COVID-19 vaccines and adverse events of special interest: A multinational Global Vaccine Data Network (GVDN) cohort study of 99 million vaccinated individuals.

BACKGROUND: The Global COVID Vaccine Safety (GCoVS) Project, established in 2021 under the multinational Global Vaccine Data Network™ (GVDN®), facilitates comprehensive assessment of vaccine safety. This study aimed to evaluate the risk of adverse events of special interest (AESI) following COVID-19 vaccination from 10 sites across eight countries. METHODS: Using a common protocol, this observational cohort study compared observed with expected rates of 13 selected AESI across neurological, haematological, and cardiac outcomes. Expected rates were obtained by participating sites using pre-COVID-19 vaccination healthcare data stratified by age and sex. Observed rates were reported from the same healthcare datasets since COVID-19 vaccination program rollout. AESI occurring up to 42 days following vaccination with mRNA (BNT162b2 and mRNA-1273) and adenovirus-vector (ChAdOx1) vaccines were included in the primary analysis. Risks were assessed using observed versus expected (OE) ratios with 95 % confidence intervals. Prioritised potential safety signals were those with lower bound of the 95 % confidence interval (LBCI) greater than 1.5. RESULTS: Participants included 99,068,901 vaccinated individuals. In total, 183,559,462 doses of BNT162b2, 36,178,442 doses of mRNA-1273, and 23,093,399 doses of ChAdOx1 were administered across participating sites in the study period. Risk periods following homologous vaccination schedules contributed 23,168,335 person-years of follow-up. OE ratios with LBCI > 1.5 were observed for Guillain-Barré syndrome (2.49, 95 % CI: 2.15, 2.87) and cerebral venous sinus thrombosis (3.23, 95 % CI: 2.51, 4.09) following the first dose of ChAdOx1 vaccine. Acute disseminated encephalomyelitis showed an OE ratio of 3.78 (95 % CI: 1.52, 7.78) following the first dose of mRNA-1273 vaccine. The OE ratios for myocarditis and pericarditis following BNT162b2, mRNA-1273, and ChAdOx1 were significantly increased with LBCIs > 1.5. CONCLUSION: This multi-country analysis confirmed pre-established safety signals for myocarditis, pericarditis, Guillain-Barré syndrome, and cerebral venous sinus thrombosis. Other potential safety signals that require further investigation were identified.

Background rates of adverse events of special interest for COVID-19 vaccines: A multinational Global Vaccine Data Network (GVDN) analysis.

BACKGROUND: The Global COVID Vaccine Safety (GCoVS) project was established in 2021 under the multinational Global Vaccine Data Network (GVDN) consortium to facilitate the rapid assessment of the safety of newly introduced vaccines. This study analyzed data from GVDN member sites on the background incidence rates of conditions designated as adverse events of special interest (AESI) for COVID-19 vaccine safety monitoring. METHODS: Eleven GVDN global sites obtained data from national or regional healthcare databases using standardized methods. Incident events of 13 pre-defined AESI were included for a pre-pandemic period (2015-19) and the first pandemic year (2020). Background incidence rates (IR) and 95% confidence intervals (CI) were calculated for inpatient and emergency department encounters, stratified by age and sex, and compared between pre-pandemic and pandemic periods using incidence rate ratios. RESULTS: An estimated 197 million people contributed 1,189,652,926 person-years of follow-up time. Among inpatients in the pre-pandemic period (2015-19), generalized seizures were the most common neurological AESI (IR ranged from 22.15 [95% CI 19.01-25.65] to 278.82 [278.20-279.44] per 100,000 person-years); acute disseminated encephalomyelitis was the least common (<0.5 per 100,000 person-years at most sites). Pulmonary embolism was the most common thrombotic event (IR 45.34 [95% CI 44.85-45.84] to 93.77 [95% CI 93.46-94.08] per 100,000 person-years). The IR of myocarditis ranged from 1.60 [(95% CI 1.45-1.76) to 7.76 (95% CI 7.46-8.08) per 100,000 person-years. The IR of several AESI varied by site, healthcare setting, age and sex. The IR of some AESI were notably different in 2020 compared to 2015-19. CONCLUSION: Background incidence of AESIs exhibited some variability across study sites and between pre-pandemic and pandemic periods. These findings will contribute to global vaccine safety surveillance and research.

Acute disseminated encephalomyelitis and routine childhood vaccinations - a self-controlled case series.

