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Comparative In Vitro Pediculicidal Efficacy of Treatments in a Resistant Head Lice Population in the United States
Terri L. Meinking, BA;
Lidia Serrano;
Bruce Hard, MA;
Pamela Entzel, JD, MPH;
Glendene Lemard, MA;
Elisabeth Rivera;
Maria Elena Villar, MPH
Arch Dermatol. 2002;138:220-224.
ABSTRACT
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Objective To compare the pediculicidal activity of 5 head lice products available
in the United States on head lice from south Florida.
Design In vitro pediculicidal product comparison.
Setting Lice Source Services, Inc, located in Plantation, Fla, a clinic for
the treatment and grooming of individuals with pediculosis capitis.
Participants Head lice were collected from healthy clients with Pediculus capitis that came to Lice Source Services, Inc, to seek their
services.
Interventions Within 2 to 6 hours of capture, lice were placed in continuous direct
contact with the pediculicide products and observed at regular intervals.
Results were compared with findings of a recent study of a treatment-sensitive
population of head lice conducted in Panama.
Main Outcome Measure Percentage of lice dead at regular observation intervals between 5 minutes
and 3 hours of continuous exposure to the pediculicides.
Results Two prescription products, Ovide lotion (0.5% malathion) and 1% lindane
shampoo, were ranked in the same order as in 2 previous studies (first and
last, respectively). The order of effectiveness from most to least effective
was as follows: Ovide lotion, A-200 shampoo (a natural pyrethrin product synergized
with piperonyl butoxide), undiluted Nix (1% permethrin), diluted Nix, RID
(a natural pyrethrin product synergized with piperonyl butoxide), and 1% lindane
shampoo.
Conclusions There were statistically significant differences in the efficacy of
all the products when compared with the results found in the recent study
in Panama, except for Ovide lotion. Of those tested, Ovide was the only pediculicide
in the United States that had not become less effective. The difference in
efficacy of 1% lindane, Nix, and pyrethrins between the Panama and Florida
studies supports the argument that some head lice in the United States have
become resistant to these treatments.
INTRODUCTION
INFESTATION with head lice is on the rise in the United States and worldwide.1-3 The most likely targets
are school-aged children between 3 and 11 years2-4
and their immediate contacts (such as day care providers, family members,
and playmates). In the United States, families spend more than $160 million
annually on head lice treatments purchased from pharmacies and supermarkets.5 The total cost of products purchased at health food
stores or over the Internet is unknown, but these sales seem to be increasing.
Each head lice product ranges in price from approximately $10 to $28 per person
per treatment, and most products require 2 treatments. People who visit Lice
Source Services, Inc (LSS), a lice and nit removal clinic located in Plantation,
Fla, a suburb of Fort Lauderdale, have treated themselves an average of 5
times before seeking its services. Unlike prescription pediculicides, insurance
plans, Medicare, or Medicaid do not cover over-the-counter (OTC) products.
The cost of purchasing head lice treatments could amount to much more when
consumers find that most currently marketed products do not cure them even
when used as directed.
In 1986, when Nix (1% permethrin) (Warner Lambert Co, Morris Plains,
NJ [now manufactured by Pfizer Inc, New York, NY]) crème rinse was
approved by the Food and Drug Administration (FDA) and came on the market
as a prescription product, lindane and pyrethrin products had an average ovicidal
activity of only 70%.6-7 Thus,
a second treatment was recommended 1 week later to kill any nymphs that hatched
from eggs, surviving treatment. Also, nit removal with a fine-toothed comb
or "fingernail" technique was necessary to prevent reinfestation. The introduction
of Nix revolutionized the management of pediculosis capitis. Although Nix
was only 70% ovicidal,7 the residual permethrin
bound to the hair and scalp was sufficient to kill lice that hatched from
the eggs, providing almost 100% efficacy with a single 10-minute application.7 Many schools allowed children back in class without
nit removal if they brought in the used bottle of Nix. However, because of
the currently poor pediculicidal and ovicidal activity of Nix and other treatments,
even more time and money is now spent on special nit combs, grooming services,
environmental sprays, laundry, dry cleaning, vacuuming, bagging stuffed animals,
and replacing earphones, helmets, and other head gear suspected of being sources
of reinfestation. When adding the time spent and the salary lost from work,
many parents have estimated the cost of their "never-ending" head lice experience
to be in the thousands of dollars.
