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Head Lice : Single Drug Versus Combination Therapy With One Percent and Trimethoprim/Sulfamethoxazole

Ronaldo B. Hipolito, MD*; Florinda G. Mallorca, MD‡; Zoraya O. Zuniga-Macaraig, MD‡; Patricia C. Apolinario, MD§; and Jan Wheeler-Sherman, PhDʈ

ABSTRACT. Background. (HLI) ABBREVIATIONS. HLI, head lice infestation; PPB, pyrethrins is a vexing problem for pediatricians and families be- with piperonyl butoxide; 1% PER, 1% permethrin creme rinse; cause lice are becoming resistant to approved antipedicu- TMP/SMX, trimethoprim/sulfamethoxazole. losis agents. Objective. This study compared the efficacy of 3 dif- ferent treatments for HLI and determined whether com- ead lice infestation (HLI) caused by Pediculus bination therapy reduced treatment failures. humanus var capitis is a worldwide public Design and Setting. A randomized, clinical trial per- health concern that affects mostly school- H 1 ϳ formed in 3 private practices. aged children. In the United States, 6 to 12 million Participants. The population was children ranging in persons are infested with head lice,2 with an esti- age from 2 to 13 years. mated $100 million being spent annually on treat- Methods. HLI was diagnosed by direct inspection of ment.3 HLI does not produce an illness, but it is the hair and scalp. Children were assigned to 1 of 3 physically unpleasant and bears a significant nega- ؍ groups: 1) 1% permethrin creme rinse (1% PER; n 39); tive social stigma.4 2) oral administration of trimethoprim/sulfamethoxazole Historically, permethrin creme rinse has been the ؍ (TMP/SMX; n 36); and 3) a combination of 1% PER and drug of choice in treating pediculosis5,6 because of its Follow-up visits were done 2 and 4 .(40 ؍ TMP/SMX (n long-lasting residual effect, which may be useful in weeks later, and parents or caregivers of those who did 7 not return were interviewed by telephone. If HLI was killing nymphs. However, resistance to permethrin present at the 2-week follow-up, the child was retreated as well as other antipediculosis agents, including per their protocol. We defined successful treatment as the pyrethrins with piperonyl butoxide (PPB) and lin- absence of adult lice and nymphal stage or eggs (nits). dane, has recently been reported.6–10 Pediatricians The presence of nits alone was not considered a treat- and other pediatric health care workers are now ment failure. faced with finding new strategies to combat drug Results. At the 2-week follow-up visit, successful resistance associated with HLI. In other countries, treatment for groups 1, 2, and 3 was 79.5%, 83%, and 95%, clinicians have found rotational therapy with differ- respectively. At the 4-week follow-up, successful treat- ent agents a useful approach.1 The rotation of thera- ment was 72%, 78%, and 92.5% for groups 1, 2, and 3, peutic agents may slow the emergence of resistance,1 respectively. The absolute risk reduction for recurrence although this has yet to be proven. comparing group 1 versus group 2 was 6%, group 2 Other methods to treat HLI include applying a versus group 3 was 14%, and group 1 versus group 3 was 20%. No major adverse complications were seen in any heavy layer of petroleum jelly, olive oil, or mayon- treatment group. naise to the scalp and covering the scalp overnight Conclusion. Our findings indicate that a combination with a shower cap. This method reportedly kills lice of 1% PER and TMP/SMX is an effective alternative through asphyxiation, immobilization, and/or an in- therapy for HLI. We recommend that the dual therapy ability to feed.1,4,6 Head shaving is also used to treat with 1% PER and oral TMP/SMX be used and reserved in HLI.11 This treatment is effective for male children cases of multiple treatment failures or suspected cases of but is not socially acceptable for the female popula- lice-related resistance to therapy. Pediatrics 2001;107(3). tion in which the majority of HLI occurs. Of partic- URL: http://www.pediatrics.org/cgi/content/full/107/3/e30; ular concern is that parents and caretakers may use lice, Pediculus humanus var capitis, trimethoprim/sulfame- unsafe and dangerous methods, such as kerosene, thoxazole, resistance, permethrin. alcohol, insecticides, and other toxic chemicals to treat HLI.4,11,12 Three agents are currently approved by the US From the *Department of Pediatrics, University of California, Davis, Cali- Food and Drug Administration for the treatment of fornia; ‡Yosemite Medical Group, Tracy and Manteca, California; §Depart- HLI: lindane (Kwell, Jersey City, NJ), PPB (RID, ment of Pediatrics, San Joaquin General Hospital, Stockton, California; and the ʈDepartment of Nursing, University of California, San Francisco, Cali- Pronto, A-200, and others), and 1% permethrin creme 4,6 fornia. rinse (1% PER; Nix, Research Triangle Park, NC). Received for publication Jun 12, 2000; accepted Sep 26, 2000. Because treatment resistance has become a primary Reprint requests to (R.B.H.) University of California, Davis, School of Med- concern for clinicians, they are beginning to use ex- icine, Department of Pediatrics, Section of Neonatology, TB 193, Davis, CA 95616. E-mail: [email protected] perimental treatments, such as trimethoprim/sulfa- PEDIATRICS (ISSN 0031 4005). Copyright © 2001 by the American Acad- methoxazole (TMP/SMX), 5% permethrin (5% PER; emy of Pediatrics. Elimite, Irvine, CA), , , and car- http://www.pediatrics.org/cgi/content/full/107/3/Downloaded from www.aappublications.org/newse30 by guestPEDIATRICS on October 3, Vol. 2021 107 No. 3 March 2001 1of5 baryl to control HLI.4,13–15 Of these agents, TMP/ Group 2 SMX is a more commonly used in the Participants were given oral TMP/SMX (suspension or tablet) pediatric population. Parents are more familiar with at a dosage of 10 mg/kg/day based on TMP for 10 days in 2 TMP/SMX compared with 5% PER, malathion, iver- divided doses. Children who were able to swallow tablets were prescribed 1 tablet twice daily or 1 double strength tablet twice mectin, or carbaryl. daily for 10 days depending on their weight. Parents or caretakers Although TMP/SMX is unpopular in treating HLI were instructed to use a regular shampoo. Nits were removed because of its potential side effects, it is an emerging using a lice meister, and if not available, we recommended using practice among clinicians to treat HLI with a combi- a very fine teethed comb. Parents or