Vanessa Clifford

Community-acquired neonatal and infant sepsis in developing countries: efficacy of WHO's currently recommended antibiotics—systematic review and meta-analysis

Objective To review the aetiology and antibiotic resistance patterns of community-acquired sepsis in developing countries in infants where no clear focus of infection is clinically identified. To estimate the likely efficacy of WHOs recommended treatment for infant sepsis. Design A systematic review of the literature describing the aetiology of community-acquired neonatal and infant sepsis in developing countries. Using meta-analytical methods, susceptibility was determined to the antibiotic combinations recommended by WHO: (1) benzylpenicillin/ampicillin and gentamicin, (2) chloramphenicol and benzylpenicillin, and (3) third-generation cephalosporins. Results 19 studies were identified from 13 countries, with over 4000 blood culture isolates. Among neonates, Staphylococcus aureus, Klebsiella spp. and Escherichia coli accounted for 55% (39–70%) of culture positive sepsis on weighted prevalence. In infants outside the neonatal period, the most prevalent pathogens were S aureus, E coli, Klebsiella spp., Streptococcus pneumoniae and Salmonella spp., which accounted for 59% (26–92%) of culture positive sepsis. For neonates, penicillin/gentamicin had comparable in vitro coverage to third-generation cephalosporins (57% vs 56%). In older infants (1–12 months), in vitro susceptibility to penicillin/gentamicin, chloramphenicol/penicillin and third-generation cephalosporins was 63%, 47% and 64%, respectively. Conclusions The high rate of community-acquired resistant sepsis—especially that caused by Klebsiella spp. and S aureus—is a serious global public health concern. In vitro susceptibility data suggest that third-generation cephalosporins are not more effective in treating sepsis than the currently recommended antibiotics, benzylpenicillin and gentamicin; however, with either regimen a significant proportion of bacteraemia is not covered. Revised recommendations for effective second-line antibiotics in neonatal and infant sepsis in developing countries are urgently needed.

Mycobacteria-Specific Cytokine Responses Detect Tuberculosis Infection and Distinguish Latent from Active Tuberculosis.

RATIONALE Current immunodiagnostic tests for tuberculosis (TB), including the tuberculin skin test and IFN-γ release assay (IGRA), have significant limitations, which include their inability to distinguish between latent TB infection (LTBI) and active TB, a distinction critical for clinical management. OBJECTIVES To identify mycobacteria-specific cytokine biomarkers that characterize TB infection, determine their diagnostic performance characteristics, and establish whether these biomarkers can distinguish between LTBI and active TB. METHODS A total of 149 children investigated for TB infection were recruited; all participants underwent a tuberculin skin test and QuantiFERON-TB Gold assay. In parallel, whole-blood assays using early secretory antigenic target-6, culture filtrate protein-10, and PPD as stimulatory antigens were undertaken, and cytokine responses were determined by xMAP multiplex assays. MEASUREMENTS AND MAIN RESULTS IFN-γ, interferon-inducible protein-10 (IP-10), tumor necrosis factor (TNF)-α, IL-1ra, IL-2, IL-13, and MIP-1β (macrophage inflammatory protein-1β) responses were significantly higher in LTBI and active TB cases than in TB-uninfected individuals, irrespective of the stimulant. Receiver operating characteristic analyses showed that IP-10, TNF-α, and IL-2 responses achieved high sensitivity and specificity for the distinction between TB-uninfected and TB-infected individuals. TNF-α, IL-1ra, and IL-10 responses had the greatest ability to distinguish between LTBI and active TB cases; the combinations of TNF-α/IL-1ra and TNF-α/IL-10 achieved correct classification of 95.5% and 100% of cases, respectively. CONCLUSIONS We identified several mycobacteria-specific cytokine biomarkers with the potential to be exploited for immunodiagnosis. Incorporation of these biomarkers into future immunodiagnostic assays for TB could result in substantial gains in sensitivity and allow the distinction between LTBI and active TB based on a blood test alone.

