Journal Club 2016

Post-discharge antibiotic treatment of complicated pneumonia

Shah S, Srivastava R, Wu S, et al. Intravenous versus oral antibiotics for postdischarge treatment of complicated pneumonia. Pediatrics 2016; 138 (6): e20161692.

Background:

Complicated community associated pneumonia (pneumonia with effusion or empyema) may be treated with or without drainage. Following initial intravenous antibiotics, treatment may be continued orally or intravenously. A multicentre retrospective US study of 2123 children without comorbidities aged ≥2 months and <18 years compared treatment failure in children who post-discharge received antibiotics orally or through a peripherally inserted central catheter (PICC) for a median of 14 days.

Main findings:

Treatment failures occurred in 3.2% of PICC and 2.6% of oral recipients. The 281 PICC patients (13.2% of the total) had higher rates of surgical drainage, intensive care admission and positive cultures, suggesting they were sicker. After matching for severity, however, the treatment failure rate for PICC did not differ significantly from oral (odds ratio, OR = 1.26, 95% CI 0.54 to 2.94). PICC complications, mainly thrombosis causing malfunction, occurred in 20 (7.1%). Adverse drug reactions occurred in 0.6% overall, far more commonly in PICC recipients (OR = 19.1, 95% CI 4.2 to 87.3). Pathogens were identified in 305 (14.4%), mostly Streptococcus pneumoniae (175), Staphylococcus aureus (77, of which 56 were MRSA) and Streptococcus pyogenes (21). Pleural drainage was performed in 43.9%. Culture-negative children discharged on oral antibiotics failed 1.4% with amoxicillin and 1.9% with anti-MRSA antibiotics.

Take home message and interpretation:

Within methodological limitations, this large study suggests discharge on oral antibiotics is safer and as effective as using a PICC.

Submitted by: David Isaacs and Phil Britton, Children’s Hospital at Westmead

Effect of Maternal Influenza Vaccination on Hospitalization for Respiratory Infections in Newborns

Regan AK1, de Klerk N, Moore HC, Omer SB, Shellam G, Effler PV.
Pediatr Infect Dis J. 2016 Oct;35(10):1097-103.

Background:

Influenza infection is associated with over 1 million episodes of severe respiratory illness in children with an estimated mortality of 28,000 to 111,500 deaths per year globally. Infants less than 6 months of age are more susceptible to severe influenza infection with higher mortality rates. Current influenza vaccines are not licensed for use in infants younger than 6 months old and hence influenza vaccination during pregnancy has been recommended to protect the newborns from the infection. The goal of the study was to evaluate for the effectiveness of maternal influenza vaccination on preventing hospitalizations for acute respiratory illness among infants less than 6 months.

Main findings:

A retrospective cohort study was done in Western Australia with influenza endemic seasons. A population-based cohort of 31,028 mothers and singleton infants were included in the analysis. Admissions of infants below 6 months old with a principal or secondary diagnosis consistent with severe respiratory illness during the 2012 and 2013 influenza seasons were included in the analysis using a state-wide hospital discharge database. An infant was defined to be “maternally vaccinated” if the mother had a record of receiving the influenza vaccine ≥14 days before delivery. A cox proportional hazard model was used to compare the risk of hospitalization in maternally vaccinated and unvaccinated infants. 3169 (10.2%) of the infants were born to vaccinated mothers and there was a total of 732 hospitalizations for acute respiratory illness. 21.9 hospitalizations per 100,000 person days were identified among infants born to vaccinated mothers and 30.2 hospitalizations per 100,000 person days were identified among infants born to unvaccinated mothers. Maternally vaccinated infants were 25% less likely to be hospitalized as compared to unvaccinated infants when adjustment was made for other factors which include maternal age, socioeconomic status, maternal asthma and smoking, the infant’s indigenous status, smoking during pregnancy, parity and week of birth [adjusted hazard ratio: 0.75, 95% CI: 0.56–0.99, P = 0.04]. When the mothers were vaccinated in the third trimester, these infants had 33% reduction in the risk of hospitalizations during the influenza season as compared to unvaccinated infants [adjusted hazard ratio: 0.67, 95% confidence interval: 0.47–0.95, P = 0.03]. There was, however no significant difference in the rate of admission of maternally vaccinated infants versus unvaccinated infants during non-influenza seasons.

