Which first-line treatment protocol is most likely to be successful?
Our most commonly used scabicides in the UK are topical Permethrin 5% cream and oral Ivermectin. This is represented in the guidance given by NICE (National Institute of Clinical Excellence) and BSPAD (British Society for Paediatric and Adolescent Dermatology).
Despite multiple systematic reviews, there has long been a debate about which of these is best as the first line and in what protocol (e.g., single dose, repeated dose). The evidence so far has been scanty and low-quality, limited by the size of the studies and lack of follow-up.
Mbuagbaw et al. have published a new systematic review and meta-analysis that specifically examines the prevalence of scabies treatment failure and its associated factors. But before we look at the paper, let’s have a recap.
What is scabies?
Scabies is an infestation caused by a mite called Sarcoptes scabiei. It is transmitted by skin-to-skin contact between individuals and commonly presents as an intensely itchy rash, but symptoms and signs can differ across age groups. For instance, infants can have no pruritic symptoms at all, and this can lead to under-recognition.
It occurs worldwide but is most seen in hot, tropical climates. It is unknown whether this is because the scabies mite thrives in hot, humid conditions or because these countries are more likely to be developing countries and therefore associated with overcrowding, poor sanitation and resource-poor. Where outbreaks occur in the UK, it is in economically disadvantaged populations or institutions such as care homes and the army where crowding occurs. It is also more prevalent at the extremes of age – possibly due to environmental circumstances (e.g. the elderly in care homes and children bed-sharing).
The Global Impact of Scabies
Scabies affects around 100 million people globally at any given time, placing it in the top 50 infectious diseases in terms of disability-adjusted life years. Its impact exceeds that of diseases like dengue fever.
In Australia, especially among children, scabies prevalence is alarmingly high, with rates even higher in tropical, under-resourced regions. – Prevalence of scabies worldwide—An updated systematic literature review in 2022 – Schneider – 2023 – Journal of the European Academy of Dermatology and Venereology – Wiley Online Library
Schneider, S., Wu, J., Tizek, L., Ziehfreund, S. and Zink, A., 2023. Prevalence of scabies worldwide–an updated systematic literature review in 2022. Journal of the European Academy of Dermatology and Venereology.
Vancouver
The Biology of Scabies
Scabies is primarily caused by the mite Sarcoptes scabiei var. hominis. This microscopic arthropod has a complex lifecycle involving egg-laying, larval, and adult stages, predominantly occurring on the human host. Understanding the lifecycle is crucial for effective treatment strategies.
The female mite burrows into the epidermis, laying eggs as it progresses into the stratum corneum. These eggs hatch into larvae, which then mature into adult mites.
Pathophysiology of Scabies
Immune Response and Inflammation: The burrowing of mites and their eggs, faeces, and saliva triggers an immune response in the human host. This response leads to inflammation, characterized by intense itching and a rash, typically developing several weeks after the initial infestation.
Delayed Hypersensitivity Reaction: The itching associated with scabies is primarily due to a delayed hypersensitivity reaction to the mites. The delay in symptom onset during initial infestation is due to the time the body’s immune system takes to develop this reaction.
Types of Scabies Infestation
Simple Scabies: Also known as ordinary scabies, this form is characterized by a limited number of mites on the body, usually less than 15. Symptoms include itching and a pimple-like rash, with burrows visible upon close examination.
Crusted Scabies: This more severe form of scabies, also known as Norwegian scabies, occurs primarily in individuals with weakened immune systems, such as those with HIV/AIDS, cancer, or those on immunosuppressive drugs. It is characterized by thick crusts of skin containing thousands of mites and eggs. Crusted scabies is highly contagious and more challenging to treat.
How is scabies spread?
Scabies is predominantly transmitted through prolonged skin-to-skin contact. This makes certain populations, such as children in schools, patients in healthcare facilities, and individuals living in crowded conditions, particularly vulnerable.
While scabies mites cannot survive long without a human host, transmission can occasionally occur through contaminated bedding, clothing, or furniture. This indirect transmission is more common with crusted scabies due to the higher number of mites.
Why is it important to us now?
The incidence of scabies in developed countries, including the UK, has sky-rocketed. Treatment failure is thought to play a part and may occur in 1 in 3 cases.
An increasing number of patients are visiting primary and secondary care with scabies, particularly when it is resistant to treatment. To manage this effectively, we need to understand the latest evidence on how to treat it successfully the first time, identify the factors that can lead to treatment failure, and know the best options for second-line treatments.