Ethanol lock therapy in pediatric hematology and oncology

Central venous catheters are essential for treatment of cancer and hematologic disorders in children. Central line‐associated bloodstream infection (CLABSI) is the most common important complication and can lead to serious sequelae. Conventional antibiotic treatment is often unsuccessful. Ethanol lock therapy (ELT) has been shown to prevent CLABSI in various patient groups and might also be beneficial as adjunctive treatment for active infection. Efficacy and safety have not been adequately studied in the pediatric hematology/oncology population. Catheter occlusion and intraluminal clots have been reported. Routine use of ELT should not be recommended in this population until more data are available. Pediatr Blood Cancer 2013; 60: 18–25.

Antimicrobial resistance in group B streptococcus: the Australian experience

Intrapartum chemoprophylaxis for pregnant group B streptococcus (GBS) carriers reduces vertical transmission, with a resultant decrease in neonatal as well as maternal morbidity from invasive GBS infection. Current Australian guidelines recommend penicillin for intrapartum prophylaxis of GBS carriers, with erythromycin or clindamycin for those with a β-lactam allergy. Recent reports globally suggest that resistance to erythromycin and clindamycin may be increasing; hence, a study was undertaken to promote an evidence base for local clinical guidelines. Samples collected for standardized susceptibility testing included 1160 invasive GBS isolates (264 isolates retrospectively from 1982 to 2001 and prospectively from 2002 to 2006, plus 896 prospectively collected colonizing GBS isolates gathered over a 12 month period from 2005 to 2006) from 16 laboratories around Australia. All isolates displaying phenotypic macrolide or lincosamide resistance were subsequently genotyped. No isolates showed reduced susceptibility to penicillin or vancomycin. Of the invasive isolates, 6.4 % demonstrated phenotypic erythromycin resistance and 4.2 % were clindamycin resistant. Of the erythromycin-resistant isolates, 53 % showed cross-resistance to clindamycin. Very similar results were found in colonizing specimens. There was no statistically significant change in macrolide-resistance rates over the two study periods 1982-2001 and 2002-2006. Genotyping for macrolide and lincosamide-resistant isolates was largely consistent with phenotype. These findings suggest that penicillin therapy remains an appropriate first-line antibiotic choice for intrapartum GBS chemoprophylaxis, with erythromycin and/or clindamycin resistance being low in the Australian population. It would, nevertheless, be appropriate for laboratories screening for GBS in obstetric patients to consider macrolide sensitivity testing, particularly for those with β-lactam allergy, to ensure appropriate chemoprophylaxis.

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.

Cytokines for monitoring anti-tuberculous therapy: A systematic review

The ability to monitor response to therapy for tuberculosis (TB) and confirm adequate treatment would be a major advance. The low reversion rate of interferon-gamma based assays means that they are unlikely to be useful for monitoring therapy. Several exploratory studies have evaluated the diagnostic potential of cytokine biomarkers other than interferon-gamma for monitoring anti-tuberculous therapy. A systematic review of these studies was performed to identify the most promising candidate biomarkers. TNF-α, IL-2, IL-6, IL-10 and IL-12 were the most extensively investigated cytokines. There was significant heterogeneity between studies in relation to study design and laboratory methodology, complicating direct comparisons. There was marked variation between studies in the observed changes during treatment for many of the biomarkers. Further longitudinal studies in sufficiently large patient cohorts with rigorous methodology are needed to determine the true potential of individual cytokine biomarkers, or combinations, for monitoring TB treatment.

Antibiotic prophylaxis in obstetric and gynaecological procedures: A review

Surgical site infections are a common complication of obstetric and gynaecological surgeries; up to 10% of gynaecological patients undergoing an operative procedure will develop a surgical site infection. In surgeries with high rates of post‐operative infection, antibiotic prophylaxis (using an antibiotic with an appropriate microbiological spectrum and administered in a timely manner) can play a major role in improving outcomes. This review examines the medical literature to assess the indications and appropriate antibiotic choices for prophylaxis to prevent surgical site infection in obstetric and gynaecological surgery. For some procedures, such as caesarean section, surgical termination of pregnancy and hysterectomy, antibiotic prophylaxis is clearly indicated. For other procedures, such as insertion of an intrauterine device, medical termination of pregnancy and laparoscopy, antibiotic prophylaxis is usually not required. For several other procedures where the evidence for antibiotic prophylaxis is unclear or inadequate, we discuss the current evidence for and against prophylaxis. Guidelines for infective endocarditic prophylaxis with surgery are also discussed.