Acute disseminated encephalomyelitis (ADEM) is an autoimmune, central nervous system demyelinating disorder that follows antecedent immunologic challenges, such as infection or vaccination. This study aimed to investigate the potential association between routine childhood vaccinations and ADEM. Children under 7 years of age admitted to the two tertiary level pediatric hospitals in Victoria, Australia with ADEM from 2000-2015 had their clinical information linked to vaccination records from the Australian Childhood Immunization Register. Chart review was undertaken utilizing the Brighton Collaboration ADEM criteria. The self-controlled case-series (SCCS) methodology was employed to determine the relative incidences of ADEM post-vaccination in two risk intervals: 5-28 days and 2-42 days. Forty-six cases were eligible for SCCS analysis with a median age of 3.2 years. Of the forty-six cases, three were vaccine proximate cases and received vaccinations 23, 25 and 28 days before ADEM onset. Two vaccine proximate cases received their 4-year-old scheduled vaccinations (MMR and DTPa-IPV) and one vaccine proximate case the 1-year old scheduled vaccinations (MMR and Hib-MenC). The relative incidence of ADEM during the narrow and broad risk intervals were 1.041 (95% CI 0.323-3.356, p = 0.946) and 0.585 (95% CI 0.182-1.886, p = 0.370) respectively. Sensitivity analyses did not yield any substantial deviations. These results do not provide evidence of an association between vaccinations routinely provided to children aged under 7 years in Australia and the incidence of ADEM. However, these results should be interpreted with caution as the number of ADEM cases identified was limited and further research is warranted.

Phase I trial of RV3-BB rotavirus vaccine: a human neonatal rotavirus vaccine.

INTRODUCTION: RV3 is a human neonatal rotavirus strain (G3P[6]) that has been associated with asymptomatic neonatal infection and replicates well in the infant gut. RV3-BB rotavirus vaccine has been developed as a rotavirus vaccine candidate for administration at birth. METHODS: A single-centre, double-blind, randomised placebo-controlled Phase I study evaluated the safety and tolerability of a single oral dose of the second generation RV3-BB rotavirus vaccine (8.3×10(6)FFU/mL) in 20 adults, 20 children and 20 infants (10 vaccine and 10 placebo per age cohort). Vaccine take was defined as seroconversion (a 3-fold increase in serum anti-rotavirus IgA or serum neutralising antibody (SNA) from baseline at day 28 post-dose) or evidence of RV3-BB viral replication in the faeces by RT-PCR analysis 3-6 days post-vaccination. RV3-BB presence was confirmed by sequence analysis. RESULTS: The RV3-BB vaccine was well tolerated in all participants, with no pattern of adverse events shown to be associated with the study vaccine. In the infant cohort, vaccine take was demonstrated in 8/9 infants following a single dose of vaccine compared with 2/7 placebo recipients. In the infant vaccine group, 5/9 infants exhibited either IgA or SNA seroconversion and 7/9 infants had evidence of RV3-BB replication on days 3-6, compared with 2/7 infants who seroconverted and 0/10 infants with evidence of replication in the placebo group. Two infants in the placebo group had serological evidence of a rotavirus infection within the 28-day study period: one demonstrated an IgA and the other an SNA response, with wild-type virus replication detected in another infant. CONCLUSION: A single dose of RV3-BB rotavirus vaccine was well tolerated in adults, children and infants. Most infants (8/9) who received RV3-BB demonstrated vaccine take following a single dose. These data support progression of RV3-BB to Phase II immunogenicity and efficacy trials.

Nosocomial vs community-acquired pandemic influenza A (H1N1) 2009: a nested case-control study.

BACKGROUND: The characteristics of nosocomial influenza in children are not well described. AIM: To compare the characteristics of nosocomial and community-acquired pandemic influenza A (H1N1) 2009 (pH1N1) in Australian children. METHODS: In a nested case-control study, the clinical and epidemiological features of nosocomial vs community-acquired pH1N1 were compared among hospitalized children aged <15 years in six paediatric hospitals in Australia between 1 June and 30 September 2009. FINDINGS: Of 506 hospitalized children with pH1N1, 47 (9.3%) were of nosocomial origin. These 47 cases were compared with 141 gender- and age-matched controls. Cases had a significantly higher proportion of underlying medical conditions compared with controls (81% vs 42%, P < 0.001), and were more likely to be exposed to household smokers (36% vs 20%, P = 0.02). Fewer children with nosocomial influenza presented with classical symptoms of influenza, including subjective fever and lethargy. A higher proportion of children with nosocomial influenza received treatment with oseltamivir (77% vs 43%, P < 0.001), and they required a longer stay in hospital following the onset of influenza (mean 8.5 days vs 4.5 days, P = 0.006). Three children (2%) in the community-acquired group died of pH1N1, but there were no deaths in the nosocomial group. CONCLUSION: This study shows that children with pre-existing diseases and those who are exposed to household smokers are more susceptible to nosocomial pH1N1. They may have 'occult presentation' of influenza, but their course of illness is not markedly different from that of children with community-acquired influenza.