The paper
Lawrence Mbuagbaw, Behnam Sadeghirad, Rebecca L Morgan, Dominik Mertz, Shahrzad Motaghi, Maryam Ghadimi, Ifeoluwa Babatunde, Babalwa Zani, Tejanth Pasumarthi, McKenzie Derby, Venkata N Kothapudi, Nicole R Palmer, Anton Aebischer, Thomas Harder, Felix Reichert, Failure of scabies treatment: a systematic review and meta-analysis, British Journal of Dermatology, Volume 190, Issue 2, February 2024, Pages 163–173, https://doi.org/10.1093/bjd/ljad308
What were the results? – the statistical bit (skip to the next section for the highlights!)
147 studies were included.
The lowest levels of treatment failure were in Europe (6.0%, 95% CI 1.5-12.4, I2 = 95.3), and the highest were in the Western Pacific (26.9%, 95% CI 14.4-41.2; I2 = 94.1).
Ivermectin (83 studies) and Permethrin (62 studies) were the most commonly used treatments. In 8 studies, patients were treated with more than one agent, either sequentially or in combination. In 87 studies, participants also received additional treatment advice alongside their medication. This included instructions on treating close contacts and washing bedding and other items.
Treatment failure was reported in 23 studies, defined as reinfestation, the need for retreatment, recurrence, persistent itching, or lack of mite susceptibility. However, some studies did not provide a clear definition. The overall prevalence of treatment failure was 15.2% (95% CI 12.9–17.6; I² = 95.3%). When comparing adults and children, children showed a higher prevalence of treatment failure at 18.6% (95% CI 13.3–24.5) compared to 14.1% (95% CI 10.4–18.2) in adults, though the difference was not statistically significant.
Pooled prevalence for treatment failure for commonly used agents was:
| Agent | Pooled prevalence for treatment failure |
| Topical Ivermectin | 9.3% (95% CI 5.1-14.3, I2 = 82.1%) |
| Oral Ivermectin – single dose | 11.8% (95% CI 8.4-15.4, I2 = 92.5%) |
| Topical Permethrin | 10.8% (95% CI 7.5-14.5, I2 = 93.5%) |
| Lindane | 18.1% (95% CI 12.5-24.3, I2 = 92.8%) |
| Benzyl Benzoate | 25.3% (95% CI 16.4-35.3, I2 = 97.7%) |
| Crotamiton | 27.7% (95% CI 17.9-38.7, I2 = 90.6%) |
For agents where doses were repeated:
| Agent | Pooled prevalence for treatment failure | P Value |
| Oral Ivermectin – single dose | 15.2% (95% CI 10.8-20.2) | P= 0.021 |
| Oral Ivermectin – two doses | 7.1% (95% CI 3.1-12.3) | |
| Topical Permethrin – single application | 8.5% (95% CI 3.6-15.1) | P = 0.757 |
| Topical Permethrin – two applications | 7.3% (95% CI 3.3-12.4) |
For all of these above, in any dosing regimen, when combined with additional measures to increase compliance or minimise mistakes in application, the prevalence of failure dropped even further in all categories.
Studies that used objective methods, such as microscopy or dermatoscopy, to confirm the presence or absence of infestation were more likely to report treatment failure, with a prevalence of 19.5% (95% CI 16.0–23.3; I² = 95.2%). In contrast, studies relying on subjective methods, such as clinical examination and patient history, reported a lower prevalence of treatment failure at 12.2% (95% CI 9.7–14.9).
Treatment failure was more commonly reported in recent studies (published after 2011), with a prevalence of 17.4% (95% CI 14.4–20.5; I² = 93.8%), compared to studies published before 2011, which reported a prevalence of 12.8% (95% CI 10.0–15.8; I² = 93.9%).
What does this mean?
Treatment failure is seen more in developing than developed countries.
Children are more likely than adults to see their treatment fail, although this finding wasn’t statistically significant.
A variety of pharmacological agents and treatment regimens exist worldwide.
Ivermectin (both topically and orally) and topical Permethrin are the least likely to be associated with treatment failure.
When doses of each agent are repeated, treatment failure rates are even lower.
When pharmacological agents are combined with advice on general management, treatment failure rates are lower.
Treatment failure has increased progressively over time (approximately 0.2% per year rise).
But how good is the paper?
Let’s take a look at the CASP checklist :
1. Did the review address a clearly focused question?
Yes, the question was about the prevalence of treatment failure in patients with scabies and the investigation of associated factors.
2. Did the authors look for the right type of papers?
The review included various study types, such as randomised controlled trials (RCTs), quasi-RCTs, prospective and retrospective cohort studies, observational studies, and case series. While all these studies addressed the question of interest, their differences created significant heterogeneity, limiting the authors’ ability to combine the results statistically in a meta-analysis.
3. Do you think all the important, relevant studies were included?
The systematic review searched multiple major bibliographic databases, including MEDLINE and EMBASE, with no language or publication status restrictions. It included studies from database inception up to August 2021, but more recent studies were not included. There is no mention of grey literature being searched, and experts in the field were not consulted to identify additional studies. Furthermore, a funnel plot to assess potential publication bias was not provided.