Implications for practice:

Although it is possible that a proportion of the admissions for severe respiratory illness were not due to influenza infection, this study shows significant reduction in the hospitalization for severe respiratory illness of maternally vaccinated infants. Despite the potential benefits of influenza immunizations during pregnancy, some studies indicate poor influenza vaccination rate during pregnancy in Australia, United States and other parts of the world. This study provides additional basis for recommending influenza vaccination to pregnant women living in the influenza endemic areas during the third trimester, in addition to studies similar to Zaman et al (NEJM 2008) and Madhi et al (NEJM 2014). More studies will be required to evaluate for the possible side effects and psychosocial receptiveness of influenza vaccination in order to further convince the pregnant women and the obstetricians regarding the benefits of influenza vaccinations in the third trimester.

Submitted by: Kai-Qian Kam, KK Women’s and Children’s Hospital, Singapore

Reducing Mortality from Paediatric Septic Shock with a Quality Improvement Initiative

Lane RD, Funai T, Reeder R, Larsen GY. High Reliability Pediatric Septic Shock Quality Improvement Initiative and Decreasing Mortality. Pediatrics 2016; September 7: e20154153 [Epub ahead of print].

Supplemental Information

Background and study outline:

Sepsis and septic shock remain significant contributors to paediatric morbidity, mortality and healthcare costs. Fluid administration, antibiotic selection / timing and laboratory evaluation are inconsistent. As such, emergency departments worldwide are increasingly using standardised sepsis management pathways for adults and children.

This is a single centre, US paediatric ED study from a department with 41,000 presentations annually, of which <0.5% are due to septic shock. Between February 2007and December 2014, a quality improvement initiative concentrating on the recognition and treatment of paediatric sepsis was implemented using a standardised screening algorithm. A positive screen initiated movement of the patient to a treatment room, medical review within 10 – 15 minutes and a standard set of observations. Hypotension or poor perfusion initiated the septic shock pathway including notification of an intravenous team and pharmacist (to assist with antibiotic ordering and delivery), minimum requirements for monitoring and laboratory investigations and guidance on the commencement of vasopressors in the setting of fluid-refractory shock.

Patients presenting with sepsis were identified retrospectively with their charts assessed by a system improvement analyst for compliance with process measures [timely receipt of antibiotics (initially within 3 hours, but this was reduced to one hour in 2012) and intravenous fluids for the rapid reversal of perfusion abnormalities]. Outcome measures included mortality, PICU admission and hospital length of stay (LOS).

Main findings:

On average ≤ 5 children screened positive for sepsis each day. 1380 children and adolescents were treated for septic shock; 93% met screening criteria at triage. The screening algorithm was shown to have a high sensitivity for the diagnosis of septic shock (97% in 2013 and 100% in 2014, respectively) with a negative predictive value of 100%. Positive predictive values were 24% and 15% in the same time periods.

Timely antibiotic and intravenous fluid administration improved from 73% to 84%. Medical review within 10-15 minutes after a positive screen averaged 55% in the first two years and increased to 84% in the last two years.

Amongst patients who received pathway compliant care, 1.2% (13 patients) died compared with 4.2% (11 patients) of those who did not (P < .001). Pathway non-compliance and altered mental status were the only two variables independently associated with an increased risk of death. PICU admission and hospital LOS were unaffected by pathway-compliant care. No deaths were attributed to program interventions.

Take home message and interpretation:

This study confirms that standardised management pathways for paediatric sepsis can lead to improvements in septic shock recognition and care in the emergency department and can be associated with reduced mortality without over-burdening hospital resources.

