Antibiotic prescribing in children – top-tips

Fever in children is extremely common and results in over 50% of primary care activity in children under 5 years of age. Although parental anxiety about missing a serious infection is driving this increasing activity, the absolute risk of a child having a serious bacterial infection has markedly reduced since the introduction of conjugate vaccines against strep pneumo, HiB and meningococcus.

• It provides a proper ‘health-check’ and in their opinion, removes any ‘health-threat’
  • Parents lack confidence to distinguish self-limiting illnesses from serious ones but believe that clinicians can
• They want advice on what symptoms to look out for and when to seek help
• They do not generally seek antibiotics (although this is something that can be clarified during the consultation). Parents generally believe that Abs are required to treat ‘severe’ infections rather than to treat bacterial infections:
  • parents often believe that features suggesting a severe infection include high fever, prolonged duration of symptoms and degree of impact on the child (sleep / school)
  • Parents perception of susceptibility also plays a role in their expectation for Abs (younger, underlying health issues)

• Perceived vulnerability of children, especially young children.
• Seeking safety in the face of uncertainty (especially if re-presentation)
  • Uncertainty is driven by the difficulty in distinguishing bacterial and viral infections.
  • Perceived risk of suppurative complications from an untreated bacterial respiratory tract infection, especially in young children.
• Repercussions of ‘missing something’ in a child
  • The media are inclined to pick up on any cases where significant morbidity/death in a child that has resulted from a healthcare professional ‘missing’ a severe infection.
  • Staff with little experience of seeing unwell children are less confident at ruling out severe infection.

Young children have far lower rates of suppurative complications than older children, even when antibiotics are not prescribed: 

• Rate of mastoiditis following otitis media (age 0-4 years versus 5-15 years): 1.33 vs 2.39 per 10,000
• Rate of quinsy after tonsillitis (age 0-4 years versus 5-15 years): 1.59 vs 5.99 per 10,000

There is good evidence to show that addressing parental concerns during a consultation results in significant reductions in future reconsultation rates, as well as marked reductions in Ab prescribing (Francis NA, BMJ 2009):

• Focus on the reasons the parent sought a consultation (rather than the distinction between viral and bacterial infections).
• Reassure the family that although their child has an infection that is having an impact on their sleep/feeding, their symptoms are not indicative of a severe infection in terms of objective parameters / ‘red-flags’. Parents should also be provided with information about the likely duration of symptoms and advice on how to manage them.
• Most importantly, one must clearly explain the symptoms that parents should look out for and the actions required if they were to occur. All this information should ideally be provided both verbally and in writing - see Healthier Together safety netting sheet: http://www.what0-18.nhs.uk/health-professionals/primary-care-staff/safety-netting-parents/fever-children-less-5-years-age/

One of the major challenges facing clinicians is distinguishing whether a child presenting with an RTI has a bacterial or viral infection. It is often extremely difficult to make this decision clinically and there are few reliable diagnostic tests that can assist in a community based setting. This uncertainty often results in clinicians prescribing “just in case”. However, there is an increasing body of evidence to show that antibiotics to do not significantly reduce severity or duration of symptoms in the majority of children with RTIs, irrespective of the aetiology:

1. Acute otitis media (AOM)
   A systematic review of 13 RCTs (3401 children and 3938 AOM episodes) from high-income countries demonstrated that antibiotics have no early effect on pain, a slight effect on pain in the days following and only a modest effect on the number of children with tympanic perforations, contralateral otitis episodes and abnormal tympanometry findings at two to four weeks and at six to eight weeks compared with placebo. This suggests that in high-income countries, most cases of AOM spontaneously remit without complications (Venekamp, R. P. et al. Antibiotics for acute otitis media in children. The Cochrane database of systematic reviews, 2015.) Even in children with AOM under 2 years of age, there is evidence to suggest that antibiotics make very little difference to the severity of symptoms in the majority of children (Hoberman A et al. Treatment of acute otitis media in children under 2 years of age. N Engl J Med. 2011 Jan; 364(2):105-115)
2. Tonsillitis
   There are data to suggest that antibiotics have little or no impact in reducing the severity of symptoms in the majority of children with acute tonsillitis (Little P et al. Open randomised trial of prescribing strategies in managing sore throat. BMJ 1997). The study recruited children aged 4 years and over.
3. Lower respiratory tract infections (LRTIs)
   Antibiotics are not indicated in the majority of children presenting to primary care with a LRTI. In a randomised controlled trail recruiting children between 6 months and 12 years of age presenting with an acute uncomplicated LRTI (defined as an acute cough judged to be infective in origin, lasting <21 days), children were randomised to either an antibiotic arm (amoxicillin) or placebo for 7 days. Results - median durations of moderately bad or worse symptoms were similar between the groups (5 days [IQR 4-11] in the antibiotics group vs 6 days [4-15] in the placebo group; hazard ratio [HR] 1·13 [95% CI 0·90-1·42]). No differences were seen for the primary outcome between the treatment groups in the five prespecified clinical subgroups (patients with chest signs, fever, physician rating of unwell, sputum or chest rattle, and short of breath) (Little P et al. Antibiotics for lower respiratory tract infection in children presenting in primary care in England (ARTIC PC): a double-blind, randomised, placebo-controlled trial. Lancet 2021, 398(10309), 1417–1426.
   