The screening process involved pairs of trained reviewers who assessed titles and abstracts using a standardised, pilot-tested form with systematic review software, minimising subjectivity. Disagreements were resolved by a third reviewer. Full-text reviews of potentially eligible studies were conducted, but there is no comment on whether the reviewers consistently adhered to their eligibility criteria.
An interesting point is the inclusion of persistent itching as a criterion for treatment failure. The British Society for Paediatric and Adolescent Dermatology (BSPAD) notes that itching can continue for up to six weeks after successful treatment. This raises the possibility that some patients classified as “treatment failures” might have been successfully treated. According to the supplementary material, this accounted for four studies (2.5% of the total).
A PRISMA flow diagram was provided, outlining the screening process, duplication removal, exclusions (with reasons), and the final number of included studies. Full lists of included and excluded studies are available in the supplementary material.
4. Did the review’s authors do enough to assess quality of the included studies?
The risk of bias for each study was evaluated using a validated tool developed by Hoy et al., which is specifically designed for systematic reviews. This tool has demonstrated excellent interrater agreement, with a Kappa value of 0.82 (95% CI 0.76–0.86), ensuring assessment reliability. As with the study screening process, any disagreements between reviewers were resolved through discussion with a third reviewer, further enhancing the robustness of the evaluation process.
The findings were summarised in a bar chart in Figure 2, highlighting that the overall risk of bias in the included studies was predominantly moderate (51.7%) or high (31.3%). Low scores were primarily attributed to issues such as non-randomisation of the sample, lack of representativeness, inadequacies in the sampling frame, and insufficient follow-up time (prevalence period).
5. If the results of the review have been combined, was it reasonable to do so?
This was primarily a systematic review due to the high methodological heterogeneity that would have made a meta-analysis inappropriate.
A meta-regression was used to look at the prevalence of treatment failure over time, and subgroup analyses were conducted in:
- Method of diagnosis
- Type and route of scabicide used
- Region/country
The subgroup analyses presented were post-hoc, meaning they were not pre-specified and were conducted after the study results had been compiled. This approach, often called data-dredging, involves searching for multiple outcomes from a single dataset. The more outcomes examined, the higher the likelihood of finding a statistically significant result purely by chance, increasing the risk of a Type 1 error. Importantly, no adjustments for multiple testing appeared to have been made.
As a result, the conclusions drawn from these subgroup analyses should be interpreted cautiously and viewed as observational rather than definitive. Additionally, even with these analyses, significant unexplained heterogeneity remained, with I² scores consistently exceeding 75%. This highlights persistent variability that the subgroup analyses could not account for.
6. What are the overall results of the review?
The overall prevalence of treatment failure was 15.2% (95% CI 12.9-17.6; I² = 95.3%, moderate-certainty evidence).
Topical Ivermectin performs best, with the prevalence of treatment failure at 9.3% (95% CI 5.1-14.3; I² = 82.1%), followed by topical Permethrin 10.8% (95% CI 7.5-14.5; I² = 93.%%), followed by oral Ivermectin 11.8% (95% CI 8.4-15.4; I² = 92.5%).
Reported factors associated with treatment failure are as follows:
| Drug characteristics | Limited drug potency |
| Taking only a single agent | |
| Single-dose treatments | |
| Resistance | |
| Lower-doses of medication | |
| Long delay between treatments | |
| Disease characteristics | Severity |
| Treatment issues | Delay between symptom onset and first treatment |
| Contact with untreated/Reinfection | |
| Incorrect application | |
| No decontamination of bedding etc | |
| Lack of water for bathing | |
| Using corticosteroids concomitantly | |
| Failure to reach/treat contacts | |
| Patient characteristics | Nursing professional |
| Female | |
| Cognitive or physical impairment | |
| Ageing skin |
From the subgroup analyses:
- The lowest levels of treatment failure were in Europe (6.0%, 95% CI 1.5-12.4; I² = 95.3) vs the Western Pacific (26.9%, 95% CI 14.5-41.2; I² = 94.1). P = 0.003. A forest plot can be found in the supplementary material.
- Objective methods (microscopy/dermatoscopy) for diagnosing infestation were more likely to report treatment failure than subjective ones (history/examination) 19.5%, 95% CI 16.0-23.3; I² = 95.2% vs 12.2%, 95% CI 9.7-14.9; P = 0.001)
- There was a 0.27% increase in treatment failure for every 1-year increase in publication year (95% CI 0.01-0.50); P= 0.017).
7. How precise are the results?
For the primary outcome, the narrow confidence intervals suggest that the sample result is precise and closely reflects the result expected in the overall population.
