobacterium Tuberculosis (MTB)/Rifampicin (RIF) Ultra (Ultra) and mycobacterial cultures in routine clinical care at a tertiary paediatric hospital. Methods: Children treated for PTB and who had at least one respiratory specimen investigated by Ultra and mycobacterial culture before tuberculosis (TB) treatment was commenced were included. The findings of this retrospective study were summarised using descriptive and inferential statistics. Results: A total of 174 children were included. The median age was 2.5 years. Microcytic anaemia, airway compression, cavitary disease and miliary TB were significantly observed in children with microbiologically confirmed TB (cTB). Tuberculosis was microbiologically confirmed in 93 (53.4%) children. The positive yield from testing the first respiratory specimens was 68/174 (39.1%) on Ultra and 82/174 (47.1%) on combined Ultra and mycobacterial culture. In the subset of children (n = 70) tested with Ultra on two sequential respiratory specimens, the incremental yield from the second specimen was 30.3%. In the subset of children (n = 16) tested with Ultra on three sequential respiratory specimens, the incremental yield from the second and third specimens was 16.7% and 0.0%, respectively. When Ultra and mycobacterial culture results were combined, the incremental yield in children who had two sequential respiratory specimens tested was 24.4% and 3.1% on Ultra and mycobacterial culture, respectively. Conclusion: Ultra and mycobacterial culture on a single respiratory specimen resulted in a high microbiological yield. Ultra-testing on a second respiratory specimen increased the yield of microbiologically cTB. Additional diagnostic testing may require further study.

Current antimicrobial management of community-acquired pneumonia in HIV-infected children.

INTRODUCTION: Community-acquired pneumonia is a leading cause of morbidity and mortality amongst HIV-infected infants and children. Polymicrobial infection is common and, due to the difficulties in confirming the etiology of pneumonia, empiric broad-spectrum antimicrobial therapy is frequently used. AREAS COVERED: The author based this article on literature identified from PubMed. The author's search terms included: pneumonia, community-acquired pneumonia, HIV, children. The articles reviewed included original studies, recent review articles and current guidelines on the management of pneumonia in HIV-infected children. The microbiological etiology and the empiric and pathogen-specific antimicrobial therapy of community-acquired pneumonia in HIV-infected and HIV-exposed infants and children are also discussed. EXPERT OPINION: There are many changing epidemiological factors impacting antimicrobial management of community-acquired pneumonia in the context of HIV infection in infants and children. These include vaccination strategies, antimicrobial prophylaxis, emerging drug-resistant pathogens, and recognition of the importance of viruses and tuberculosis in the etiology of community-acquired pneumonia. Further research is needed on optimal amtimicrobial management strategies in HIV-exposed uninfected children, and HIV-infected children receiving antiretroviral therapy.

Effects of rifampin-based antituberculosis therapy on plasma efavirenz concentrations in children vary by CYP2B6 genotype.

OBJECTIVES: An efavirenz-based antiretroviral therapy (ART) regimen is preferred for children more than 3 years of age with tuberculosis. However, rifampin, a key component of antituberculosis therapy, induces CYP2B6. An increased dose of efavirenz is recommended in adults weighing more than 50 kg who require rifampin, but there is scant information in children being treated for tuberculosis. DESIGN: Plasma efavirenz concentrations were compared in 40 children during concomitant treatment for tuberculosis and HIV-1, after stopping rifampicin, and in a control group of children without tuberculosis. Associations with antituberculosis treatment, metabolizer genotype (based on CYP2B6 516G→T, 983T→C, and 15582C→T), weight, and time after dose were evaluated. RESULTS: Compared to children with extensive metabolizer genotypes, efavirenz concentrations were increased 1.42-fold (95% confidence interval, CI 0.94­2.15) and 2.85-fold (95% CI 1.80­4.52) in children with intermediate and slow metabolizer genotypes, respectively. Concomitant antituberculosis treatment increased efavirenz concentrations 1.49-fold (95% CI 1.10­2.01) in children with slow metabolizer genotypes, but did not affect efavirenz concentrations in extensive or intermediate metabolizer genotypes. After adjustment for dose/kg, each kilogram of weight was associated with a 2.8% (95% CI 0.9­4.7) decrease in efavirenz concentrations. Despite higher milligram per kilogram doses, a higher proportion of children in the lowest weight band (10­13.9 kg) had efavirenz concentrations less than 1.0 mg/l than larger children. CONCLUSION: Antituberculosis treatment was not associated with reduced efavirenz concentrations in children, which does not support increased efavirenz doses. Children with slow metabolizer genotype have increased efavirenz concentrations during antituberculosis treatment, likely due to isoniazid inhibiting enzymes involved in accessory metabolic pathways for efavirenz.

BCG Vaccination in HIV-Infected Children.

Despite the use of Bacillus Calmette-Guérin (BCG) vaccination for many years, infants and young children exposed to adults with infectious forms of tuberculosis (TB) are at high risk of developing complicated TB disease. This risk is much higher among HIV-infected children, and data on BCG protective efficacy in HIV-infected children is lacking. Recent research on BCG safety in HIV-infected infants has resulted in policy shifts, but implementation is challenging. New approaches to preventing TB among infants and children, particularly HIV-infected infants, are needed. This paper briefly reviews BCG safety and efficacy considerations in HIV-infected infants and discusses other approaches to preventing TB, including new TB vaccines and vaccination strategies.

