Oral or IV antibiotics?

Cite this article as:
Alison Boast. Oral or IV antibiotics?, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.24974

There are many self-perpetuating myths when it comes to antibiotic use in children. A few that seem intuitive, and come up almost daily, include the idea that intravenous antibiotics are ‘better’, that children require lower doses than adults, and ‘longer is better’ when it comes to treatment duration.

A few key concepts can be helpful to understand why certain routes and doses of antibiotics are required:

  • Pharmacokinetics: the effect of the body on the drug – how the body absorbs, distributes, metabolizes and excretes the antibiotic
  • Pharmacodynamics: the effect of the drug on the body – how the antibiotic effects bacteria in the body 
  • Bioavailability: the amount of the antibiotic which is effectively absorbed when given orally and reaches the bloodstream

Here are some points to consider next time you need to chart antibiotics for a child.

 

When are intravenous antibiotics absolutely required?

  1. Speed – if there is a life (think sepsis, meningitis) or limb-threatening (eg. necrotising fasciitis) intravenous antibiotics are required as they reach peak plasma levels in seconds/minutes, rather than hours
  2. Absorption – for children with poor or unreliable oral absorption (eg. inflammatory bowel disease, short gut) intravenous antibiotics will likely be required
  3. Neonates – in general neonates are considered to have poor oral absorption, therefore antibiotics are usually given intravenously
  4. No oral options – in some cases there may be no oral option available; this is particularly relevant for highly resistant organisms such as extended-spectrum beta-lactamase producing organisms
  5. High dose – if a very high dose of an antibiotic is required the volume of liquid required for a child to consume may be excessive, in these cases intravenous antibiotics may be required
  6. Nil per os – in children who are not able to take any oral medications (eg. bowel obstruction) intravenous antibiotics may be required; remember insertion of a nasogastric tube and NG medications may be an option particularly for younger children
  7. Worsening infection on oral antibiotics – this one can be a little tricky as factors such as wrong dose (antibiotics are commonly under-dosed in the community), wrong antibiotic, and poor compliance need to be considered, but sometimes children may require admission for intravenous antibiotics

 

When can you change to oral antibiotics?

There are four general principles guiding the change from intravenous to oral antibiotics (McMullen et al.)

  • Clinical condition – note that fever alone does not need to prevent switch
  • Ability to absorb oral antibiotics
  • Availability of an appropriate oral antibiotic
  • Practical issues

The above reference gives a thorough discussion on the evidence of when to switch to oral antibiotics for a range of common paediatric infections (skin and soft tissue, urinary tract infections etc).

 

What are other factors need to be taken into account?

Bioavailability – some drugs have excellent oral absorption, therefore there it is almost criminal to give them IV if the child can swallow them! Think metronidazole, rifampicin, doxycycline, ciprofloxacin and clindamycin (which all have good tissue penetration)

“Help – my child refuses to take oral antibiotics!” – this is a tricky one and the use of an experienced paediatric pharmacist is invaluable as there are many aids that can be used to help resilient toddlers take their medications

 

Why is this important?

The implications of shortening the course of intravenous antibiotics and antibiotics overall are numerous…

  • Shorter courses of antibiotics may affect antimicrobial resistance
  • Shorter inpatient stays (required unless outpatient antimicrobial therapy available through a hospital in the home service) associated with improved quality of life in children and their families, and money-saving for the hospital system
  • Intravenous antibiotics may be associated with line complications, pain and traumatic experiences for children

 

Selected references

McMullan BJ, Andresen D, Blyth CC, Avent ML, Bowen AC, Britton PN, Clark JE, Cooper CM, Curtis N, Goeman E, Hazelton B. Antibiotic duration and timing of the switch from intravenous to oral route for bacterial infections in children: systematic review and guidelines. The Lancet Infectious Diseases. 2016 Aug 1;16(8):e139-52.

COVID and Hydroxychloroquine

Cite this article as:
Alison Boast. COVID and Hydroxychloroquine, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.24968

There has been lots of media attention around hydroxychloroquine use for COVID-19 in recent days, largely stemming from this press release where Donald Trump discussed its effectiveness.

 

However, as many have since pointed out, the evidence is very limited, and care needs to be taken when trying new drugs in a clinical context, even in a pandemic. There are many risks associated with using a drug for a new indication, particularly in patients who are otherwise unwell.

 

What is hydroxychloroquine?

Hydroxychloroquine is a prescription medication currently used in both adults and children for autoimmune diseases including lupus and for the treatment of malaria.

 

What is the evidence so far?

The evidence for hydroxychloroquine can be divided into two types – in vitro (in the test tube) and in vivo (in people).

