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Evaluation of spinosad for the oral treatment and control of flea infestations on dogs in Europe

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  • INP- École Nationale Vétérinaire de Toulouse

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The novel ectoparasiticide spinosad is a naturally occurring mixture of spinosyns A and D formed during a fermentation process. The spinosyns are tetracyclic macrolides with a unique ring system. Their mode of action differs from that of other commercially available insecticides. Laboratory and field trials were conducted to evaluate the use of spinosad in a chewable tablet at a dose range of 45 to 70 mg/kg for the treatment and control of flea infestations on dogs in Europe. Laboratory studies with artificially infested dogs confirmed persistent activity against Ctenocephalides felis of higher than 99 per cent at three weeks post-treatment with values of 96.5 to 97.8 per cent at four weeks. Two multicentric field trials with naturally infected client-owned animals in five European countries used selamectin as comparator. Monthly doses were given during the summer when many homes were heavily infested. Households with spinosad-treated dogs showed cumulative benefits with flea burdens reduced by about 97 per cent at 14 and 30 days and by 99.6 per cent at 60 and 90 days. Corresponding figures for selamectin were significantly lower (P<0.05) at all time points: between 88.5 and 91 per cent at 14 and 30 days, then 97.8 and 98.2 per cent at 60 and 90 days. Thus, the performance of spinosad compared favourably with that of the established reference product.
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Evaluation of spinosad for the oral treatment
and control of flea infestations on dogs in Europe
S. Wolken, M. Franc, E. Bouhsira, S. Wiseman, B. Hayes,
B. Schnitzler, D. E. Jacobs
The novel ectoparasiticide spinosad is a naturally occurring mixture of spinosyns A and D
formed during a fermentation process. The spinosyns are tetracyclic macrolides with a
unique ring system. Their mode of action differs from that of other commercially available
insecticides. Laboratory and field trials were conducted to evaluate the use of spinosad in
a chewable tablet at a dose range of 45 to 70 mg/kg for the treatment and control of flea
infestations on dogs in Europe. Laboratory studies with artificially infested dogs confirmed
persistent activity against Ctenocephalides felis of higher than 99 per cent at three weeks
post-treatment with values of 96.5 to 97.8 per cent at four weeks. Two multicentric field trials
with naturally infected client-owned animals in five European countries used selamectin
as comparator. Monthly doses were given during the summer when many homes were
heavily infested. Households with spinosad-treated dogs showed cumulative benefits with
flea burdens reduced by about 97 per cent at 14 and 30 days and by 99.6 per cent at 60
and 90 days. Corresponding figures for selamectin were significantly lower (P<0.05) at all
time points: between 88.5 and 91 per cent at 14 and 30 days, then 97.8 and 98.2 per cent
at 60 and 90 days. Thus, the performance of spinosad compared favourably with that of the
established reference product.
DESPITE the introduction over the past 10 to 15 years of a number
of highly effective long-acting topically applied pulicidal compounds
such as imidacloprid, fipronil, selamectin, pyriprole and metaflumi-
zone (Dryden 2009), fleas continue to be a frequent cause of discom-
fort and canine disease throughout much of Europe (Farkas and others
2009). The so-called ‘cat flea’, Ctenocephalides felis, feeds on humans as
well as on a variety of domesticated and wild animals, and is the com-
monest species found on dogs. Fleas mostly cause minor irritation,
unless present in large numbers, but some dogs may develop hyper-
sensitivity reactions (flea-allergic dermatitis) of greater or lesser sever-
ity. Fleas may also transmit other potential pathogens such as the tape-
S. Wolken, DrMedVet,
University of Veterinary Medicine
Hannover, Institute for Parasitology,
Buenteweg 17, 30559 Hannover,
Germany
M. Franc, PhD, DVM, DipEVPC,
E. Bouhsira, DVM,
Université de Toulouse, INP, ENVT-
Parasitologie-Dermatologie, Ecole
Nationale Vétérinaire, 23 chemin des
capelles, 31076 Toulouse cedex, France
S. Wiseman, PhD,
B. Hayes, BSc,
B. Schnitzler, DrMedVet,
Elanco Animal Health, Lilly House,
Priestley Road, Basingstoke, Hampshire,
RG24 9NL, UK
D. E. Jacobs, BVMS, PhD, DipEVPC,
FRCVS, FRCPath,
Department of Pathology and Infectious
Diseases, Royal Veterinary College,
University of London, Hawkshead Lane,
North Mymms, Hatfield, Herts, AL9
7TA, UK
Correspondence to Dr Schnitzler,
e-mail: schnitzler_beate@lilly.com
Provenance: not commissioned;
externally peer reviewed
Accepted October 5, 2011
Published Online First December 2,
2011
Veterinary Record (2012) 170, 99 doi: 10.1136/vr.100211
worm, Dipylidium, and microorganisms including some Bartonella and
Rickettsia species (Rolain and others 2003, Shaw and others 2004). Cat
fleas have shown a propensity to develop resistance to earlier insecti-
cidal classes, such as cyclodienes, carbamates, organophosphates and
pyrethroids. Extending the longevity of currently effective therapies
should be a major goal of the veterinary community (Rust 2005).