Briony Hazelton & Asha Bowen, Princess Margaret Hospital for Children, Perth, October 2016.

Two very contrasting papers: one looking at reducing narrow spectrum antibiotic (amoxicillin) use in a population at high risk of bacterial sepsis (children with severe acute malnutrition in Africa) because of concerns about cost and antimicrobial resistance; the other promoting the use of a broad spectrum antibiotic (azithromycin) to reduce inconvenience suffered by children with wheezy episodes in the USA.

Isanaka, S. et al. Routine Amoxicillin for uncomplicated severe acute malnutrition in children. New England Journal of Medicine 2016;374(5):444-453.

Background and study outline:

Children with severe acute malnutrition who were being managed as outpatients in Niger were randomized to get either amoxicillin or placebo. Unlike previous studies, it was conducted in an area with low HIV rates (only 1 out of 2412 randomised was HIV positive).

Main findings:

There was no significant difference in the proportion of children with nutritional recovery between the groups (about 65% recovered in both), but those on amoxicillin had faster early weight gain, recovered slightly quicker (28 vs 30 days), were less likely to get transferred to inpatient care, and had less diarrhoea at 1 week.

Take home message and interpretation:

The paper's discussion more or less argues against the routine use of antibiotics in severe acute malnutrition in areas with low rates of HIV and kwashiorkor, despite the modest benefits it describes from amoxicillin, because of the cost and potential antimicrobial resistance implications. It would be interesting to compare how many perfectly well children with URTIs are given amoxicillin (achieving nothing) with the number of children with severe acute malnutrition whose amoxicillin may prevent them from being admitted to hospital – and ask where the antimicrobial stewardship efforts would be most sensibly pursued. It is important to bear in mind the previous studies which still make the case for routine antibiotics in settings with high rates of HIV and kwashiorkor (eg 2013 NEJM paper which found significant benefit in terms of reducing treatment failure and mortality in Malawi).

Bacharier L.B. et al. Early administration of azithromycin and prevention of severe lower respiratory tract illnesses in preschool children with a history of such illnesses. A randomized clinical trial. JAMA 2015;314(19):2034-2044.

Background and study outline:

This well-designed and well-conducted RCT found that early administration of big doses of azithromycin (60mg/kg over 5 days) significantly reduced the risk of children going on to get severe LRTI. Sounds amazing. But the devil is in the detail.

Preschool children were enrolled on the basis of a history of recurrent severe wheezing - severe defined as a wheeze that resulted in a prednisone prescription or an 'unscheduled' visit to a doctor. How terrible. Kids on asthma preventers or who had been in hospital more than once were excluded. Those enrolled were randomised and provided with azithromycin or placebo, which the parents were to start when the child started getting symptoms of a respiratory tract infection - a runny nose I guess.

Main findings:

The primary outcome, the number of treated respiratory tract infections that didn't progress to becoming severe LRTIs, needs to be taken in the context of the definition used for severe LRTI, which was entirely dictated by parent/guardian report of any of the following: symptoms that were worse than mild after a burst of 3 lots of albuterol, needing albuterol more often than q4h, moderate-severe cough or wheeze 5 days after starting study medicine.

Based on this (novel) definition of severe LRTI, the absolute risk of progressing with the first respiratory tract infection was 0.05 in the azithromycin group and 0.08 in the placebo group, hazard ratio for the azithromycin group 0.64 (95% CI 0.41-0.98, p=0.04). Over the period of nearly 4 years, only 11/600 participants (fewer than 2%) were ever admitted to hospital in the context of a treated episode of respiratory tract infection (5 from azithromycin group, 6 from placebo group). There were no deaths.

Take home message and interpretation:

There are some more complicated statistical analyses, and some acknowledgement that azithromycin resistant organisms did emerge in the nasopharynx of treated children. But the take home message is that "azithromycin started at the earliest signs of a respiratory tract infection was effective in significantly reducing the risk of experiencing progression to severe LRTI". The authors state that "prevention of severe LRTIs is a highly desirable outcome" but I wonder, with that definition of severe LRTI, and in a cohort of children who were virtually never even admitted to hospital, what harms are we actually trying to prevent here? And whatever it is, is it worth throwing azithromycin at every kid with runny nose and a history of wheeze?