   A clinical scoring system (STARWAVe tool) can be used to identify children at highest risk of requiring admission to hospital - in children presenting with acute RTI and cough, the following characteristics can be used to predict the likehood of hospitalisation in the following 30 days:

   Characteristics:

   ·       age <2 years

   ·       current asthma

   ·       illness duration of 3 days or less

   ·       parent-reported moderate or severe vomiting in the previous 24 h

   ·       parent-reported severe fever in the previous 24 h or a body temperature of 37·8°C or more at presentation

   ·       clinician-reported intercostal or subcostal recession

   ·       clinician-reported wheeze on auscultation

   If 0 or 1 characteristic, 3/1000 risk of hospitalisation in the following 30 days

   If 2 or 3 characteristics – 1.5% risk of future hospitalisation in the following 30 days

   If 4 or more characteristics – 12% risk of future hospitalisation in the following 30 days: monitor closely and consider if antibiotic treatment is required and/or discussion with local paediatrician.

Ensuring consistent prescribing approaches across the urgent care pathway is paramount – inconsistent approaches erodes parental confidence, drives parental anxiety and promotes health seeking behaviour. Consistent approaches for identifying children requiring Ab treatment for RTIs are being implemented across primary (SCAN) and secondary care (PIER) in Wessex

1. Acute otitis media (AOM)

Children over 2 years: only consider starting oral antibiotics if any of the following criteria are met in a child prresenting with AOM (bulging ear drum or discharge):

•  Symptoms not improving after 3 days
• Purulent discharge from ear canal (not due to otitis externa)
• Systemically unwell
• Has high risk of complications

Children aged 6 months-2 years, start antibiotics if any of the following:

• Bilateral AOM, or

• Purulent discharge from ear canal (otorhoea) not due to otitis externa

• Symptoms not improving after 3 days

Children under 6 months – start antibiotics if presumed AOM

2. Tonsillitis

Base decision to treat on FeverPAIN score (Fever, Purulence, Attend within 3 days of onset or less, severely Inflamed tonsils, No cough or coryza):

• score 0-1 = 18% streptococci: use no antibiotics
• score 2-3: 34-40% streptococci, use back up/delayed antibiotic
• score ≥4: 62-65% streptococci, use immediate Ab
• This score is validated in children aged 3 years and older. However, younger children are less likely to have a bacterial aetiology and are less likely to develop complications.

3. LRTIs

A  pragmatic approach is required, with consideration of antibiotics if persistent/recurrent fever over preceding 24-48 hours with chest wall recession and tachypnoea in the child presenting with likely pneumonia. Consider viral and non-infectious causes of cough. Use of the STARWAVe tool can help identify which children presenting with an acute RTI and cough are likely to require urgent referral to hospital.

Compliance with treatment re taste of oral antibiotic suspensions and frequency of dosing. Aim to use an antibiotic that is palatable and minimises dosing frequency in order to optimise adherence. Ideally, promote tablets over suspension and signpost families to guidance on pill swallowing. Penicillin V and flucloxacillin suspensions are not well tolerated by children due to their taste.

• Although there has been great anxiety about prescribing amoxicillin in patients with tonsillitis due to the risk of adverse events associated with EBV, there is emerging data to suggest that the use of amoxicillin does not significantly increase the risk of rash in acute EBV – see https://www.ncbi.nlm.nih.gov/pubmed/23589810 and https://adc.bmj.com/content/101/5/500 . In addition, data suggest that EBV accounts for as little as 1% of tonsillitis presenting to doctors - see https://www.ncbi.nlm.nih.gov/pubmed/17904463 and more importantly, EBV is extremely rare prior in children below 12 years of age. For this reason, the current recommendation is to use penicillin V bd tablets for children able to swallow tablets.
• For review of dosing frequency bd versus qds, see https://www.ncbi.nlm.nih.gov/pubmed/10654979

It is extremely difficult for a clinician to confidently distinguish a mild/moderate bacterial infection from a viral illness. Yet we remain obsessed about making this distinction. This partly stems from our firmly held belief that if a bacterial infection is not treated with antibiotics, the patient is likely to come to harm.

