Mini-CAT Final                                                        Name: Ruthie Schreiber

 

 

Clinical Question:

 

26 year old female presents to the emergency room complaining of intense pruritus, especially at night. You notice linear burrows in her web spaces, prompting you to make a diagnosis of scabies. Patient said her roommate was treated for scabies last week with ivermectin, but her brother had it last year and was treated with permethrin.

 

Search Question:

 

In patients diagnosed with scabies, is permethrin more effective than ivermectin as first line treatment?

 

PICO Question:

 

P	I	C	O
Scabies Patient	Permethrin	Ivermectin	Complete clearance of infection
Sarcoptes scabiei infection	Permethrin topical management	Ivermectin oral management	Symptom resolution
			Adverse effects

 

 

 

Search tools and strategy used:

 

PubMed

            ~Scabies treatment 2,472 results

                        *Filter: meta-analysis, systematic review  83 results

                                    *Filter: 5 years publication date 19 results

 

            ~ Permethrin Ivermectin scabies 179 results

                        *Filter: meta-analysis, systematic review 7 results

                                    *Filter: 5 years publication date 3 results

           

Cochrane

            ~ Scabies treatment 180 results

                        *Filter: review 3 results

 

Google Scholar

            ~ Permethrin Ivermectin scabies  3,390 results

                        *Filter: since 2016 970 results

 

 

In determining which articles to include for this miniCAT, it was important to find articles that were of the highest evidence available (i.e. systematic review or meta analysis) and to include studies that were conducted recently. I chose to include my specific articles due to their explicit relevance to both my PICO question and clinical scenario. Additionally, these articles feature both meta-analyses as well as systematic reviews, both of which are of high level evidence. Furthermore, these articles were recently published within the past couple years, making them pertinent and extremely up to date.

                                   

 

Articles Chosen:

 

• Rosumeck  S, Nast  A, Dressler  C. Ivermectin and permethrin for treating scabies. Cochrane Database of Systematic Reviews 2018, Issue 4. Art. No.: CD012994. DOI: 10.1002/14651858.CD012994.

 

https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD012994/epdf/full

Background

Scabies is an intensely itchy parasitic infection of the skin. It occurs worldwide, but is particularly problematic in areas of poor sanitation, overcrowding, and social disruption. In recent years, permethrin and ivermectin have become the most relevant treatment options for scabies.

Objectives

To assess the efficacy and safety of topical permethrin and topical or systemic ivermectin for scabies in people of all ages.

Search methods

We searched the following databases up to 25 April 2017: the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, Embase, LILACS, and IndMED. We searched the World Health Organization International Clinical Trials Registry Platform, the ISRCTN registry, CenterWatch Clinical Trials Listing, ClinicalTrials.gov, TrialsCentral, and the UK Department of Health National Research Register for ongoing trials. We also searched multiple sources for grey literature and checked reference lists of included studies for additional trials.

Selection criteria

We included randomized controlled trials that compared permethrin or ivermectin against each other for people with scabies of all ages and either sex.

Data collection and analysis

Two review authors independently screened the identified records, extracted data, and assessed the risk of bias for the included trials.

The primary outcome was complete clearance of scabies. Secondary outcomes were number of participants re‐treated, number of participants with at least one adverse event, and number of participants withdrawn from study due to an adverse event.

We summarized dichotomous outcomes using risk ratios (RR) with 95% confidence intervals (CI). If it was not possible to calculate the point estimate, we described the data qualitatively. Where appropriate, we calculated combined effect estimates using a random‐effects model and assessed heterogeneity. We calculated numbers needed to treat for an additional beneficial outcome when we found a difference.

We assessed the certainty of the evidence using the GRADE approach. We used the control rate average to provide illustrative clearance rates in the comparison groups.