In the last 5 years, when a treatment failure is reported the blame
seems to fall on the consumer, suggesting that parents did not adhere to the
instructions, remove all nits, or adequately clean the environment. However,
in the original Nix studies submitted for FDA approval,8-9
there was no nit removal, combs, or environmental treatment. Our study7 was conducted in Panama in populations with no electricity
or running water, making it impossible to wash bedding or vacuum homes. In
the double-blind, placebo-controlled clinical trial, children slept 4 to a
hammock, yet participants who received active crème rinse remained
free of lice 2 weeks after a single treatment.7
There are several reasons for the increasing frequency of treatment
failures reported worldwide.2 In the United
States, our 2 primary reasons of concern are subtle changes in product formulation
over the years1 and the increasing development
of pesticide resistance.4, 10-16
To address these questions, investigators from the Field Epidemiology Survey
Team (FEST) at the University of Miami, Miami, Fla, conducted an in vitro
baseline study in Panama (which we refer to as Update 20001 to prevent confusion with the 1986
study6), where head lice are still sensitive
to prescription and OTC products. The primary goal of this study was to assess
the extent to which possible formulation, ingredient sources, or manufacturing
changes over the last 16 years may have affected product efficacy.1
In Update 2000,1
we compared the killing time of 5 widely sold products: 2 prescription products,
Ovide lotion (0.5% malathion) (Medicis Pharmaceutical Corp, Phoenix, Ariz),
which in 1986 was formerly available as Prioderm lotion (Purdue Frederick
Company, Norwalk, Conn), and 1% lindane shampoo, which until 1995 was formerly
available under the brand name Kwell shampoo (Reed & Carnrick, Jersey
City, NJ); 2 OTC synergized natural pyrethrins, RID (Pfizer, Inc, New York,
NY) and A-200 shampoo (Hogil Pharmaceutical Corp, Purchase, NY); and a synthetic
pyrethroid, Nix. Both pediculicidal and ovicidal activity were evaluated1 and compared with the data of the 1986 study.6
The study we report here is a replication of Update
20001 in Panama, conducted in a population
of head lice in south Florida, where permethrin- and lindane-resistant head
lice have been reported.3, 15 Ovicidal
activity was not evaluated in Florida because previous treatments and combing
could damage nits and result in unreliable information. Our main goal was
to compare the results of these 2 identical studies to assess the degree of
resistance in south Florida. It is evident from Update 20001 that some currently available pediculicides
differ from the formulations we tested 16 years ago.6
We attribute the differences in results from the lice tested in Florida and
those of the recent study in Panama to resistance because we have already
controlled for formulation changes.
METHODS
The lice used in the present study were collected from over 25 children
and adults seen at LSS. The study was conducted between July and November
2000. Individuals using the services of LSS are usually residents of Palm
Beach, Broward, or Miami-Dade counties. These clients are often referred to
LSS by school nurses, pediatricians, child care centers, public health departments,
and foster care agencies.
From our experience in south Florida, we have found that resistant and
sensitive lice can live on the same person's head at the same time.3, 17 Because some individuals had self-treated
their infestation and some had not, lice collected from LSS clients may include
both treatment resistant and treatment sensitive. To ensure that this did
not skew the results, we pooled all lice collected on study days and tested
all products on that day's pool of lice. To provide sufficient numbers of
lice, we conducted numerous runs on different days using lice from several
infested individuals. The number of dead lice was recorded at each predetermined
interval.
Investigators from LSS and FEST conducted the assessments under the
supervision of the principal investigator (T.L.M.). Four members of our team
who conducted Update 2000,1
also did some of the experiments in the present study and worked closely with
the LSS researchers to ensure that the methods were conducted exactly as in Update 2000.