Interferon gamma release assays for monitoring the response to treatment for tuberculosis: A systematic review.

INTRODUCTION The ability to monitor the response to therapy for tuberculosis (TB) and confirm adequate treatment would be a major advance. The utility of interferon gamma assays (IGRA) for this purpose remains uncertain. METHODS A systematic search of all studies investigating commercial IGRA to monitor anti-tuberculous treatment was done. Studies were included if they included an IGRA before the start of, and at least once during, treatment for active or latent TB. RESULTS We identified 30 studies, of which 24 used QuantiFERON-TB (QFT), three used T-SPOT.TB and three used both QFT and T-SPOT.TB. Most studies were done in low TB incidence countries. No uniform pattern was seen in IGRA conversion and reversion rates at the end of treatment for active or latent TB. In most studies, the majority of IGRA results remained positive at the end of treatment. In many studies, the quantitative levels of IFN-γ decreased during treatment, particularly in active TB. There was significant heterogeneity in the included studies. CONCLUSION While quantitative IGRA responses generally fall during treatment for TB, the large degree of variation in results between participants in each study means that IGRAs are unlikely to be useful for monitoring anti-tuberculous treatment in clinical practice for any individual patient.

Prevention of neonatal group B streptococcus disease in the 21st century

There have been significant reductions in early‐onset neonatal group B streptococcus (GBS) disease following implementation of maternal intrapartum antibiotic prophylaxis (IAP) policies. Nevertheless, GBS remains a leading cause of neonatal sepsis in Australia and New Zealand resulting in considerable morbidity and mortality, particularly among preterm infants. In the United States, the universal screening‐based approach for identifying women for IAP results in apparently lower rates of early‐onset neonatal GBS infection than risk‐based assessment. In addition, IAP has altered the profile of newborn infants who develop early‐onset disease. Many affected infants lack the typical intrapartum risk factors for GBS infection, are born to mothers with a negative GBS screen or represent missed opportunities for prevention. Clinicians should remain alert for signs of sepsis in any newborn infant. We provide an update of GBS preventative management strategies in the perinatal period taking into account recent United States, Australian and New Zealand guidelines.

The age-related risk of co-existing meningitis in children with urinary tract infection

Objective The primary aim of this study was to determine age-stratified rates of co-existing bacterial meningitis in children with urinary tract infection (UTI). The secondary aims of this study were to determine the causative pathogens of UTI, and the clinical features and outcome of children with co-existing meningitis. Methods Analysis of data collected over a nine-year period at a tertiary pediatric hospital in Australia. Study population: children below 16 years of age with culture-confirmed UTI and a paired CSF sample. Results A total of 748 episodes in 735 cases were included in the final analysis. The commonest pathogens causing UTI were Escherichia coli (67.4%), Enterococcus faecalis (8.4%), Klebsiella oxytoca (3.5%) and Klebsiella pneumoniae (3.5%). Only two (1.2%; 95% CI: 0.15–4.36%) of 163 neonates (between 0 and 28 days of age) with UTI had co-existing meningitis. Both presented with pyrexia, irritability and lethargy, and recovered uneventfully with antibiotic treatment. There were no cases of co-existing meningitis among 499 infants (between 29 days and 12 months of age) with UTI (95% CI: 0.00–0.74%), or any of the 86 children aged 12 months or over (95% CI: 0.00–4.20%). Conclusions These findings indicate that clinicians should have a low threshold to perform a lumbar puncture in neonates with UTI, as the risk of co-existing meningitis is not insignificant in this age group. In contrast, beyond the neonatal period, the risk is small and a more selective approach is warranted.