Submitted by: Joshua Francis, Royal Darwin Hospital, Darwin, September 2016

Nonsteroidal Anti-Inflammatory Drug without Antibiotics for Acute Viral Infection Increases the Empyema Risk in Children: A Matched Case-Control Study

Le Bourgeois M, Ferroni A, Leruez-Ville M, Varon E, Thumerelle C, Bremont F, et al, on behalf of the Children, Antibiotics, Nonsteroidal Anti-inflammatory Drugs and Childhood Empyema (ChANCE) Study Group. Nonsteroidal Anti-Inflammatory Drug without Antibiotics for Acute Viral Infection Increases the Empyema Risk in Children: A Matched Case-Control Study. Journal of Pediatrics 2016;175:47-53.

Background and study outline:

The rate of paediatric pleural empyema continues to increase worldwide despite the introduction of PCV 7 and a concomitant decrease in invasive pneumococcal disease and uncomplicated pneumococcal pneumonia. The impact of PCV13 on the incidence of paediatric empyema in Australia is soon to be examined.

In the meantime, studies from France and the UK have found an association between the use of NSAIDs for viral illnesses and subsequent development of severe bacterial infections, including empyema. The initial studies were retrospective and had the major flaw of being unable to determine whether NSAID use preceded or followed the development of empyema. More recent studies are prospective but lack details regarding consumption of NSAIDs.

The strengths of this most recent paper are that it is a multi-centre, matched case-control study where cases and controls were drawn from the same source population of children with acute viral infections. A gap of at least 24 hours of apyrexia was required between recovering from viral symptoms and the diagnosis of empyema in a case to exclude the possibility that NSAIDs were being used to treat the symptoms of an existing empyema. Detailed and standardised records were kept of daily use of all medications – antibiotics, glucocorticoids, NSAIDs and paracetamol in both cases and controls. Immunisation status and microbiology results were collected as well.

Main findings:

The cases and controls were well-matched including for PCV7 vaccination and fever at viral (mostly URTI) onset. There were no significant differences in types of virus in cases or controls. S.pneumoniae accounted for 86% of cases of empyema and was almost entirely non-PCV7 strains. Medication use within 72 hours of onset of acute viral infection was considered – NSAIDs or paracetamol at least 1 day, antibiotics at least 6 days. Multivariate analysis demonstrated an increased risk of empyema associated with NSAID exposure. This risk was increased when coupled with antibiotic use for less than 6 consecutive days. There was no association with paracetamol use.

Take home message and interpretation:

This study provides strong support for an increased risk of empyema for children with acute viral infection exposed to NSAIDs. Existing literature supports a broader association between NSAIDs and other bacteria (S.pyogenes, Fusobacterium necrophorum) and infections (retropharyngeal abscess, necrotising fasciitis). This risk is highest when NSAIDs are used without concomitant antibiotics. It is possible that the observed increase in empyemas represents, at least in part, an unintended consequence of recommendations to prescribe symptomatic relief rather than antibiotics in children presenting in the community with viral illnesses. The agent chosen for symptom relief may be important in that no association has been shown when paracetamol is used. Guidelines for management of viral URTI produced by French health authorities now warn against the use of NSAIDs but no such warnings are given in Australia. Advising caution in the use of NSAIDs is a potentially powerful public health tool to help reduce the risk of empyema following viral RTI in Australian children.