Main results

Fifteen studies (1896 participants) comparing topical permethrin, systemic ivermectin, or topical ivermectin met the inclusion criteria. Overall, the risk of bias in the included trials was moderate: reporting in many studies was poor. Nearly all studies were conducted in South Asia or North Africa, where the disease is more common, and is associated with poverty.

Efficacy

Oral ivermectin (at a standard dose of 200 μg/kg) may lead to slightly lower rates of complete clearance after one week compared to permethrin 5% cream. Using the average clearance rate of 65% in the trials with permethrin, the illustrative clearance with ivermectin is 43% (RR 0.65, 95% CI 0.54 to 0.78; 613 participants, 6 studies; low‐certainty evidence). However, by week two there may be little or no difference (illustrative clearance of permethrin 74% compared to ivermectin 68%; RR 0.91, 95% CI 0.76 to 1.08; 459 participants, 5 studies; low‐certainty evidence). Treatments with one to three doses of ivermectin or one to three applications of permethrin may lead to little or no difference in rates of complete clearance after four weeks’ follow‐up (illustrative cures with 1 to 3 applications of permethrin 93% and with 1 to 3 doses of ivermectin 86%; RR 0.92, 95% CI 0.82 to 1.03; 581 participants, 5 studies; low‐certainty evidence).

After one week of treatment with oral ivermectin at a standard dose of 200 μg/kg or one application of permethrin 5% lotion, there is probably little or no difference in complete clearance rates (illustrative cure rates: permethrin 73%, ivermectin 68%; RR 0.93, 95% CI 0.74 to 1.17; 120 participants, 1 study; moderate‐certainty evidence). After two weeks of treatment, one dose of systemic ivermectin compared to one application of permethrin lotion may lead to similar complete clearance rates (extrapolated cure rates: 67% in both groups; RR 1.00, 95% CI 0.78 to 1.29; 120 participants, 1 study; low‐certainty evidence).

There is probably little or no difference in rates of complete clearance between systemic ivermectin at standard dose and topical ivermectin 1% lotion four weeks after initiation of treatment (illustrative cure rates: oral ivermectin 97%, ivermectin lotion 96%; RR 0.99, 95% CI 0.95 to 1.03; 272 participants, 2 studies; moderate‐certainty evidence). Likewise, after four weeks, ivermectin lotion probably leads to little or no difference in rates of complete clearance when compared to permethrin cream (extrapolated cure rates: permethrin cream 94%, ivermectin lotion 96%; RR 1.02, 95% CI 0.96 to 1.08; 210 participants, 1 study; moderate‐certainty evidence), and there is little or no difference among systemic ivermectin in different doses (extrapolated cure rates: 2 doses 90%, 1 dose 87%; RR 0.97, 95% CI 0.83 to 1.14; 80 participants, 1 study; high‐certainty evidence).

Safety

Reporting of adverse events in the included studies was suboptimal. No withdrawals due to adverse events occurred in either the systemic ivermectin or the permethrin group (moderate‐certainty evidence). Two weeks after treatment initiation, there is probably little or no difference in the proportion of participants treated with systemic ivermectin or permethrin cream who experienced at least one adverse event (55 participants, 1 study; moderate‐certainty evidence). After four weeks, ivermectin may lead to a slightly larger proportion of participants with at least one adverse event (extrapolated rates: permethrin 4%, ivermectin 5%; RR 1.30, 95% CI 0.35 to 4.83; 502 participants, 4 studies; low‐certainty evidence).

Adverse events in participants treated with topical ivermectin were rare and of mild intensity and comparable to those with systemic ivermectin. For this comparison, it is uncertain whether there is any difference in the number of participants with at least one adverse event (very low‐certainty evidence). No withdrawals due to adverse events occurred (62 participants, 1 study; moderate‐certainty evidence).

It is uncertain whether topical ivermectin or permethrin differ in the number of participants with at least one adverse event (very low‐certainty evidence). We found no studies comparing systemic ivermectin in different doses that assessed safety outcomes.