Australian immunisation registers: established foundations and opportunities for improvement.

The National Immunisation Program Schedule in Australia is formulated and funded nationally under the population-wide Medicare system. The policy is implemented by the eight state and territory jurisdictions. The national immunisation registers consist of the Australian Childhood Immunisation Register (ACIR), and, more recently, the National Human Papillomavirus (HPV) Vaccination Program Register. Moreover, a variety of jurisdiction-based registers and primary care practice software systems exist, which interact with the national registers. General practitioners can obtain reports listing patients under seven years attending their practice and recorded as 'not fully immunised', and immunisation coverage rates for their practice linked to government incentives through Medicare. A 2011 report documents national coverage of 91.8% fully immunised at 12 months, and 92.6% at 24 months. The HPV register provides information on vaccination coverage with the potential to link with a register of cervical cancer screening results. Limitations of current national register include inability to easily access immunisation histories beyond seven years of age, and issues of underreporting and timeliness, which impact significantly the immunisation coverage estimates. The linkage of these registers with healthcare outcome data will further enhance public health outcomes by enabling rapid, population-level vaccine safety and effectiveness investigations in a nation with a track record as an 'early adopter' of new childhood vaccines.

Intussusception following rotavirus vaccine administration: post-marketing surveillance in the National Immunization Program in Australia.

INTRODUCTION: In Australia, post-marketing surveillance for intussusception following vaccination commenced with funding of RotaTeq(®) and Rotarix(®) vaccines under the National Immunization Program (NIP) in July 2007. METHODS: Two active surveillance mechanisms (hospital-based case ascertainment and monthly reports from paediatricians) identified intussusception cases between 1st July 2007 and 31st December 2008 in four states. Linkage to vaccination records identified cases occurring within 1-7 and 1-21 days of rotavirus vaccination. Expected cases within the post-vaccination windows were calculated by applying rates of intussusception from national hospitalisation data over 6 years (mid-2000 to mid-2006), by age and state, to numbers vaccinated (by dose) according to the Australian Childhood Immunization Register. RESULTS: Combining exposure windows associated with all doses of rotavirus vaccine from 1 to 9 months of age, there was no evidence of an increased risk of intussusception following vaccination for either vaccine. However, in infants 1 to <3 months of age, there was suggestive evidence of excess intussusception cases 1-7 and 1-21 days following dose 1 (1-7 days: RotaTeq(®) relative risk (RR)=5.3, 95% confidence interval [CI] 1.1,15.4; Rotarix(®) RR 3.5, 95% CI 0.7,10.1; 1-21 days: RotaTeq(®) RR 3.5, 95% CI 1.3, 7.6; Rotarix(®)RR 1.5, 95% CI 0.4, 3.9). There was no evidence that clinical outcome of intussusception occurring within 21 days of rotavirus vaccination differed from that in cases occurring later post-vaccination. CONCLUSION: Although we found no overall increase in intussusception following receipt of rotavirus vaccine, there was some evidence of an elevated risk following the first dose of both vaccines. Larger population-based studies using linked databases are required to provide more definitive evidence.

Maternal antibodies to rotavirus: could they interfere with live rotavirus vaccines in developing countries?