Submitted by: Celia Cooper, Women's and Children's Hospital, Adelaide, August 2016

Intestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children

Korpela K, Salonen A, Virta LJ, Kekkonen RA, Forslund K, Bork P, de Vos WM. Intestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children. Nat Commun. 2016 Jan 26;7:10410. doi: 10.1038/ncomms10410. (full text readily accessible via Pubmed)

Background and study outline:

Most human microbiome studies of immediate and longer-term health outcomes are small, largely performed in adults, and cross-sectional, so causal inferences cannot be made. Antibiotics reduce the diversity of the enteric microbiome and increase antibiotic resistance in resident microflora. Antibiotic use in early life has been associated with later obesity, inflammatory bowel disease and asthma. Although animal models implicate changes to the microbiome, there are important differences in microflora, diet and metabolism between mice and humans. Early life antibiotics may be especially important, as may the effects of different antibiotic classes on the microbiome.

In Finland, there are national linked data on all prescriptions dispensed, including all antibiotics. In this relatively large, longitudinal study of Finnish children aged 2-7 years attending day care, the authors linked these antibiotic prescription data to the results of microbiome analysis (largely 16S PCR, with metagenomics in a minority) on faecal samples obtained once (n=27) or twice (n=115, seven months apart). A control group were children who had not received antibiotics in the preceding 2 years and who had received <1 antibiotic prescription prior to this period.

Main findings:

Most children received either a penicillin or a macrolide, largely for ‘respiratory infection’ and the analysis was restricted to these antibiotic classes. Macrolide - and to a much lesser extent penicillin - exposure was associated with significant shifts in faecal microbiota composition and metabolism, and an increase in the prevalence of macrolide resistant commensals. Changes to the microbiota persisted for 7 months but largely resolved by 12-24 months. There was limited evidence for an effect of lifetime cumulative antibiotic exposure on microbiota composition, although the study wasn’t designed to assess this specifically.

In a much smaller sub-group analysis, there was some evidence of an association between macrolide exposure, a distinct microbiota composition, and asthma and obesity. However these analyses were not adjusted for possible confounders, such as probiotic use (participants were drawn from a probiotic trial), nor for respiratory infections, and other allergic disease (for the asthma outcome), maternal BMI and weight gain in pregnancy, birth weight and postnatal weight gain (for the obesity outcome).

Take-home message and interpretation:

This study provides evidence that macrolide use in early life is associated with compositional changes to the faecal microbiome. It is larger than many previous studies and sampling occurred at two time points in most participants. Careful consideration of confounders and other determinants would aid interpretation of possible causation. It is unclear how informative analysis of the faeces is regarding the effects of more proximal gut microbiome; are we trying to understand the workings of the internal combustion engine by looking at the oily residue on the garage floor?

Submitted by: Dave Burgner, Department of Infection and Immunity, Monash Children’s Hospital, July 2016

Procalcitonin as a Marker of Bacteremia in Children With Acute Lymphoblastic Leukemia and Fever

Vyles D et al. Pediatr Emerg Care. 2016; 373: [Epub ahead of print]

Background

In children with acute lymphoplastic leukemia (ALL) who present with fever, it is difficult to identify those with bacteraemia. Procalcitonin (PCT) is a potential serum biomarker to help identify bacterial infection and therefore help avoid unnecessary antibiotics and hospitalization. This study retrospectively reviewed inflammatory marker results of children with ALL and fever to compare the performance of each as biomarkers of significant bacteraemia.

Main findings

Over a 3-year period, 492 children had 735 visits to the emergency department with ALL and fever. Inflammatory makers and blood cultures (BC) were obtained at each visit. After exclusion of possible contaminants, 76 (10.3%) BC were positive. The area under the receiver operating characteristic curves (AUC ROC) for each marker was:

  • 0.73 (95% CI, 0.66-0.79) for PCT
  • 0.69 (95% CI, 0.53-0.82) for ESR
  • 0.62 (95% CI, 0.46-0.80) for CRP
  • 0.57 (95% CI, 0.48-0.65) for WBC

There was a significant difference in mean PCT level between patients with a positive BC compared with those with a negative BC (6 ng/ml vs 0.8 ng/ml; p < 0.0001). When logistic regression was used, only PCT was significantly associated with a positive BC. In relation to a positive BC, PCT with a cut-off of 0.5 had a sensitivity of 0.59, a specificity of 0.75, a positive predictive value (PPV) of 0.21 and negative predictive value (NPV) of 0.94.