Authors’ conclusions

We found that for the most part, there was no difference detected in the efficacy of permethrin compared to systemic or topical ivermectin. Overall, few and mild adverse events were reported. Our confidence in the effect estimates was mostly low to moderate. Poor reporting is a major limitation.

 

• Thadanipon K, Anothaisintawee T, Rattanasiri S, Thakkinstian A, Attia J. Efficacy and safety of antiscabietic agents: A systematic review and network meta-analysis of randomized controlled trials. J Am Acad Dermatol. 2019;80(5):1435‐ doi:10.1016/j.jaad.2019.01.004

 

https://www.jaad.org/article/S0190-9622(19)30071-4/pdf

 

Background: Many drugs have been used to treat scabies, but it is unclear which of them is the most efficacious.

 

Objective: To evaluate the comparative efficacy and safety of antiscabietic agents. Methods: A systematic review of randomized controlled trials was conducted. Direct and network meta-analyses were applied to 13 antiscabietic agents on 3 outcomes (cure, persistent itching, and adverse events). Their probability of having highest efficacy and safety was estimated and ranked.

 

Results: A network meta-analysis of 52 trials including 9917 patients indicated that permethrin (the reference treatment) had a significantly higher cure rate than sulfur, malathion, lindane, crotamiton, and benzyl benzoate. Combination permethrin plus oral ivermectin had a nonsignificantly higher cure rate than permethrin. Combination permethrin plus oral ivermectin was ranked highest in terms of cure, topical ivermectin in terms of persistent itching, and synergized pyrethrins in terms of adverse events. On the basis of clustered ranking, permethrin, oral ivermectin, and synergized pyrethrins seemed to retain balance between cure and adverse events.

 

Limitations: There are small numbers of trials and patients in some comparisons and a high risk of bias in some trials.

 

Conclusion: There is no 1 treatment that ranked highest in all aspects. Physicians should consider the drug’s efficacy and safety profiles, along with ease of administration. ( J Am Acad Dermatol 2019;80:1435-44.)

 

 

• May PJ, Tong SYC, Steer AC, et al. Treatment, prevention and public health management of impetigo, scabies, crusted scabies and fungal skin infections in endemic populations: a systematic review. Trop Med Int Health. 2019;24(3):280‐ doi:10.1111/tmi.13198

 

https://onlinelibrary.wiley.com/doi/pdf/10.1111/tmi.13198

 

Abstract:

 

We conducted a systematic review of the treatment, prevention and public health control of skin infections including impetigo, scabies, crusted scabies and tinea in resource-limited settings where skin infections are endemic. The aim is to inform strategies, guidelines and research to improve skin health in populations that are inequitably affected by infections of the skin and the downstream consequences of these. The systematic review is reported according to the PRISMA statement. From 1759 titles identified, 81 full text studies were reviewed and key findings outlined for impetigo, scabies, crusted scabies and tinea. Improvements in primary care and public health management of skin infections will have broad and lasting impacts on overall quality of life including reductions in morbidity and mortality from sepsis, skeletal infections, kidney and heart disease.

 

 

• Chiu S, Argaez C. Ivermectin for Parasitic Skin Infections of Scabies: A Review of Comparative Clinical Effectiveness, Cost-Effectiveness, and Guidelines. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2019.

 

https://www.ncbi.nlm.nih.gov/books/NBK545083/pdf/Bookshelf_NBK545083.pdf

 