Pediculicidal activity was tested by exposing lice continually to cotton
disks impregnated with the pediculicide products. The procedure for preparing
and impregnating the cotton disks and the rationale for using this methodology
has been described extensively.1, 6, 18
The same bottles tested in Update 20001
in Panama were returned to south Florida and used to impregnate the cloth
disks tested in the present study, and new bottles recently purchased locally
were also tested. As in the Panama studies,1, 6
lot number, expiration date, place of purchase, and date opened were recorded
for each bottle used in each experiment to ensure that differences in results
could not be attributed to poor stability, oxidation, storage problems, or
"bad" batches.
Because Nix is to be applied to clean "towel-dried" hair, there is a
dilution factor to account for, although the dilution will vary by user. We
took a conservative dilution, consisting of 9 parts Nix to 1 part water (90%
Nix solution), as in Update 2000,1
and for the US studies, we also added a more "realistic" dilution of 3 parts
Nix to 1 part water (75% Nix solution).
Depending on the amount of lice collected from the clients of the clinic
on each day of the study, usually between 10 and 15 lice were placed on the
impregnated disk and observed at regular intervals for 3 hours. The lab at
LSS was maintained at the same temperature and humidity range as our field
station in Panama, even though the screening and treatment rooms were air
conditioned.
RESULTS
Ovide (0.5% malathion) was the fastest and most effective pediculicide
tested, killing 88% of lice at 10 minutes and 100% at 20 minutes. The second
best product, the synergized natural pyrethrin A-200, killed 60% of lice at
20 minutes, 82% at 1 hour, and 100% at 3 hours. Although RID has the same
active ingredients as A-200 (pyrethrum extract equivalent to 0.33% plus 4%
piperonyl butoxide), it had a slow killing time with only 8% of lice dead
in 20 minutes and only 34% dead after 3 hours of continuous exposure (Table 1). We attribute this large difference
of efficacy between the synergized natural pyrethrin products A-200 and RID
to formulation and vehicle differences.
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Table 1. Pediculicidal Activity, South Florida
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Nix was tested at 3 concentrations: undiluted and 2 dilutions (90% Nix
[9 parts Nix to 1 part water] and 75% Nix [3 parts Nix to 1 part water]).
As expected, undiluted Nix was the most effective of the 3, killing 84% of
the lice at 3 hours. The difference between 90% and 75% Nix dilutions was
not significant; however, there was a highly significant difference between
undiluted and diluted Nix at the 1-hour and 3-hour intervals (P<.001 for both dilutions at 1 and 3 hours). After 10 minutes, which
is the indicated application time, only 3% to 5% of lice exposed to Nix were
dead, regardless of whether or not it was diluted, and only 8% to 10% at 20
minutes. Even after 3 hours of continuous exposure to undiluted Nix, over
25% of lice were still alive. With diluted Nix used to simulate towel-dried
hair, more than half of the lice were still alive at 3 hours (Table 1).
The slowest and least effective of all products tested was once again
1% lindane shampoo, killing only 2% of lice at 20 minutes and 8% at 1 hour;
after 3 hours of continuous exposure only 17% of the lice tested were dead
(Table 1). These results, which
confirm the findings in the previous 2 studies,1, 6
are of concern, considering that 1% lindane shampoo has an indicated application
time of less than 10 minutes. Increasing the treatment time, which we have
seen many parents do in an effort to increase efficacy, could result in increased
percutaneous absorption and toxic effects on the central nervous system.3, 19
Ovide lotion was equally effective in the present study as in Update 2000,1 killing 100%
of lice within 20 minutes at both sites. The only other product tested that
killed all lice in both sites at 3 hours was A-200 shampoo. When comparing
the efficacy of all other products in Update 20001 with the present study, we found that all but 1% lindane
shampoo (exposed for 1 hour) yielded statistically significant differences
(Table 2).
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Table 2. Florida and Panama1 Comparative Efficacy Results*
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COMMENT
It is important for treatments to kill, or at least immobilize, lice
within the application time because parents, children, and infested individuals
experience anxiety and psychological stress when they see lice crawling and
walking after treatment. All of the treatments tested in the present study,
with the exception of Ovide, are labeled to be rinsed off within 10 minutes.