caretakers were asked to nation of 1% PER and oral TMP/SMX. To the best of comb the participant’s hair as many strokes as they could during the course of the treatment. our knowledge, no one has reported the therapeutic efficacy of combining the 2 in the treat- Group 3 ment of HLI, especially when patients have experi- Participants were prescribed both 1% PER and TMP/SMX as enced recent treatment failures or when lice-related same protocol outlined above. Nits were removed using a comb resistance is suspected. The purpose of this study provided by 1% PER. Parents or caretakers were asked to comb was to compare the efficacy of using single therapy the participant’s hair as many strokes as they could during the course of the treatment. (1% PER or oral TMP/SMX alone) versus combina- Compliance in taking TMP/SMX was determined using 1 of 2 tion therapy with 1% PER and oral TMP/SMX in methods. The child’s parents recorded the administration of each treating P humanis var capitis infestation. This ap- dose in a small diary that was supplied at study entry and/or the proach might represent a better and safer alternative amount of dispensed medication (liquid volume or tablets) that for treating HLI when treatment failure has occurred remained was evaluated at the follow-up visit. or lice-related resistance is suspected. Follow-Up Observations and Subsequent Treatment Children were reexamined at 2 and 4 weeks after treatment for METHODS HLI. A pediatrician or family practice physician performed exam- inations of scalp and hair. We defined treatment failures as the Population, Enrollment, and Assignment presence of adult lice, and nymphal stage, or eggs (nits) and not The study was conducted between July 1996 and December just the presence of nits alone. On follow-up visits, we used a 1999 in San Joaquin County, California. The study sites were 3 magnifying glass to identify a true viable egg with an empty egg private pediatric and family practices. The sample population was casing to confirm HLI. If the child at 2 weeks still had HLI, the comprised of children ranging from 2 to 13 years old who were participants were retreated. The protocol for retreatment was as diagnosed with HLI in the physicians’ offices. The diagnosis of follows: group 1: reapplication of 1% PER; group 2: another course HLI was confirmed by clinical inspection of scalp and hair for the of oral TMP/SMX suspension; and group 3: another course of 1% presence of adult lice, nymphal stage, or eggs (nits). Inclusion PER and oral TMP/SMX suspension. The participants were then criteria for the study included a positive diagnosis of HLI by evaluated 4 weeks after the initial diagnosis. If the participants did visual inspection and informed consent from the parents or care- not return for their follow-up visit, telephone interviews with the givers that they understood the study design and were willing to parents or caregivers were used for deciding outcome. participate. Exclusion criteria for the study included a hypersen- A retrospective review of charts on all the participants who had sitivity to TMP/SMX, a hypersensitivity to 1% PER, and/or a their follow-up by telephone interviews in both first and second history of parental noncompliance or neglect. follow-up was performed at least 6 months after the enrollment. Demographic data including age, race, sex, and childcare at- The review involved recording any repeat office visit(s) attribut- tendance were obtained for all participants. A history of previous able to HLI. HLI was obtained from medical records and parental anecdotes. All children who met the inclusive criteria and whose caregiv- Statistics ers gave informed consent were enrolled in the study. Children The sample size was estimated based on the recommendations were randomly assigned to 1 of 3 groups. Participants assigned to of Cohen.16 Using an ␣ of 0.05, a power of 0.80, and an effect size group 1 received 1% PER for 10 minutes over hair and scalp (per of 0.50, a minimum of 39 participants were necessary for each manufacturer’s instruction), with a repeat application after 1 week group. if necessary. Participants assigned to group 2 were prescribed oral Statistical analysis of results was performed using the Fisher’s TMP/SMX suspension 10 mg/kg/day based on TMP in 2 divided exact test and Student’s t test as was appropriate.16,17 Absolute doses for 10 days. Participants assigned to group 3 were treated risk reduction was calculated to compare the efficacy of treatment with a combination of 1% PER and TMP/SMX as described for between groups. groups 1 and 2. During the visual inspection of lice, parents were educated on how to recognize different stages of lice (adult lice, nymphal stage, RESULTS or eggs/nits). Photographs of different stages of lice were also Population Characteristics shown. Parents of all participants were given information on recognition of HLI and methods to prevent reinfestation (cleaning Over a 3-year period from July 1996 to December of the home, bedding, and personal hygiene items; treatment of 1999, 115 children were entered into the study. There other family members; and other precautions to prevent reinfes- were a total of 125 participants recruited with HLI, tation). but 10 participants were excluded. Seven partici- pants with HLI were not entered into the study Drug Administration and Compliance because of previous hypersensitivity to TMP/SMX ϭ ϭ Group 1 (n 2), hypersensitivity to 1% PER (n 2), and a parental history of noncompliance/neglect (n ϭ 3). Participants were given 1% PER as described by manufacturer’s insert package. In brief, the parents were instructed to wash their Three participants were removed from the study child’s hair with regular shampoo and then rinse clean, shake the because of rash caused by TMP/SMX. The attrition bottle of 1% PER, and apply the creme rinse to the scalp and hair rate was 2%. for 10 minutes. Thereafter, the hair was rinsed with water and was Demographic characteristics of the participants are towel dried. Nits were removed using the comb provided with the 1% PER. Parents or caretakers were asked to comb participant’s shown in Table 1. Analysis of the demographic data hair as many strokes as they can after using the medication. The among the 3 treatment groups revealed no differ- procedure was repeated after 1 week if HLI was still evident. ences. In all groups, ϳ53% of the children were be-