Take home message:

This study evaluates the value of PCT in children with ALL and fever in a large sample size. Its limitations, aside from its retrospective design, include the fact that not all of the other inflammatory markers were obtained at each visit. In summary, PCT was superior to ESR, CRP and WBC in predicting bacteraemia in children with ALL and fever. Although significantly associated with positive BC results, the sensitivity and specificity of PCT in this setting is only moderate. Despite the relatively high NPV, the key question is whether it is safe to withhold antibiotics when the PCT is <0.5 thus, as claimed by the authors, helping to reduce unnecessary use of antibiotics and decrease hospital stay.

Submitted by: Dr Petra Zimmermann and Prof Nigel Curtis, Royal Children’s Hospital Melbourne, 20 June 2016.

Pebody RG. et al. Uptake and impact of vaccinating school age children against influenza during a season with circulation of drifted influenza A and B strains, England, 2014/15.

euro surveillance. 2015;20(39)pii=30029

Background

Questions remain as to best age groups to target with influenza vaccine to achieve both direct and indirect protection.

The UK started a phased roll out of LAIV to children in the 2013/4 season. This report is from the second (2014/5) season where LAIV was offered to all healthy 2-4 yr olds and, in an expanded number of pilot areas, to 4-11 yr olds, and in a few areas to 11-13 yr olds; total target population approx 700,000 school children.

Main findings

Vaccinating primary school age children resulted in significant reductions in cumulative incidence/ laboratory confirmed positivity in the targeted age group in pilot compared with non- pilot areas for GP ILI consultations (94% reduction, p=0.018); ED respiratory attendances (-74%, p=0.035); confirmed influenza hospital admissions (-93%, p=0.012); with non-significant reductions in GP swabbing positivity (-75%, p=0.213) and confirmed influenza ICU admissions (-76%, p=0.271).

Indirect but non-significant effects were seen on the same indicators in under 5s in the primary school vaccinated areas and to a lesser degree in the older unvaccinated group (>17yrs). The size of some of these effects may have been helped by the primary school pilot areas having a higher rate of preschooler vaccination (44.1%) cf. secondary school areas (35.1%)

Significant reduction in respiratory excess mortality was observed in primary school pilot vs non-pilot areas, but no reduction in excess all cause mortality.

Overall no such differences in influenza indicators were observed in areas where only 11-13 yr olds were vaccinated, but vaccination of all secondary school years has not yet been explored.

This was a moderately intense season with early circulation of A(H3N2) followed by B, both with drifted strains from vaccine strains. Most pilot areas used school based delivery and achieved >50% uptake, cf 30% when pharmacy-delivered.

Take home messages

Vaccination of primary school children, in addition to preschoolers, with LAIV offers potential for significant direct and some indirect protection: interruption of population transmission of influenza has been previously modeled to occur at uptake rates in children over 30%, a level that seems readily achievable in these pilot studies if school based delivery is employed. It is likely that a nasal spray vaccine is more acceptable to children than an injectable vaccine. This UK report also demonstrated LAIV effectiveness even when drifted A and B strains were circulating. Neither Australia nor New Zealand currently have this vaccine and we should follow this UK roll out with interest as it may guide best implementation.

Submitted by: Liz Wilson, Starship Childrens Hospital, May 2016


Detection of Bacteriuria by Canine Olfaction

Maurer M et. al. Open Forum Infectious Diseases, Advance Access Published March 8, 2016

Background: The development of novel methods of early detection of urinary tract infections (UTIs) in unprocessed clinical specimens could lead to more rapid determination of an infected state and initiation of appropriate treatment. These developments are particularly pertinent given the prevalence of UTIs, their clinical impact and the growing problem of antimicrobial resistance.