Effect of rifampicin on efavirenz pharmacokinetics in HIV-infected children with tuberculosis.

SETTING: Rifampicin may reduce plasma efavirenz concentrations by inducing the expression of the cytochrome P450 2B6, which metabolizes efavirenz. However, there is no data in pediatric patient populations. METHODS: We measured plasma efavirenz concentrations in 15 children during and after rifampicin-based antitubercular treatment. They were receiving standard doses of efavirenz as part of antiretroviral treatment. Trough concentration (Cmin) was estimated by extrapolation of the log-linear concentration-time line to 24 hours after the previous dose. RESULTS: Wide interpatient variation and marked bimodality of efavirenz concentrations were observed. Efavirenz Cmin was not significantly different during vs. after antitubercular treatment (median 0.83 mg/L interquartile range 0.59-6.57 vs. median 0.86 mg/L interquartile range 0.61-3.56; P = 0.125). Nine (60%) and 8 (53%) children had subtherapeutic Cmin (<1 mg/L) during and after antitubercular treatment, respectively. CONCLUSIONS: Concomitant rifampicin-based antitubercular treatment was not an important determinant of efavirenz concentrations. The substantial proportion of participants with estimated Cmin <1 mg/L could result in the rapid emergence of efavirenz-resistant mutations and treatment failure.

Effect of rifampicin on lopinavir pharmacokinetics in HIV-infected children with tuberculosis.

OBJECTIVE: Rifampicin dramatically reduces plasma lopinavir concentrations (coformulated with ritonavir in a 4:1 ratio). A study in healthy adult volunteers showed that this reduction could be ameliorated if additional ritonavir is given. We evaluated the effect of additional ritonavir on plasma lopinavir concentrations in HIV-infected children receiving rifampicin-based treatment for tuberculosis. METHODS: We measured plasma lopinavir concentrations in 2 parallel groups receiving combination antiretroviral therapy that included lopinavir-ritonavir, with and without rifampicin-based antitubercular treatment. Additional ritonavir was given (lopinavir/ritonavir ratio of 1:1) during antitubercular treatment. Lopinavir concentrations were determined using liquid chromatography-tandem mass spectrometry. RESULTS: There were 15 children (aged 7 months to 3.9 years) in each group. Lopinavir pharmacokinetic measures (median [interquartile range]) for children with and without rifampicin, respectively, were maximum concentration (Cmax) of 10.5 [7.1 to 14.3] versus 14.2 [11.9 to 23.5] mg/L (P = 0.018), area under the curve from 0 to 12 hours (AUC0-12) of 80.9 [50.9 to 121.7] versus 117.8 [80.4 to 176.1] mg/h/L (P = 0.036), and trough concentration (Cmin) of 3.94 [2.26 to 7.66] versus 4.64 [2.32 to 10.40] mg/L (P = 0.468). Thirteen of 15 children receiving antitubercular treatment (87%) had a lopinavir Cmin greater than the recommended minimum therapeutic concentration (1 mg/L). CONCLUSIONS: The effect of rifampicin-based antitubercular treatment on lopinavir concentrations was attenuated by adding ritonavir to rifampicin. Although the median Cmax and AUC0-12 were lowered by 26% and 31%. respectively, the Cmin was greater than the minimum recommended concentration in most children.

High prevalence of subtherapeutic plasma concentrations of efavirenz in children.

OBJECTIVE: Efavirenz-containing regimens using concentration-controlled dosing have been shown to provide potent antiretroviral activity in children. In many settings, concentration-controlled dosing is not available. In this study, efavirenz plasma concentrations were evaluated in South African HIV-infected children receiving efavirenz-based antiretroviral treatment. METHODS: Three consecutive blood samples were drawn between 12 and 24 hours after dosing in 15 HIV-infected children receiving the recommended daily doses of efavirenz. Validated liquid chromatography tandem mass spectrometry methods were used to determine plasma levels of efavirenz. The trough concentration (Cmin) of efavirenz was estimated by extrapolation of the log-linear regression line of the 3 concentration versus time points to 24 hours. RESULTS: The estimated Cmin was <1 mg/L in 6 (40%) of the children. Three of the 5 children with detectable viral loads had low efavirenz concentrations. Marked bimodality in efavirenz concentrations was observed. CONCLUSIONS: Our findings, together with those of previous studies, indicate that many children dosed according to the current guidelines do not achieve adequate efavirenz exposure. Because low efavirenz concentrations are associated with the rapid emergence of efavirenz-resistant mutations and treatment failure, the current recommended efavirenz doses should be re-evaluated, especially in developing countries, where therapeutic drug monitoring is seldom available.

Progressive multifocal leukoencephalopathy after initiation of highly active antiretroviral therapy in a child with advanced human immunodeficiency virus infection: a case of immune reconstitution inflammatory syndrome.

Five weeks after commencing highly active antiretroviral therapy, a 12-year-old boy with advanced human immunodeficiency virus infection presented with acute cerebellar dysfunction and hemiparesis. Progressive multifocal leukoencephalopathy was diagnosed by cerebrospinal fluid polymerase chain reaction for JC virus and magnetic resonance imaging of the brain. Rapid and sustained improvement followed a prolonged course of glucocorticosteroid therapy while continuing antiretrovirals.