INTRODUCTION: Past experience with live oral vaccines including licensed rotavirus vaccines demonstrates a trend towards reduced vaccine efficacy in developing countries compared with developed countries. The reasons behind this disparity are not well understood. Transplacental transfer of maternal antibodies and breast milk ingestion may attenuate vaccine responses in infants in developing countries where rotavirus infections are endemic, and maternal antibody levels are high. We examined the prevalence and level of rotavirus antibody in maternal and cord serum, colostrum and breast milk in a developing country setting. METHODS: 100 mother-infant pairs were prospectively recruited from December 2008 to February 2009 at Dr. Sardjito Hospital, Yogyakarta, Indonesia. Maternal and cord sera were collected during delivery. Colostrum and transitional breast milk were collected between day 0-3 and day 7-10 postpartum respectively. Rotavirus-specific IgA and IgG were estimated for all specimens and virus neutralization assays were conducted on a subset of milk specimens. RESULTS: All maternal and cord serum samples were positive for rotavirus-specific IgG antibodies with a strong correlation between levels of rotavirus-specific IgG in mothers and levels transferred to infants in cord blood (r=0.86; p=0.001). 78% of colostrum and 67% of transitional breast milk specimens were positive for rotavirus-specific IgA. There was a median 4-fold decrease in rotavirus-specific IgA from colostrum to transitional breast milk. Neutralizing antibodies were present in 56% of colostrum specimens assayed (19/34) and in 41% of transitional milk specimens assayed (14/34). CONCLUSIONS: Maternal serum and breast milk antibodies to rotavirus are highly prevalent in a developing country setting. Evaluation of the impact of maternal anti-rotavirus serum and breast milk antibody upon vaccine immunogenicity would help to inform rotavirus vaccination strategies, especially in developing settings.

Rotavirus within day care centres in Oxfordshire, UK: characterization of partial immunity.

Repeated measures data for rotavirus infection in children within 14 day care centres (DCCs) in the Oxfordshire area, UK, are used to explore aspects of rotavirus transmission and immunity. A biologically realistic model for the transmission of infection is presented as a set of probability models suitable for application to the data. Two transition events are modelled separately: incidence and recovery. The complexity of the underlying mechanistic model is reflected in the choice of the fixed variables in the probability models. Parameter estimation was carried out using a Bayesian Markov chain Monte Carlo method. We use the parameter estimates obtained to build a profile of the natural history of rotavirus reinfection in an individual child. We infer that rotavirus transmission in children in DCCs is dependent on the DCC prevalence, with symptomatic infection of longer duration, but no more infectious per day of infectious period, than asymptomatic infection. There was evidence that a recent previous infection reduces the risk of disease and, to a lesser extent, reinfection, but not duration of infection. The results provide evidence that partial immunity to rotavirus infection develops over several time scales.

Guidelines for the prevention of sepsis in asplenic and hyposplenic patients.

Asplenic or hyposplenic patients are at risk of fulminant sepsis. This entity has a mortality of up to 50%. The spectrum of causative organisms is evolving as are recommended preventive strategies, which include education, prophylactic and standby antibiotics, preventive immunizations, optimal antimalarial advice when visiting endemic countries and early management of animal bites. However, there is evidence that adherence to these strategies is poor. Consensus-updated guidelines have been developed to help Australian and New Zealand clinicians and patients in the prevention of sepsis in asplenic and hyposplenic patients.

Influenza in the neonatal intensive care unit.

Influenza has historically been an uncommon illness in the newborn period, although epidemic outbreaks in neonatal intensive care units have been described. There is currently significant concern about the possibility of a new pandemic of influenza in the near future. During a pandemic neonates are likely to be exposed, with significant illness more likely in pre-term newborns due to reduced levels of passively transferred protective maternal antibodies. While newer therapies have been shown to be effective in reducing the severity of illness in adults and children, such therapies are untried in neonates. Supportive care and measures to contain and prevent spread of infection may well be the most important measures in the event of a neonate acquiring influenza, including the avian variety.

Performance of a whole blood interferon gamma assay for detecting latent infection with Mycobacterium tuberculosis in children.