Excerpt

Scabies is a skin condition caused by the parasitic infestation of the mite Sarcoptes scabiei. Scabies results in intense, debilitating itching and skin papules, nodules, and vesicles and is transmitted through direct contact. In a small proportion of cases, typically in those with immunosuppression, hyperinfestation and crusted scabies can develop and lead to secondary bacterial infection associated with significant morbidity and mortality.^– The Global Burden of Disease study estimated that the global prevalence of scabies was approximately 200 million in 2015. High prevalence of scabies is associated with tropical regions, resource-poor settings, and overcrowded settings.^– Outbreaks of scabies have previously been reporting in chronic health care facilities in Canada. In Canada, common scabicides for the treatment of scabies include: topical 5% permethrin, topical crotamiton 10%, pharmacy-compounded topical sulfur 5% to 10%, and topical or oral ivermectin. According to the Canadian Paediatric Society Position Statement on scabies, topical treatments applied from the neck down are typically used to treat scabies and first-line treatment is topical permethrin. Some topical treatments, including permethrin, are repeated after one to two weeks to improve effectiveness as they do not affect mite eggs. Treatment is recommended not only for the patient with scabies but also all close contacts at the same time to prevent transmission to others and re-infestation in the originally affected patient.^–, Similarly, washing linens and clothing in hot water is a precautionary measure to prevent fomite transmission.^, Lindane and benzyl benzoate are treatment options for scabies that are not currently approved by Health Canada. There are concerns with neurotoxicity with lindane and benzyl benzoate is associated with skin irritation. Oral ivermectin previously was obtained through the Health Canada Special Access Programme for treating parasitic infections.^, Recently, topical and oral ivermectin have been approved by Health Canada and their approved indications are for the treatment of rosacea and intestinal strongyloidiasis and onchocerciasis, respectively.^, Therefore, these treatment options can now be evaluated for drug plan coverage decisions. Ivermectin is not approved for use in children less than 15 kg in weight or patients who are pregnant or breastfeeding. The objective of this report is to review the evidence regarding clinical effectiveness and cost-effectiveness of ivermectin for the treatment of parasitic skin infections of scabies. Additionally, this reports aims to review the evidence-based guidelines regarding the use of ivermectin for the treatment of parasitic skin infections of scabies. A 2010 CADTH report summarized evidence on the clinical effectiveness and safety of treatments for lice and scabies.

 

 

 

Summary of the Evidence:

Author (Date)	Level of Evidence	Sample/Setting (# of subjects/ studies, cohort definition etc. )	Outcome(s) studied	Key Findings	Limitations and Biases
Rosumeck  S, Nast  A, Dressler  C. (2018)	Systematic Review	-The following databases were searched for this study: the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, Embase, LILACS, and IndMED. Additionally, the WHO international clinical trials registry platform, the ISRCTN registry, CenterWatch clinical trials listing, clinicaltrials.gov, trialscentral and the UK department of health national research register were all searched for ongoing trials. -15 randomized controlled trials (total of 1896 participants) were included that compared the use of permethrin vs. ivermectin for individuals with scabies regardless of age or gender	-The primary outcome of this review was complete clearance of scabies   -Secondary outcomes that were analyzed were the number of participants that required re-treatment, number of participants with at least one adverse event, and the number of participants that were ultimately withdrawn from the study due to an adverse event.	-Ultimately 15 studies of 1896 participants were included that compared topical permethrin, systemic ivermectin, or topical ivermectin -Oral ivermectin may lead to slightly lower rates of complete clearance after one week when compared to permethrin cream (low-certainty evidence), but there is little to no difference in rates of complete clearance by week two (low-certainty evidence) -There is likely little to no difference in complete clearance rates after one week of treatment with oral ivermectin or one application of permethrin lotion (moderate-certainty evidence) -There is likely little to no difference in rates of complete clearance between systemic ivermectin at standard dose vs. topical ivermectin lotion four weeks after initiating treatment (moderate-certainty evidence) -After 4 weeks, ivermectin lotion likely leads to little to no difference in rates of complete clearance vs. permethrin cream (moderate-certainty evidence)	-The authors recognized that poor reporting was a major limitation to their study. Furthermore, high-certainty studies would be necessary to strengthen the confidence in their results (mostly low to moderate).   -Overall the authors rated the risk of bias in the included trials to be moderate (due to poor reporting in many studies)
Thadanipon K, Anothaisintawee T, Rattanasiri S, Thakkinstian A, Attia J. (2019)	Systematic Review & Meta Analysis	– The following databases were searched for this study: MEDLINE, PubMed, Scopus, Cochrane Central Register of Controlled Trials, Online Computer Library Center, Thai-Journal Citation Index Centre, and WHO international clinical trials registry platform.   -52 trials (total of 9117 patients) were included for this network meta-analysis that analyzed the efficacy and safety of specific anti-scabietic agents.	-The goal of this review was to determine which of the varying drugs that have been used to treat scabies has the highest level of efficacy and safety.   -The primary outcome was treatment efficacy, defined as the clinical cure and microscopic/parasitic cure   -There were 3 secondary outcomes of interest: persistent itching, re-infestation, and adverse effects.	-Ultimately there were 52 trials consisting of 9917 patients that demonstrated permethrin had a significantly higher cure rate than other agents (i.e. sulfur, malathion, lindane). -The combination of permethrin with oral ivermectin had a non-significantly higher cure rate than the use of permethrin alone. -The combination of permethrin with oral ivermectin ranked highest for cure -Topical ivermectin ranked highest for persistent itching -Synergized pyrethrins ranked highest for cure -No single treatment ranked highest in all aspects analyzed	-The authors recognized that there were some limitations of their study. For instance, they had a small number of trials and patients, along with a possible high risk of bias in specific trials (particularly the older studies)
May PJ, Tong SYC, Steer AC, et al. (2019)	Systematic Review	-This review used their search strategy to identify 1759 titles, 455 abstracts for screening, and ultimately 193 met the inclusion criteria.   -This resulted in 81 full texts to be included in the final version that analyzed the treatment, prevention, and public health control of various skin infections (i.e. impetigo, scabies, tinea)   -Seven studies specifically addressed topical-antiparasitic agents for scabies, with low to moderate quality evidence for either topical permethrin or topical ivermectin	-The primary outcome of this review was the cure or decrease in prevalence for population-based studies of the specific skin infection   -Secondary outcomes of this review included microbiological cure, symptom relief, recurrence, adherence, acceptability, adverse events, as well as spread to contacts	-Topical 5% permethrin vs. oral ivermectin: lesion count and presence of pruritus was significantly lower for those using permethrin after 1 week   -Topical 5% permethrin vs. oral ivermectin: clinical cure at 4 weeks was the same   – Topical 5% permethrin vs. oral ivermectin: superior symptom relief with permethrin at 2 weeks (low quality evidence)	-The authors recognize the possibility of restriction to English language publications or being unable to find the full text publication. However, they do add that <30 full text studies were excluded for this very reason   -The reviewers used the Cochrane Collaboration’s tool for assessing risk of bias to eliminate as much bias from this study as possible
Chiu S, Argaez C. (2019)	Review with Critical Appraisal	– The following databases were searched for this study: Medline, EMBASE, the Cochrane Library, University of York Centre for Reviews and Dissemination databases, Canadian and major international health technology agencies   -Three systematic reviews, one randomized controlled trials and three guidelines were identified as relevant to this search	-The primary outcome was cure (clinical or microscopic/parasitic cure) at one to two weeks, and at three to six weeks, complete clearance of lesions at 1,2, and 4 weeks, and treatment failure (i.e. persistent lesions, new lesions, or confirmation of live mite)   -Secondary outcomes included persistent itching, re-infestation, number of patients re-treated, and adverse events	-For cure/ complete clearance of scabies, there was no conclusive evidence in differentiating between oral vs. topical ivermectin -Oral ivermectin was less clinically effective in treating scabies vs. topical permethrin at one to two weeks, but ultimately there was no difference in treatment at later time point -No difference in clinical effectiveness between topical ivermectin and permethrin	-Limited sample sizes in the included trials   -Potential sources of bias were identified in most of the primary trials (i.e. lack of blinding, incomplete outcome reporting)   -Safety conclusions were limited by deficiencies in adverse event reporting

 

Conclusion(s):

 

Article #1:  Rosumeck  S, Nast  A, Dressler  C.  concluded that overall there was no difference detected in the efficacy of permethrin when compared to systemic or topical ivermectin.