2of5 PERMETHRIN, TRIMETHOPRIM/SULFAMETHOXAZOLE,Downloaded from www.aappublications.org/news by guest AND on October HEAD 3, LICE2021 TABLE 1. Demographic Characteristics of the Study Population With Head Lice Infestation Treatment Groups Group 1 Group 2 Group 3 Total 1% PER TMP/SMX 1% PER ϩ (n ϭ 115) (n ϭ 39) (n ϭ 36) TMP/SMX (n ϭ 40) n (%) n (%) n (%) n (%) Age (y) 2–5 10 (26) 9 (25) 10 (25) 29 (25) 6–10 20 (51) 21 (58) 22 (55) 63 (55) 11–13 9 (23) 6 (17) 8 (20) 23 (20) Race White 10 (26) 10 (28) 9 (22.5) 29 (25) Black 5 (13) 4 (11) 5 (12.5) 14 (12) Hispanic 15 (38) 20 (55.5) 21 (52.5) 56 (49) Asian 9 (23) 2 (5.5) 5 (12.5) 16 (14) Sex Male 13 (33) 11 (31) 10 (25) 34 (30) Female 26 (67) 25 (69) 30 (75) 81 (70) Previous history of HLI 13 (33) 12 (33) 15 (37.5) 40 (35) Day care attendees Yes 15 (38.5) 12 (33) 14 (35) 41 (36) No 24 (61.5) 24 (67) 26 (65) 74 (64)