The present study demonstrates that many of the pediculicides sold in the
United States do not meet their advertising claims that they "kill lice and
eggs on contact." Slow-killing pesticides, poor formulations, and residual
pediculicide concentrations on the hair that expose lice to sublethal doses
are more likely to encourage the development of resistance.2-3,20
In the present study conducted in south Florida, we found that Ovide
was the fastest killing pediculicide and the only one of the 5 products tested
that had not become less effective compared with the findings from the Panama
studies.1, 6 There has been confusion
among consumers and health care professionals regarding the safety of malathion,
the active ingredient in Ovide. Negative publicity and statements made concerning
"toxicity" rarely distinguish between pharmaceutical and agricultural grade
malathion. Products for nonhuman use may contain impurities that have been
associated with reported "toxicity" or adverse experiences. The pharmaceutical
grade malathion used in Ovide has a high level of purity. Its safety and efficacy
have been well documented.2, 21
Although Ovide (formerly Prioderm) was approved by the FDA 2 decades ago,
it has spent a relatively short time on the US market, while in many countries
it has remained one of the treatments of choice for decades. Malathion lotion
has been on the market twice in the United States and withdrawn in 1995 by
the manufacturer (prior to the development of resistant lice) because of commercial
failure.2-3 The long application
time, odor, and flammability of this prescription alcoholic lotion was not
appealing to consumers who could successfully cure an infestation with a 10-minute
application of an OTC product. Unlike permethrin that originally provided
"residual activity" on the hair and scalp within 10 minutes, malathion takes
several hours to achieve this action. The overnight application time was originally
chosen by the Purdue Frederick Company for clinical trials and FDA submission
because 20 years ago residual activity on the hair and scalp was considered
to be a "good thing." However, it is now recognized that residual activity
and prophylactic use only add to the development of resistant lice.3, 20 The FDA approval confirms that Ovide
lotion is the only product we tested with the toxicity profile and data to
support an 8- to 12-hour application, even though our in vitro results show
that a much shorter exposure time is highly effective. Resistance to malathion
has developed in France and the United Kingdom2, 16, 22;
however, the 0.5 % malathion products available in these countries are not
the same as Ovide lotion. The Ovide vehicle contains components such as dipentene,
terpineol, and 78% isopropanol, which increase the pediculicidal and ovicidal
activity of the malathion. Further studies to better define the enhancing
activity of the vehicle are in progress.
The other prescription product, 1% lindane shampoo, was the least effective
pediculicide tested, performing poorly in Panama in a population with treatment-sensitive
lice infestation and even worse in south Florida. Lindane resistance has been
a worldwide problem for decades.3, 17
We encountered lindane treatment failures in Florida 16 years ago and find
it to be increasingly ineffective at curing infestations. Because of the increasing
treatment failures of OTC products over the past 6 years and the trend toward
prescription products under insurance and other health care plans, lindane
is still widely used in the United States. Lindane, like DDT (chlorophenothane),
is an organochlorine insecticide, and recently California has banned the sale
of lindane for head lice and scabies because of environmental problems.23 In view of extremely poor pediculicidal and ovicidal
activity, potential toxic effects on the central nervous system, resistance,
and environmental contamination, we see no reason for continued use of lindane
in the United States, and as stated in Update 2000,1 we strongly recommend its removal from the market.
There were statistically significant differences in the efficacy of
pyrethrin and permethrin products when compared with the results found in Update 2000.1 One interesting
observation between the 2 studies was that the 2 synergized natural pyrethrin
products, RID and A-200 shampoo, which contain the same active ingredients
and concentrations, performed so differently. The RID used in the 1986 study6 was in a brown glass bottle and contained benzyl alcohol
as an inactive ingredient, probably due to its properties as a preservative.