There is also a very real risk that focusing on whether an infection is caused by a bacteria or virus (and then trying to justify why a patient does not need antibiotics in terms of “it’s just a virus”) negatively impacts on the effectiveness of the consultation. Parents seek the advice of a healthcare professional because are worried that their child might be seriously unwell. The role of the clinician is to establish whether or not this is the case, and if not, to effectively convey their professional opinion to the family. Examining the patient thoroughly and checking physiological parameters (heart rate, respiratory rate, capillary refill) can help reassure the parent. Explaining your findings in terms of objective markers of severity (red, amber, green criteria) and providing the family with clear information about what to watch out for (safety netting) is also extremely effective in allaying parental anxiety.

Clinicians should adopt a severity of illness approach when deciding whether to prescribe antibiotics rather than relying on their ability to distinguish bacterial from viral infections. Not only is this likely to significantly reduce antibiotic prescribing, but an effective consultation that effectively addresses the concerns of the parent is far more likely to reassure them and to empower them in the long-term. Perhaps they will feel confident enough to not seek your input the next time their child has a fever?

Most children labelled with a penicillin allergy are not allergic to penicillin – there are lifelong implications of attaching a label of penicillin allergy in childhood in terms of likelihood of adverse infective outcomes and colonisation with resistant organisms:

• Features suggestive of a true penicillin allergy (type 1 hypersensitivity):
  • Timing post Ab (within 60 mins of first dose)
  • Symptoms: urticaria, angio-oedema, wheeze, anaphylaxis
• Penicillin allergy is not herediatary- true penicillin allergy rare in childhood

• Focus on clearer advice on when to prescribe and when not to
• Pragmatism versus purism:
  • If children require Abs, use a drug that is palatable (Baguley D et al. https://adc.bmj.com/content/97/3/293.long)
    • Amoxicillin suspension instead of pen V
    • Cefalexin suspension versus flucloxacillin suspension –research study being planned
  • If children require Abs, avoid qds dosing due to reduced adherence with therapy Falagas ME et al. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4283966/)
    • Amoxicillin 40mg/kg bd (max 1g/dose) – WHO dosing recommendation
    • Pen V tablets bd for older children with tonsillitis
    • Reduce duration of Ab course where possible
      • Tonsillitis treatment course 5 days, not 10 days
    • Prescribe adequate dosing 

• Meta-analysis comparing overall cure rates between BID or once-daily (QD) versus more frequent dosing schedules in the treatment of streptococcal tonsillopharyngitis (Lan AJ. The impact of dosing frequency on the efficacy of 10-day penicillin or amoxicillin therapy for streptococcal tonsillopharyngitis: A meta-analysis. Pediatrics. 2000 Feb;105(2)
• A study was eligible for inclusion if it was a randomized clinical trial that compared the efficacies of different dosing frequencies of 10-day penicillin or amoxicillin in the treatment of streptococcal tonsillopharyngitis (6 studies met eligibility criteria).
• Results: BID dosing of 10-day penicillin is as efficacious as TDS/QID dosing regimens in the treatment of streptococcal tonsillopharyngitis. This result also holds true in a subgroup analysis confined to pediatric cases. Similar findings with amoxicillin.

• Mantra about avoiding ampicillin in tonsillitis due to risk of EBV rash: 80-100% risk of rash reported
  • Risk of rash in children with confirmed EBV 29% with amoxicillin (23% in untreated children) - Chovel-Senna A et al. Incidence of Rash After Amoxicillin Treatment in Children With Infectious Mononucleosis. Pediatrics. 2013 May;131(5):e1424-7
  • EBV rare in children <12 years of age - Worrall GJ. Acute sore throat. Can Fam Physician. 2007 Nov; 53(11): 1961–1962
  • EBV accounts for as little as 1% of tonsillitis presenting to doctors - Hurt C et al. Diagnostic evaluation of mononucleosis-like illnesses. Am J Med. 2007 Oct;120(10):911.e1-8

• Mantra about avoiding ampicillin in tonsillitis due to risk of EBV rash: 80-100% risk of rash reported
  • Risk of rash in children with confirmed EBV 29% with amoxicillin (23% in untreated children) - Chovel-Senna A et al. Incidence of Rash After Amoxicillin Treatment in Children With Infectious Mononucleosis. Pediatrics. 2013 May;131(5):e1424-7
  • EBV rare in children <12 years of age - Worrall GJ. Acute sore throat. Can Fam Physician. 2007 Nov; 53(11): 1961–1962
  • EBV accounts for as little as 1% of tonsillitis presenting to doctors - Hurt C et al. Diagnostic evaluation of mononucleosis-like illnesses. Am J Med. 2007 Oct;120(10):911.e1-8