tween the ages of 6 and 10 years. The predominant TABLE 2. ARR* Shows the Efficacy of Treatment Among the gender was female (female 70% and male 30%). The Groups predominant ethnicity was Hispanic (48.7%). Groups ARR (%) P Value* Group 1 vs 2 6 .74 Treatment Groups Group 2 vs 3 14 .14 At 2 weeks after therapy began, HLI was still Group 1 vs 3 20 .03† present in 16 participants (Fig 1). The success rate of ARR indicates absolute risk reduction. treatment for groups 1, 2, and 3 was 79.5%, 83%, and * Fisher’s exact test ϭ P value. 95%, respectively. After 4 weeks of therapy, failures † Statistically significant. were present in 22 participants (Fig 1). The success rate for treatment at the 4-week follow-up for groups 1, 2, and 3 was 72%, 78%, and 92.5%, respectively. Follow-Up Observations and Subsequent Treatment Table 2 shows the calculation of the absolute risk Table 3 shows the numbers of office visits versus reduction comparing the efficacy of treatment among telephone interviews that were required at the first groups. Treatment with 1% PER and TMP/SMX was and second follow-up visits. All treatment failures in more likely to prevent recurrence of HLI. groups 1, 2, and 3 showed up for their follow-up office visits.

Group 1 At first follow-up, 8 participants were retreated with 1% PER. At the second follow-up, there were 11 treatment failures. Of 8 treatment failures in the first follow-up, 4 participants needed another course of treatment, while 4 participants were free of lice both adult and nymphal stage or eggs (nits). Seven par-

TABLE 3. Numbers of Enrolled Participants Who Kept Ap- pointed Follow-Up Visits at Two or Four Weeks After Treatment Began or Required Telephone Follow-Up Interviews to Determine Outcome First Follow-Up Second Follow-Up Office Telephone Office Telephone Visits Interviews Visits Interviews Group 1 23 (58%) 16 (42%) 21 (54%) 18 (46%) Fig 1. Relationship between the number of enrolled patients and (n ϭ 39) the number of treatment failures at the first (2-week) and second Group 2 25 (69%) 11 (31%) 18 (50%) 18 (50%) (4-week) follow-up appointments. Group 1 ϭ 1% PER; group 2 ϭ (n ϭ 36) oral administration of TMP/SMX (10 mg/kg/day divided into Group 3 16 (40%) 24 (60%) 20 (50%) 20 (50%) twice-daily dosing); and group 3 ϭ combined 1% PER and TMP/ (n ϭ 40) SMX.