This precision is also evident in the subgroup analyses, although the confidence intervals for the group reporting the highest levels of treatment failure (Western Pacific) are slightly wider. Nevertheless, the P value for this group remains below 0.05, indicating statistical significance.
In the meta-analysis examining specific treatment regimens combined with “additional precautions,” the forest plot demonstrates that the confidence intervals for the cumulative effect of each category (represented by the diamonds) are narrow and do not cross the line of zero effect. This indicates that the results are both precise and statistically significant.
8. Can the results be applied to the local population?
The systematic review included all age groups, not just children, making drawing conclusions specific to paediatric populations challenging. The reasons for treatment failure in children, which may differ from those in adults, were not explicitly addressed.
The studies analysed were conducted globally, which might appear inclusive but introduce complexities. The scabies mite thrives in hot, humid climates and is endemic in developing countries, where environmental factors may contribute to higher treatment failure rates. These conditions differ from those in the developed, Western world, like the UK, and may not fully represent the local context. Additionally, there may be inherent differences in the biology of the scabies mite in tropical climates compared to the UK, potentially leading to greater treatment resistance and higher failure rates.
However, the increased burden of scabies infestation in the UK warrants consideration of local factors such as rising social deprivation. Overcrowded living conditions and limited access to washing and laundry facilities may contribute to the spread of scabies and treatment challenges. These factors enhance the generalisability of the study to UK populations while highlighting the importance of addressing socioeconomic determinants of health.
Were all important outcomes considered?
The primary outcome of interest in the systematic review was the prevalence of treatment failure across various scabicidal regimens, particularly given the rising prevalence of scabies.
However, it would have been valuable to also investigate the susceptibility of mites to different treatments to assess potential drug resistance. Resistance is frequently hypothesised as a factor contributing to treatment failure, but none of the included studies examined this aspect. Such data would have provided critical insights into whether resistance to scabicidal agents drives treatment challenges, allowing for more targeted and effective therapeutic strategies.
Are the benefits worth the harms and costs?
Yes. This paper concludes that two doses of oral ivermectin result in the lowest treatment failure prevalence compared to a single dose. Single-dose topical ivermectin and permethrin follow as the next most effective options. Both of these agents are well-established and routinely used safely within UK practice. Other agents examined in the study are not typically used in the UK.
Neither ivermectin nor permethrin has been associated with serious adverse events in other studies, but poor reporting remains a limitation. Additionally, there are no comparative studies specifically evaluating the safety and efficacy of scabicidal agents in infants and small children.
While ivermectin is more expensive than permethrin, it may offer advantages in compliance, particularly in adolescents who might be less inclined or effective at applying full-body topical treatments. Using oral ivermectin could help reduce treatment failure rates. However, it is important to note that oral ivermectin is only approved for use in children weighing more than 15kg. This limitation may restrict its use in younger or smaller children, underscoring the need for careful consideration when selecting treatment options.
What can we take away from this study?
According to current NICE guidelines, permethrin is recommended as the first-line treatment for scabies in adults and children over 2 months old. If treatment fails, oral ivermectin is advised for those weighing more than 15kg. A second dose of oral ivermectin is reserved for individuals with “profuse and crusting scabies,” rather than being routinely recommended for other cases.
This study highlights a crucial question in the management of scabies:
Should we consider adopting a two-dose ivermectin regimen as our first-line treatment? This approach may align better with patient preferences, particularly for those who find topical treatments difficult to apply or comply with, potentially improving outcomes for a significant portion of the UK population.
Alternatively, should we maintain permethrin as the first-line treatment due to its lower cost but revise our second-line treatment strategy? Switching from single-dose oral ivermectin to a standard two-dose regimen could enhance effectiveness by targeting newly hatched mites during the second treatment, addressing ivermectin’s lack of ovicidal properties.
Balancing cost, patient compliance, and treatment efficacy is key to determining the optimal approach.
When considering future advancements, it is worth watching for emerging research on moxidectin, an oral agent with a longer half-life. Early clinical trials have demonstrated promising efficacy with single dosing, potentially making it a valuable alternative for scabies treatment.
For now, continue following NICE guidelines and your local departmental protocols. However, it is essential to remain mindful that the effectiveness of topical treatments relies heavily on patient compliance. Offering patients (or their parents) a choice of treatment options can empower them and improve adherence.
Additionally, emphasise the importance of environmental decontamination and provide thorough advice on preventing recontamination. Measures such as washing bedding and clothing and treating close contacts play a vital role in achieving successful treatment outcomes and preventing re-infestation.
References
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- British Society for Paediatric and Adolescent Dermatology. British Association of Dermatologists. 2023 [cited 2024 Nov 28]. Management of scabies in the UK: expert consensus guidance. Available from: https://cdn.bad.org.uk/uploads/2023/10/Scabies-guidance-OCT-2023.pdf
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