• 412 and 408 children 2-60 months of age with non-severe pneumonia received amoxicillin thrice or twice daily, respectively (Vilas-Boas AL at al; Comparison of oral amoxicillin given thrice or twice daily to children between 2 and 59 months old with non-severe pneumonia: a randomized controlled trial. J Antimicrob Chemother. 2014 Jul;69(7):1954-9)
• Treatment failure was detected in 94 (22.8%) and 94 (23.0%) patients in intention-to-treat analysis (risk difference 0.2%; 95% CI: -5.5%-6.0%) and in 80 (20.1%) and 85 (21.3%) patients in per-protocol analysis (risk difference 1.2%; 95% CI: -4.4%-6.8%).
• Pneumonia was radiologically confirmed in 277 (33.8%) cases, among whom treatment failure was registered in 25/133 (18.8%) and 27/144 (18.8%) participants from the thrice and twice daily doses subgroups, respectively (risk difference -0.05%; 95% CI: -9.3%-9.2%).

• Study comparing the clinical efficacy and side-effects of amoxycillin in two groups of children at the age of ≤ 6 years randomised to amoxycillin 40 mg/kg/day either two (n=180) or three times daily (n=187) for the clinical diagnosis of acute respiratory tract infections (>80% of cases in both groups had acute OM) - Valtonen M et al. Comparison of amoxycillin given two and three times a day in acute respiratory tract infections in children. Scand J Prim Health Care. 1986 Nov;4(4):201-4
• Results: 82% of the patients with otitis media were cured in bd group vs 86% in tds group. Equivalence in terms of disappearance of the symptoms/improvement of the signs. Rate of side-effects same in both groups, 6.4% and 6.7% respectively. 

• Thirty-four children with upper or lower respiratory tract infections were randomly allocated to receive either a twice daily or three times daily dose of amoxycillin 50 mg /kg/day - Fonseca W et al. Comparing Pharmacokinetics of Amoxicillin Given Twice or Three Times per Day to Children Older than 3 Months with Pneumonia. Antimicrob Agents Chemother. 2003 Mar; 47(3): 997–1001
• On day 1, 16 of 27 children in the b.i.d. group and 11 of 26 children in the t.i.d. group had concentrations that were above 2.0 μg/ml for <50% of the dose interval
• On day 3, 18 of 31 children in the b.i.d. group and 8 of 31 children in the t.i.d. group had concentrations that were above 2.0 μg/ml for <50% of the dose interval.
• Data supports dosing of 30-40mg/kg bd

• Three to six days of oral antibiotics has comparable efficacy compared to the standard duration 10-day course of oral penicillin in treating children with acute GABHS pharyngitis. These findings are not applicable to areas where the prevalence of rheumatic heart disease is still high - The effect of short duration versus standard duration antibiotic therapy for streptococcal throat infection in children, Cochrane Database of Systematic Reviews 2012

• Meta-analysis of randomized, controlled trials that involved bacteriological confirmation of GAS tonsillopharyngitis, random assignment to receive either azithromycin or a 10-day comparator antibiotic - Casey JR et al. Higher dosages of azithromycin are more effective in treatment of group A streptococcal tonsillopharyngitis. Clin Infect Dis 2005;40:1748-55
• In children, azithromycin administered at 60 mg/kg per course was superior to the 10-day courses of comparators (P < .00001), with bacterial failure occurring 5 times more often in patients receiving the 10-day courses of antibiotics.
• Azithromycin administered at 30 mg/kg per course was inferior to the 10-day courses of comparators (P = .02), with bacterial failure occurring 3 times more frequently in patients receiving azithromycin. Three-day regimens were inferior to 5-day regimens (P = .002).
• SCAN guidelines recommend 5 day course duration of macrolide (clarithromycin)

• RCT comparing cefalexin bd to dicloxacillin qds in adults with staph aureus skin infections (n=70) - Dillon HC Jr. Treatment of staphylococcal skin infections: a comparison of cephalexin and dicloxacillin. J Am Acad Dermatol. 1983 Feb;8(2):177-81
• Results – no difference in treatment failures pr recurrence. Conclude that twice-daily therapy with cephalexin for staphylococcal skin and skin structure infections can be recommended with confidence.

• Concerns that current BNFc dosing recommendations risk underdoing in children - Bielicki JA et al. Not too little, not too much: problems of selecting oral antibiotic dose for children. BMJ. 2015 Nov 3;351:h5447.
• Methods for selecting dose of oral antibiotics in childhood must balance simplicity with accuracy
• Although using exact weight is most accurate, it requires a recent weight and may not fit with fixed dose formulations
• Age bands result in a substantial proportion of children receiving doses outside the recommended range and are context specific
• National study currently ongoing looking at dosing of penicillins in children- Neonatal and Paediatric Pharmacokinetics of Antimicrobials Study (NAPPA study)
• Provision data (awaiting publication) demonstrates underdosing with current BNFc co-amoxiclav dosing recommendations.