In vitro evidence

The in vitro evidence for hydroxychloroquine is promising. It works in two ways:

  1. Direct inhibition of SARS-CoV-2
  2. Immune modulation

Severe disease occurs in COVID-19 due to the pro-inflammatory cascade and cytokine sstorm causing acute respiratory distress syndrome (ARDS). The inflammatory cytokine interleukin-6 (IL-6) has been particularly implicated in this pathway, and there is evidence to show that hydroxychloroquine has anti-inflammatory effects decreasing the production of a number of cytokines including IL-6.

In vivo evidence

The evidence for hydroxychloroquine in COVID-19 is currently limited to a few small prospective studies in adults. These studies have many methodological limitations increasing the risk of bias, and more randomised controlled trials are required before commenting on its efficacy. There are also concerning reports of cardiac toxicity with hydroxychloroquine use, which highlights the importance of only using new drugs in the context of clinical trials.

 

What evidence is there in children?

In short – none!

So far there have been no clinical trials of hydroxychloroquine in children. As it is already used in children with other conditions, we do know that is safe in the ‘well’ child and have some information about appropriate dosing. However, if it is prescribed to children with moderate to severe disease COVID-19, we cannot assume that the distribution around the body and clearance (pharmacokinetics) and its interaction with the body (pharmacodynamics) is the same.

 

Where to from here?

As per the World Health Organisation experimental therapies should not be used outside of registered clinical trials. The future use of hydroxychloroquine in children with COVID-19 is therefore dependent on whether clinical trials are conducted.

 

Why is this important?

For any new therapeutic agent to be used in children it requires the same rigorous assessment in clinical trials in adults. Often due to ethical issues and the inherent challenges of performing clinical trials with children, these studies do not occur. This is a huge issue in paediatrics in general, as almost all new drugs are only tested thoroughly in adults.

Paediatricians are often forced to prescribe drugs ‘off label’ (use of drugs for a different age group, indication, dosage, frequency or route) or ‘unlicensed’ (where a drug is used despite it not being approved by the licencing body such as Therapeutic Goods Australia). Many commonly used drugs are actually prescribed ‘off label’ including ondansetron, salbutamol and even paracetamol. There are well-documented risks of adverse effects with off-label and unlicensed prescribing. Without clinical trials there is no other option.

 

In conclusion…

It would be great if hydroxychloroquine was the wonder-drug we were all waiting for, with the in vitro data certainly promising. However, further clinical trials to assess its efficacy and safety are required, particularly before its use in children.

 

References

Liu J, Cao R, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020;6:16.

Mackenzie AH. Dose refinements in long-term therapy of rheumatoid arthritis with antimalarials. Am J Med. 1983;75(1a):40-5.

Yao X, Ye F, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of SARS-CoV-2. Clin Infect Dis. 2020.

Chen Z, Hu J, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv. 2020. **PREPRINT

Chen J, Liu L, et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19. J Zhejiang Univ (Med Sci). 2020;49(1):0-.

Gautret P, Lagier JC, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020:105949.

Coomes EA, Haghbayan H. Interleukin-6 in COVID-19: A Systematic Review and Meta-Analysis. medRxiv. 2020:2020.03.30.20048058. **PREPRINT

Savarino A, Boelaert JR, et al. Effects of chloroquine on viral infections: an old drug against today’s diseases? Lancet Infect Dis. 2003;3(11):722-7.

The Higher Tech Kid in the ED

Cite this article as:
Pascoe, E. The Higher Tech Kid in the ED, Don't Forget the Bubbles, 2018. Available at:
https://dontforgetthebubbles.com/higher-tech-kid-ed/

This month’s Podcast of the Month is from the Pediatric Emergency Playbook.

In a 30 minute podcast Tim Horeczko (Emergency Physician, and Educator) demystifies vagus nerve stimulators, intrathecal pumps, and ventricular assist devices. Through clinical cases, he provides some useful tips and tricks for what to do when the ‘higher tech kid’ presents to ED with a malfunctioning device.

What’s the emergency treatment for baclofen overdose when you can’t turn the pump off?

If you only switch on one podcast this month, make it this one.

Listen to the podcast.

Guanfacine

Cite this article as:
Mary Hardimon. Guanfacine, Don't Forget the Bubbles, 2017. Available at:
https://doi.org/10.31440/DFTB.13727

On 22nd August 2017, guanfacine hydrochloride (current sole brand name Intuniv) was accepted as a new chemical entity by the Therapeutic Goods Administration in Australia.1 Whilst new to Australia, guanfacine has been available within the United States of America and Europe since 20102 and 20153 respectively. The development of generic brands within these countries has seen increased uptake of this medication as an alternative to stimulant medications.

 

So what is it?