BACKGROUND: The diagnosis of latent Mycobacterium tuberculosis (MTB) infection with a tuberculin skin test (TST) in children is complicated by the potential influence of prior exposure to Bacille Calmette Geurin (BCG) vaccination or environmental mycobacteria. A whole blood assay has recently been developed to quantitatively measure interferon gamma (IFN-gamma) production by lymphocytes specific to the MTB antigens ESAT-6 and CFP-10, but its use and assessment in children has been limited. A study was undertaken to compare the performance of the whole blood IFN-gamma assay with the TST in diagnosing latent tuberculosis (TB) infection or TB disease in children in routine clinical practice. METHODS: One hundred and six children with a high risk of latent TB infection or TB disease were enrolled in the study. High risk was defined as contact with TB disease, clinical suspicion of TB disease, or recent arrival from an area of high TB prevalence. The whole blood IFN-gamma assay was undertaken in 101 children. RESULTS: Seventeen (17%) of the 101 assays yielded inconclusive results due to failure of positive or negative control assays. There was poor correlation between the whole blood IFN-gamma assay and the TST (kappa statistic 0.3) with 26 (70%) of the 37 children defined as latent TB infection by TST having a negative whole blood IFN-gamma assay. There were no instances of a positive whole blood IFN-gamma assay with a negative TST. Mitogen (positive) control IFN-gamma responses were significantly correlated with age (Spearman's coefficient = 0.53, p<0.001) and, in children with latent TB infection identified by TST, those with a positive IFN-gamma assay were older (median 12.9 v 6.92 years, respectively, p = 0.007). The whole blood IFN-gamma assay was positive in all nine children with TB disease. CONCLUSION: There was poor agreement between the whole blood IFN-gamma assay and TST for the diagnosis of latent TB. The whole blood IFN-gamma assay may have lower sensitivity than the TST in diagnosing TB infection in children. A significant proportion of whole blood IFN-gamma assays fail when used as a screening assay in routine practice.

Determining the rate of varicella vaccine rash in children with moderate-severe eczema.

OBJECTIVES: To determine the rate and severity of vesicular reactions following varicella vaccine in children with moderate-severe eczema. Secondary endpoints included the rates and severity of local reactions and eczema severity change within 42 days of vaccination. METHODS: Prospective open intervention pilot study of varicella vaccine in children aged 12 months to 13 years with moderate-severe eczema. Children were given varicella vaccine alone and followed for 42 days after vaccination. RESULTS: Fifty children, aged 12 months to 10.5 years were recruited, with complete follow-up for 48. A vesicular rash with a single lesion occurred in one child (2.1% (95% CI: 0, 11.1%)), 10 days following vaccination. Local reactions, including erythema, swelling and tenderness, were reported in eight children (16.7%). A flare-up of moderate-severe generalized eczema was reported in one child (2.1%) during the first week following varicella vaccine. CONCLUSIONS: Vesicular rash and local reactions following varicella vaccination were no more common or severe in children with moderate-severe eczema than that reported in the published literature in children without eczema. Eczema in the 42 days following vaccination did not appear to increase in severity.

Immunogenicity and safety of a low-dose diphtheria, tetanus and acellular pertussis combination vaccine with either inactivated or oral polio vaccine as a pre-school booster in UK children.

This open, randomised controlled trial studied the immunogenicity and reactogenicity of two combined low-dose diphtheria, tetanus and acellular pertussis vaccines (Td5aP-IPV, REPEVAX, Aventis Pasteur MSD; and Td5aP, COVAXIS, Aventis Pasteur MSD + OPV, GlaxoSmithKline) in comparison with a standard dose diphtheria pre-school booster vaccine (DT2aP-IPV, TETRAVAC, Aventis Pasteur MSD) in a population of 3.5-5-year-old children administered concomitantly with measles, mumps and rubella vaccine (M-M-R II, Aventis Pasteur MSD). A linked sub-study aimed to evaluate the immunogenicity and reactogenicity of Td5aP-IPV in a population of younger children, aged 3-3.5 years. This study demonstrated non-inferiority of seroprotection rates for diphtheria and tetanus for the study vaccines and comparable immunogenicity for pertussis and polio components of the vaccines. Reactogenicity was similar for all three vaccines. The study vaccines containing low-dose diphtheria antigen (Td5aP-IPV and Td5aP + OPV) are immunogenic and have acceptable reactogenicity for use as a pre-school booster vaccine administered concomitantly with MMR.

Comprehensive health assessment for newly arrived refugee children in Australia.

Providing appropriate and responsive care to refugees from diverse backgrounds and with unique health needs is challenging. Refugee children may present with a wide range of conditions, which may be unfamiliar to health professionals in developed countries. Additionally, refugees may experience unfamiliarity with the Australian health system and distrust of authority figures and/or medical practitioners. This article provides an overview of the priority areas in health and health management for paediatric refugee patients for paediatricians as well as other relevant health care providers caring for this group. Specific issues covered include general health assessment, infectious diseases, immunization, growth and nutrition, oral health, development and disability, mental health and child protection. Comprehensive health assessment can assist in identifying children at risk of poor health and to provide them with timely and effective care, advocacy and appropriate referral.

Varicella and paediatric staff: current practice and vaccine cost-effectiveness.