Downloaded from www.aappublications.org/newshttp://www.pediatrics.org/cgi/content/full/107/3/ by guest on October 3, 2021 e30 3of5 ticipants on second follow-up were new treatment risk of infestation among family members. HLI in- failures and needed to be retreated again. flicts a negative social stigma on the children and their parents or caretakers. Because of parental and Group 2 caretaker’s frustration with resistant head lice, dan- At the first follow-up, 6 participants were retreated gerous methods of treating HLI (use of kerosene, with TMP/SMX. At the second follow-up, there were insecticides, gasoline, and head shaving) may be 8 treatment failures. Of 6 participants retreated in the used. In this trial, combination therapy had less re- first follow-up, 3 participants needed another course currences of HLI compared with treatment with ei- of treatment, while 3 participants were free of lice ther 1% PER or TMP/SMX alone. This study sug- both adult and nymphal stage or eggs (nits). Five gests an alternative therapy in the management of participants on second follow-up were treatment HLI where treatment failure or suspected lice-related failures and needed to be retreated again. Group 2 resistance exists. had a better posttreatment follow-up than group 1 The mechanism by which permethrin and TMP/ (Table 3), and we attributed this to the fact that group SMX kills lice differs from each other. Permethrin is 2 protocol is new to the parents or caretakers. a synthetic compound derived from pyrethrin and acts on the nerve cell membranes of the parasites Group 3 causing disruption of the sodium channel, delayed At the first follow-up, 2 participants were retreated nerve repolarization, and paralysis of exoskeletal with 1% PER and TMP/SMX. At the second follow- muscles. This inhibits respiration and the lice suffo- up, all of the participants retreated at first follow-up cate.18 By comparison, TMP/SMX applies the prin- were free of lice both adult and nymphal stage or ciple of a symbiotic relationship. According to eggs (nits), while 3 participants were new treatment Burns,19 TMP/SMX kills lice by inhibiting their in- failures and needed to be retreated again. Group 3 testinal flora. When lice suck the blood of treated had more telephone interviews that were used for patients, they ingest TMP/SMX. The TMP/SMX kills follow-up (Table 3), and we attributed this to the fact the bacterial flora in the gut that synthesize B vita- that combination therapy had a greater success rate mins. Lice lose their ability to obtain B vitamins and for treatment. die as a result.19 Other antibiotics can also be used in A retrospective review of charts on all the partic- the treatment of HLI, but they are still under inves- ipants who underwent telephone interviews for de- tigation by other researchers.20 So far, TMP/SMX is ciding outcomes in group 1, 2, and 3 during first and the only antibacterial agent being used as an exper- second follow-up revealed that there were no office imental therapy for HLI. visits attributable to HLI in a span of at least Ͼ6 Historically, TMP/SMX was accidentally discov- months. This signifies that HLI was treated ade- ered by Shashindran and colleagues21 as a therapy quately. for lice in 1978. These physicians were giving TMP/ SMX to a 12-year-old girl with a bacterial upper Adverse Reactions respiratory and HLI, and they noted a con- Of 115 participants, 8 had minor adverse reactions current improvement in her HLI. In their study, they to the treatment. Three participants had mild scalp used 2 courses of TMP/SMX spaced 10 days apart (1 irritation after a 10-minute application of 1% PER. tablet twice daily for 3 days), and they found that Five participants had nausea, vomiting, and/or mi- this approach eradicated the infestation without re- nor rash from oral TMP/SMX. One quarter of par- quiring any external antipediculosis therapy. Morsy ticipants (n ϭ 9) in group 2 developed intense pru- and colleagues20 also studied the efficacy of TMP/ ritus after 3 to 4 days of treatment, but the treatment SMX in treating HLI. In their study, the lice demon- was continued because the pruritus disappeared strated decreased movement and death by the fourth within 1 to 3 hours. Two participants in group 2 and to seventh day of oral TMP/SMX. The complications 1 participant in group 3 were removed from the seen in that study included severe pruritis, skin rash, study because of an allergic-appearing rash caused nausea, and vomiting. For unknown reasons, pa- by TMP/SMX. Participants who developed nausea tients in our study that combined 1% PER and TMP/ and vomiting (n ϭ 3) on TMP/SMX were not ex- SMX therapy did not experience severe pruritus, al- cluded from the study because the symptoms were though intense pruritis was seen in some children transient. Participants who developed mild scalp ir- treated with TMP/SMX alone. ritation related to 1% PER were also not excluded We propose that using both 1% PER and oral from the study. No major side effects of TMP/ TMP/SMX can provide a synergistic effect. Per- SMX—such as Stevens-Johnson syndrome; erythema methrin can kill lice immediately during the appli- multiforme; and clinical of meg- cation and it may still have a residual effect on aloblastic anemia, hemolytic anemia, neutropenia, emerging nymphs. Paradoxically, the waning resid- and renal impairment—were observed. ual levels of permethrin may promote the emergence of resistant lice.1,7 If there is a development of resis- DISCUSSION tance in some lice to permethrin, the ingestion of the Treatment of P humanis var capitis infestation has TMP/SMX may lead to their ultimate eradication. been a long-term problem for clinicians and parents.1 Moreover, after a full course of TMP/SMX, we spec- The management is complicated by increasing resis- ulate that blood levels of the medication may still tance to the presently approved antipediculosis afford protection to newly emerging lice that ingest agents.6–10 Drug resistance has also increased the blood from the human scalp.

4of5 PERMETHRIN, TRIMETHOPRIM/SULFAMETHOXAZOLE,Downloaded from www.aappublications.org/news by guest AND on October HEAD 3, LICE2021 Aside from using TMP/SMX, primary health Davis; Dr Ernesto Hipolito, Daly City, California; and my wife, workers can choose other experimental drugs in the Anna Corina Hipolito, for their helpful suggestions regarding the management of resistant head lice. These include 5% preparation of this manuscript. permethrin cream, carbaryl, malathion, and ivermec- REFERENCES 4,13–15 tin. Five percent permethrin cream still was 1. Elston DM. What’s eating you? Pediculus humanus (head and body associated with reinfestation and required retreat- louse). Cutis. 1999;63:259–264 ment.4 Malathion was reported recently by Dawes10 2. Clore ER, Longyear LA. A comparative study of seven pediculicides to have double resistance to lice. Carbaryl is carcino- and their packaged nit removal combs. 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Downloaded from www.aappublications.org/news by guest on October 3, 2021 Head Lice Infestation: Single Drug Versus Combination Therapy With One Percent Permethrin and Trimethoprim/Sulfamethoxazole Ronaldo B. Hipolito, Florinda G. Mallorca, Zoraya O. Zuniga-Macaraig, Patricia C. Apolinario and Jan Wheeler-Sherman Pediatrics 2001;107;e30 DOI: 10.1542/peds.107.3.e30

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