Guanfacine is an alpha 2 agonist. Unlike clonidine (which is non-selective and shows high affinity for all 3 subtypes of alpha 2 receptors – A, B and C), guanfacine has preferencial affinity for alpha 2A receptors. Stimulation of these receptors in the prefrontal cortex mimics noradreline/norepinephrine actions in this region, with current ADHD (Attention Deficit Hyperactivity Disorder) causal theories demonstrating noradrenergic dysfunction as underlying the cognitive and behavioural manifestations of ADHD.4

https://www.priory.com/psychiatry/clonidine.htm

 

Indications and Usage

Under current licensing in Australia, guanfacine is indicated for “the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents 6-17 years old, as monotherapy (when stimulants or atomoxetine are not suitable, not tolerated or have been shown to be ineffective) or as adjunctive therapy to psychostimulants (where there has been a sub-optimal response to psychostimulants).”

The use of guanfacine “must be used as part of a comprehensive ADHD management programme, typically including psychological, educational and social measures.1

These stipulations encourage prescribers to manage ADHD within a bio-psycho-social context, understanding that in the vast majority of cases, the condition whilst caused by a neurotransmitter imbalance may be attenuated by psychological and social strategies.

Shire Australia (whom is licensed for its distribution) recommends its use in children and adolescents 6 – 17 years of age.6 There are very limited studies7 surrounding guanfacine use in children younger than 6 years and whilst efficacy has been suggested, caution would be suggested in making ADHD diagnoses particularly in toddler years due to a great variety in “normal” in this period.

 

Dosage and Administration

Guanfacine will be released in 1mg, 2mg, 3mg and 4mg modified release tablets with administration once per day orally. Tablets should not be crushed or dissolved. Guanfacine should not be taken with high fat meals as this significantly affects absorption.

The recommended initial dose is 1mg (when used as either monotherapy or co-administered with stimulants). Dose adjustments are recommended by no more than 1mg/week with a target dose range (or based on therapeutic effect should it occur prior to this dose) of 0.05 – 0.12mg/kg/day. Doses exceeding 4mg (co-administration) and 7mg (when used as monotherapy) have not been evaluated.8

 

Recommended target dose range for maintenance therapy when guanfacine is sole agent8

Weight Target dose range (0.05 – 0.12 mg/kg/day)
25.0-33.9 kg 2-3 mg/day
34.0-41.4 kg 2-4 mg/day
41.5-49.4 kg 3-5 mg/day
49.5-58.4 kg 3-6 mg/day
58.5-91.0 kg 4-7 mg/day
≥91.0 kg 5-7 mg/day

 

Adverse effects

The most common adverse effects9 include:

  • Somnolence
  • Sedation
  • Abdominal pain
  • Dizziness
  • Hypotension
  • Dry mouth
  • Constipation

In contrast to stimulant medication, weight gain (mean of 0.5kg) is seen in patients using guanfacine.

Less common (although clinically significant) side effects10 include:

  • Atrioventricular block
  • Asthenia and chest pain
  • Increased ALT
  • Convulsion
  • Increased urinary frequency
  • Hypertension
  • Pallor

 

Drug interactions

CYP3A4 inhibitors (such as ketoconazole) and CYP3A4 inducers (such as rifampin) may affect guanfacine blood levels and subsequent clinical response.10

 

Cost

Since being introduced onto the PBS 1st September 2018, the previously prohibitive costs are now more affordable for families (although still quite expensive without a health care card) – ~$40 regular PBS price ~$6 concession PBS price.

 

References

1 https://www.tga.gov.au/prescription-medicines-registration-new-chemical-entities-australia

2 https://www.drugs.com/newdrugs/shire-announces-fda-approval-once-daily-intuniv-guanfacine-extended-release-adhd-children-1599.html

3

4 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3676929/

5 https://stahlonline.cambridge.org/content/ep/images/85702c17_fig24.jpg

6 https://www.guildlink.com.au/gc/ws/zi/pi.cfm?product=zipintun10817

7 https://onlinelibrary.wiley.com/doi/10.1002/%28SICI%291097-0355%28199723%2918:3%3C300::AID-IMHJ6%3E3.0.CO;2-Q/abstract

8 https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2017-PI-02254-1&d=2017110516114622483

9 https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022037lbl.pdf

10 https://pi.shirecontent.com/PI/PDFs/Intuniv_USA_ENG.pdf

Additional useful websites:

  1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b972af81-3a37-40be-9fe1-3ddf59852528
  2. https://pi.shirecontent.com/PI/PDFs/Intuniv_USA_ENG.pdf
  3. https://www.cms.gov/Medicare-Medicaid-Coordination/Fraud-Prevention/Medicaid-Integrity-Education/Pharmacy-Education-Materials/Downloads/stim-pediatric-factsheet11-14.pdf
  4. https://www.guildlink.com.au/gc/ws/zi/pi.cfm?product=zipintun10817