This study was undertaken to audit staff varicella policy for UK paediatric centres, and to estimate the cost-effectiveness of implementing a staff varicella vaccine policy. A telephone survey of 22 hospitals was performed to determine the policy regarding varicella immune status among healthcare workers (HCWs). All hospitals surveyed except one recorded immune status of informed HCWs, and had a policy of exclusion from work if they developed chickenpox. The total cost of vaccine implementation for nurses at the John Radcliffe Hospital neonatal unit over 5 years was estimated at 1601 pounds sterling versus 2474 pounds sterling for the estimated total cost of varicella exposure. Therefore it is likely that vaccination represents a cost-effective intervention.

Blood cultures in newborns and children: optimising an everyday test.

Effective use of blood cultures is a key component of the management of septic newborns and children. The technical and practical aspects of paediatric practice and the heightened susceptibility of children to infection because of immunological immaturity make automatic extrapolation of adult data difficult and potentially unfounded.

Vaccines against meningococcal disease: current and future technologies.

Development of the meningococcal serogroup C conjugate vaccine and its national implementation in the UK has been a major breakthrough in the prevention of meningococcal disease. New technologies are increasing the likelihood that research towards a vaccine against group B meningococcus will be successful. This review covers the recent development of vaccines against meningococcal disease and examines future vaccine candidates. The development of meningococcal polysaccharide vaccines was based on the virulence of the bacterial capsule components. The immunogenicity of these vaccines has been improved by covalent linkage to proteins in the new meningococcal C conjugate vaccines. However, the most promising developments for serogroup B disease have stemmed from other virulence determinants such as outer membrane proteins (OMPs) and lipopolysaccharides (LPS). New genome sequencing technology promises a way forward to developing a broadly cross-protective vaccine for this important pathogen.

Genetic population structure of coagulase-negative staphylococci associated with carriage and disease in preterm infants.

Coagulase-negative staphylococci (CoNS) are a leading cause of sepsis in the neonatal intensive care unit (NICU) setting. To evaluate the hypothesis that isolates of CoNS associated with disease belong to hypervirulent clones, as opposed to being drawn randomly from the neonatal unit carriage flora, we conducted a prospective, case-controlled study in a busy NICU. Using pulsed-field gel electrophoresis (PFGE), we compared the population structures of CoNS isolates associated with bacteremia with isolates from the skin of healthy and infected neonates and with blood culture contaminants. Endemic clones of CoNS were identified, but there was no difference in the distribution of the 6 species or 73 PFGE types between the carriage and disease isolate groups; this suggests that hypervirulent clones with an enhanced ability to cause disease were not present in this NICU setting.

Randomized, controlled trial comparing once daily and three times daily gentamicin in children with urinary tract infections.

OBJECTIVE: To undertake population pharmacokinetic modeling and to determine the safety and efficacy of once daily (OD) gentamicin dosing in children with severe urinary tract infections (UTI). METHODS: An open, randomized, controlled trial comparing OD with three times daily (TD) gentamicin dosing in hospitalized children ages 1 month to 12 years with UTI. Daily doses (milligrams per kg per day) of gentamicin in both groups were 7.5 (<5 years old), 6.0 (5 to 10 years old) and 4.5 (>10 years old). RESULTS: There were 179 children enrolled (90 OD, 89 TD). Baseline clinical characteristics and pathogens were similar, except that circulatory compromise and renal cortical scintigraphic defects were more common in the OD group. Median gentamicin treatment durations were 3.0 (OD) and 2.7 (TD) days. Mean peak gentamicin concentrations were 17.3 (OD) vs. 6.4 (TD) mg/l; 99% of peak concentrations were >7 mg/l in the OD group whereas 16% of peak concentrations were <5 mg/l in the TD group. Mean trough concentrations were 0.35 (OD) vs. 0.55 (TD) mg/l. In the OD group 4% of trough concentrations were > or = 2 mg/l, whereas in the TD group only 0.7% were > or = 2 mg/l. Age or prior elevated peak concentrations did not predict high trough concentrations. Population pharmacokinetic modeling of the data fitted a one-compartment model with first order elimination. There were no clinical or bacteriologic failures. The two disease-related complications were confined to the OD group. No nephro- or ototoxicity was identified. CONCLUSIONS: With age-appropriate dosing and measurement of serum trough concentrations before the second dose, OD gentamicin is safe and effective for the treatment of UTI requiring parenteral treatment in children aged 1 month to 12 years.