Main findings: Based on the established use of canine olfactory sense in fields such as drug-detection, in combination with the oft-observed canine habit of urine sniffing, this novel double-blinded case-control study examined the feasibility of training a panel of 5 labrador and golden retrievers to distinguish fresh urine samples culture-positive for >100,000 cfu/ml of bacteria from culture-negative control samples. After an 8 week training period, the dogs were able to detect urine samples positive for E. coli with a sensitivity of 99.6% and a specificity of 91.5%. Similar accuracy was observed with urine samples which were culture positive for Enterococcus (sens. 100%, spec. 93.9%), Klebsiella (sens. 100%, spec. 95.1%) and Staphylococcus aureus (sens. 100%, spec. 96.3%). For all five dogs, the sensitivity range was 99-100% and specificity ranged from 90.1 to 94.7%.

Take home message: Whether this specific analytical technique proves to have any practical use in clinical microbiology laboratories in the future remains to be seen. However, it raises the interesting possibility of using trained dogs for the early detection of infections in those patients who may be slow to present for medical evaluation eg the chronically ill, disabled and elderly. Furthermore, it represents a fascinating in vivo application of the same theoretical concept underlying in silico analysis of unprocessed clinical samples (e.g. urine, csf, breath etc.). This utilises chromatographic-mass spectrometric techniques which are presently in commercial development and are anticipated to become available in the coming years.

Submitted by: Tom Allen and Clare Nourse, Lady Cilento Children’s Hospital, Brisbane, 14 April 2016

Maternal immunization earlier in pregnancy maximises antibody transfer and expected infant seropositivity against pertussis

Eberhardt CS et al Clinical Infectious Diseases April 2016;62:829

Background: Acellular pertussis (Tdap) vaccination during pregnancy is one of the most effective public health interventions for preventing pertussis infection in infants < 3 months of age. The optimal timing of vaccination is unclear and there remains limited safety data on the use of this vaccine during pregnancy. In Switzerland, health authorities recommend maternal vaccination in the second or third trimester as compared to Australia and New Zealand where it is recommended from 28 weeks gestation. This prospective non-randomised observational cohort study compared anti-pertussis antibodies in infants delivered at term of women vaccinated in the second trimester, with those vaccinated later. Geometric mean concentrations of infant cord blood antibodies against pertussis toxin (PT) and filamentous hemagglutinin (FHA) were measured and assessed for the non-inferiority of second trimester immunisation vs third trimester immunisation.

Main Findings: The study enrolled 335 women, 213 (64%) were immunised during the third trimester and 122 (36%) during the second trimester. Both anti-PT and anti-FHA were signficantly higher in the infants whose mothers had been vaccinated in the second trimester. Almost a third of women immunised in the third trimester received their vaccine <15 days before delivery and their infants had low anti-pertussis antibody levels, similar to a control group whose mothers were unimunised.

Take home message: This study demonstrates that early immunisation with Tdap in the second trimester produces higher antibody concentrations in the infant and suggests that the gestational age-range recommended for vaccination should be broadened. There is no established correlate of protection for pertussis but earlier vaccination during pregnancy may equate to higher antibody levels in infants. It is still unclear if this would lead to better protection for those infants.

Submitted by: Tony Walls, Christchurch Hospital, 14 March 2016

In defense of doxycycline - for how long must the son bear the sins of the father?

Cross R, Ling C, Day NP, McGready R, Paris DH. Revisiting doxycycline in pregnancy and early childhood - time to rebuild its reputation? Expert Opin Drug Saf. 2016 Jan 25:1-16.

Background: If doxycycline were active only against the endosymbiont Wolbachia, and not a wide range of infections from malaria to MRSA, it would still be a cool drug. It is a pity then that the world’s coolest doctors, Paediatric Infectious Diseases physicians, have been largely prevented from using doxycycline for younger children by a widely-propagated belief that all members of the tetracycline drug class are teratogenic, affect bone growth and cause dental staining. Nested in this paper is a valuable systematic review considering the safety profile of doxycycline in children and pregnant women, and comparing it with tetracycline.