 

Article #2: Thadanipon K, Anothaisintawee T, Rattanasiri S, Thakkinstian A, Attia J. concluded that there is no single treatment ranked highest in all aspects for scabies treatment. Therefore, in choosing a drug for a patient its efficacy and safety profile and ease of administration should be considered.

 

Article #3: May PJ, Tong SYC, Steer AC, et al. concluded that although topical permethrin had a lower lesion count after 1 week, ultimately clinical cure (at 4 weeks) was the same as oral ivermectin

 

Article #4: Chiu S, Argaez C. concluded that ultimately, there is no difference in clinical effectiveness between topical ivermectin and permethrin, despite oral ivermectin being less clinically effective at one to two weeks

 

My overall conclusion for this mini-CAT assignment is that in patients diagnosed with scabies, permethrin is not clinically more effective than ivermectin as first line treatment. Although there is some evidence to suggest that permethrin was superior to ivermectin, ultimately there is no difference in clinical effectiveness. Overall, the research does not clearly indicate the use of permethrin over ivermectin or vice versa. Therefore, choosing between these two agents should be decided on an individualized level with the patient and provider coming to a joint decision together.

 

 

Clinical Bottom Line:

 

I weigh my studies in the following order:

• Article #2: Thadanipon K. et al
• Article #1: Rosumeck S et al
• Article #3: May PJ et al
• Article #4: Chiu S.et al

 

 

Thadanipon K. et al was the highest level of evidence since it was a systematic review as well as a meta-analysis and it was published in 2019. It also included 52 trials and 9917 patients that properly analyzed and compared the efficacy and safety of multiple anti-scabietic agents. Another advantage of this article was that it assessed secondary outcomes such as persistent itching, re-infestation, and adverse effects.

 

Rosumeck S et al was also at the highest level of evidence since it was a systematic review, and it was published in 2018. It also included 15 studies of 1896 patients that compared the use of topical permethrin, systemic ivermectin, or topical ivermectin among patients diagnosed with scabies.

 

May PJ et al was also at the highest level of evidence since it was a systematic review that was published in 2019. Although 81 full texts were ultimately included, only 7 studies specifically addressed topical anti-parasitic agents for scabies. Additionally, there was only low to moderate evidence for use of either topical permethrin or topical ivermectin.

 

Chiu S.et et al was ranked lowest out of the four articles. Although it is a review with critical appraisal, it was published in Canada which has a different healthcare system and may differ in healthcare decision making policies. Additionally, there were limitations of limit in sample size as well as potential sources of bias.

 

 

Magnitude of any effects:

 

The effect of using permethrin over ivermectin in patients diagnosed with scabies does not seem to be particularly high, neither for primary outcome nor for secondary outcomes, as proven by the evidence from this assignment.

 

Clinical Significance:

 

Overall the research does not clearly indicate the use of permethrin over ivermectin or vice versa. Rather, there is room to justify the use of either agent and therefore it should be decided on an individualized level based on the specific patient. In terms of patient compliance and cost, oral ivermectin might be a better choice. On the other hand, topical permethrin has been shown to be highly effective for scabies with a large percentage of cure rates seen in patients.

 

Any other considerations important in weighing this evidence to guide practice:

 

Future studies are certainly warranted and should be conducted. Elements that should be addressed include: larger sample sizes and additional outcomes (i.e. lower cost, ease of administration, use in young children, use in pregnant women). In the meantime, it is recommended that practitioners choose the agent that is best suited for the specific patient, keeping in mind the benefits unique to each one.