However, 20 years ago we found this particular alcohol alone to have quick
knockdown, but not kill. Nix was introduced on the market in 1986 in a plastic
bottle similar to the packaging of other crème rinses, not in a glass
bottle like a pediculicide. The OTC products soon picked up this safety component
for use in the bath or shower with children, and they soon came out in plastic
bottles. However, when the container for RID was changed to a plastic bottle
sometime after 1986, it no longer contained benzyl alcohol and was inferior
to the prior product. Even at small concentrations, benzyl alcohol, which
A-200 shampoo and many generic products still contain in their vehicle, seems
to have some synergistic activity, perhaps slowing down the development of
resistance as piperonyl butoxide (PBO) is now known to do.3, 15
Over a half a century ago, PBO was added as a synergist to the relatively
expensive pyrethrum extract, so less extract was needed to produce the same
insecticidal activity.24 Although originally
PBO was added purely for financial reasons, it is now known to slow down the
development of resistance at the mixed function oxidase (MFO) pathway.3
The difference in efficacy between undiluted and diluted Nix is important.
Because Nix is indicated for use on "damp" hair, there is a dilution effect
when used in vivo. This effect will vary from user to user because damp or
towel dried can mean different things to different people and certain hair
types retain more water. The dilution factor could be in part responsible
for the development of permethrin resistance because some lice may have been
exposed to sublethal doses of this insecticide. The first Nix clinical trial
published found that a single 10-minute treatment of Nix was 100% effective
at 1 week and 97% at 2 weeks due to the residual activity of permethrin on
the hair shaft.7 In this first Nix study,7 the product was applied to slightly damp hair that
had recently been shampooed with Prell concentrate (Proctor & Gamble,
Cincinnati, Ohio), an anionic stripping shampoo, to prepare the hair shaft
for the bonding of the permethrin. In 1985, shampoos with built-in conditioners
were rare. The addition of silicon or conditioning agents to shampoos may
have prevented the permethrin from firmly bonding to the hair shaft and not
providing sufficient residual activity to kill hatching nymphs.
The difference in the efficacy of Nix between the Panama and Florida
studies adds to the growing body of evidence that permethrin resistance is
reaching chronic levels in the United States. Through a collaborative effort
with the Entomology Department at the University of Massachusetts, Amherst,
a considerable amount of resistance data has been generated using knockdown
and mortality assays on lice from LSS.15 Furthermore,
through molecular cloning and sequencing from LSS lice, 2 point mutations
have been identified, therefore confirming true permethrin resistance in head
lice from south Florida.15
From our experience and that of other investigators, combing alone is
not sufficient treatment for the treatment of pediculosis capitis and is also
time-consuming, frustrating, and painful.2-3,20
Since combing alone cannot guarantee cure, treatment must also be used. The
successful off-label use of ivermectin in the United States and worldwide
for ectoparasites suggests that this be clinically evaluated for head lice.2, 17, 25 And in the United
Kingdom, Roberts et al22 found that a malathion
lotion similar to that tested here was about 3 times more effective than extensive
wet combing or "bug busting" even in a malathion-resistant population.
Unfortunately, with the increase of resistance and the decrease of efficacy
of certain commercially available pediculicides, we are finding an increasing
number of severe infestations with multiple pyodermas and excoriations of
the scalp. Thus, there is an urgent need for lice treatments that are safe,
effective, rapid killing, ovicidal, and easy to use; that do not require nit
removal for success; and that also incorporate a resistance prevention strategy.
AUTHOR INFORMATION
Accepted for publication August 8, 2001.
This study was supported by a grant-in-aid from Medicis Pharmaceutical
Corporation, Phoenix, Ariz, and by the FEST members who donated their time.
We would like to sincerely thank Lynda Dillion, Laura Belinda, and Charmaine
Gayle of Lice Source Services, Inc, for technical assistance and David Taplin
of FEST for editorial assistance.
Corresponding author and reprints: Terri L. Meinking, BA, Department
of Dermatology and Cutaneous Surgery, University of Miami School of Medicine,
PO Box 016960, R-117, Miami, FL 33101 (e-mail: tmeinkin{at}med.miami.edu).
From the Field Epidemiology Survey Team (FEST), Department of Dermatology
and Cutaneous Surgery, University of Miami School of Medicine, Miami, Fla
(Mss Meinking, Entzel, Lemard, and Villar); Lice Source Services, Inc, Plantation,
Fla (Mss Serrano and Rivera and Mr Hard); and University of Miami, School
of International Studies, Miami (Ms Lemard).
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