Main findings: The review considers teratogenicity, adverse bone and dental effects of the tetracyclines as a class. While tetracycline teratogenicity has been established, there is no evidence of human teratogenicity due to doxycycline. Of 2005 doxycycline-exposed pregnancies captured in large studies, major congenital anomalies were not more common than in controls. Likewise, for irreversible dental staining and bone growth retardation there are no data implicating doxycycline, and a number of smaller studies show no increased incidence. Doxycycline has important biochemical differences from its parent drug tetracycline. In animal studies, teratogenicity was only seen at doses >17 times the human therapeutic dose in mice and rabbits, and not at all in rats and monkeys at up to 100 times the human dose.

Take home messages: It is unfortunate that this paper is too long, includes a distracting review of doxycycline indications, and an unnecessary discursive ‘expert opinion’ epilogue. The central review argues that the case for avoiding use of doxycycline in young children, based on an unproven ‘tetracycline class effect’, is weak and circumstantial at best. A case in defense of doxycycline needs to be made to enable the prospective evaluation and optimisation of its wider paediatric use, especially for indications where it is the drug of choice.

Submitted by: Josh Osowicki, British Columbia Children’s Hospital, 24 February 2016

Antibody responses after primary immunisation in infants born to women receiving a pertussis containing vaccine during pregnancy: single arm observational study with historical comparator

Ladhani SN, Andrews NJ, Southern J et al. Clin Infect Dis 2015 61 (11) 1637-1644

Background: Antenatal immunisation programs against pertussis have been effective in preventing early infant disease and deaths. However, concerns have been raised regarding the possible interference of high maternally-derived antibody concentrations to infants’ vaccine responses. This study assessed whether antenatal pertussis immunisation adversely affected vaccine response following 2-3-4 month immunisation infants in the UK from October 2012 when antenatal pertussis immunisation (TdaP/IPV) was introduced.

Study design: Pertussis (pertussis toxin - PT, filamentous haemaglutinin - FHA, fimbriae 2 and 3 - FIMs), diphtheria, tetanus, Haemophilus influenzae B (Hib), meningococcal C (MCC) and 13-valent pneumococcal vaccine (PCV13) serotypes antibody concentrations were collected pre- and post-immunisation in infants up until 5 months of age. Antibody responses were compared against a historical cohort of infants born to mothers not vaccinated during pregnancy.

Main findings: Infants of TdaP/IPV vaccinated mothers had high PT, FHA and FIMs antibody levels pre-immunisation, however only PT antibodies increased post immunisation by a ratio of 2.64 (95% CI 2.12 -3.30). FHA antibody levels were lower post-immunisation (fold-change 0.56; 95% CI 0.48-0.65). There was a non-significant trend to lower FIMs antibody levels post immunisation (fold change 0.82; 95% CI 0.59-1.13). Compared with historical controls, PT (fold change 0.67; 95% CI 0.58-0.77), FHA (fold change 0.62; 95% CI 0.54-0.71) and FIMs antibodies (fold change 0.51; 95% CI 0.42-0.62) were all lower post vaccination. Antibody concentrations to Hib and tetanus were higher, whilst concentrations to diphtheria and some CRM (diphtheria toxin)-conjugated antigens were lower post-immunisation when compared to historical controls. Antibody concentrations to MCC were dependent on the type of MCC vaccine.

Take home messages
Antenatal pertussis immunisation resulted in high infant pre-immunisation antibody levels but impaired subsequent responses to routine pertussis immunisations and some CRM-conjugated vaccines. Despite this, the majority of infants achieved protective thresholds for conjugate vaccines after primary immunization.

There are currently no correlates of protection against pertussis, hence monitoring disease rates in infants born to mothers who were immunised antenatally is vital.

Submitted by: Julie Huynh and Brendan McMullan, Sydney Children’s Hospital, 9 February 2016