Thus, there is a continuing need to develop improved flea-control
methodologies and to expand the chemotherapeutic options available
to the veterinarian for this purpose.
The latest addition to the range of commercially available long-
acting pulicides is spinosad (Comfortis, Elanco) which is character-
ised by oral rather than topical administration and a rapid speed of
kill (Blagburn and others 2010). Spinosad is a naturally occurring
mixture of spinosyns A and D formed during a fermentation process
employing the soil-dwelling actinomycete, Saccharopolyspora spinosa.
Structurally, spinosyns are tetracyclic macrolides with a unique ring
system. They exhibit a novel mode of action primarily involving
nicotinic acetylcholine receptor binding sites (nAChRs) that are
distinct from those targeted by other insecticides (Sparks and oth-
ers 2001). The outcome is disruption of the flea’s nervous system.
A secondary effect on γ-aminobutyric acid (GABA) may potenti-
ate this pulicidal activity. The low mammalian toxicity associated
with spinosad is likely to be due to a lack of homology between
insect and mammalian nicotinic and/or GABA receptors. Spinosad
is presented for flea-control as a ‘chewable’ tablet (ie, a tablet that
is efficacious whether swallowed whole or after being chewed or
bitten). Preliminary dog studies indicated that effective flea-control
over a four-week period could be obtained with dose rates of 30 mg
spinosad/kg bodyweight or above (Snyder and others 2007). A mini-
mum dose of 45 mg/kg was selected for European laboratory studies
to ensure compliance with all local regulatory requirements (EMEA/
CVMP 2007). As is the case with all medicines presented in tablet
form, any combination of tablet sizes has to cover a range of body-
weights and tablet strengths are therefore designed to provide dosag-
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and females in each. The second, in France (study 3), was similar but
with an additional female in the control group bringing the total of
untreated dogs to nine. Whole spinosad tablets (Comfortis, Elanco) or
placebo tablets were given on day 0. Treated dogs weighing less than
12.5 kg received a tablet containing 560 mg spinosad, whereas those
over this weight received 810 mg spinosad. Fleas were placed on the
animals on the day before treatment (day –1) in the French study and
on days 7, 14, 21 and 28 in both studies.
Field studies
Study design
Field investigations included a one-month trial (study 4) covering five
European countries (UK, Netherlands, France, Germany and Italy)
and a three-month trial (study 5) confined to France but spanning
both Atlantic and Mediterranean climatic zones. Each was a blinded
positive-control multicentre study using a randomised complete block
design. Data collection was standardised using preprinted forms and
questionnaires. The experimental unit was the household represented
by one dog. Ethical considerations did not permit the use of nega-
tive (untreated) controls, and thus spinosad treatments were compared
with an established reference product. Because no alternative long-act-
ing oral pulicide was commercially available, selamectin (Stronghold,
Pfizer) was selected for this purpose. Although chemically unrelated
and topically applied, selamectin (like spinosad) is a long-acting puli-
cide with systemic activity (Sarasola and others 2002). As the two
products are so different in formulation and presentation, their iden-
tity could not be masked, but trial blinding was achieved by ensuring
that personnel conducting flea-counts were unaware of which treat-
ment had been given. In accordance with current guidelines, the ran-
domised allocation procedure allowed one positive control for every
two spinosad test homes.
Animals
For enrolment, dogs at first inspection had to be naturally infested
with at least 10 fleas but otherwise healthy, over six weeks old and
with a minimum bodyweight of 1 kg. They were not accepted if
intended for breeding within six months or if any flea treatment had
been used within a specified time period (dependent on the nature of
the product used), or if their disposition or hair-coat precluded accurate
flea-counting. Cooperating dog owners were fully informed and pro-
vided a written consent.
Treatments
Spinosad-treated dogs received an appropriate combination of whole
chewable tablets to provide a dose within the range of 30 to 90 mg/
kg (although only animals receiving 45 to 70 mg/kg were used for
efficacy evaluation, see statistical analysis section below). Their
owners, after appropriate instruction, administered the treatments
at home together with food. Selamectin was applied as per label
instructions (ie, topically as a spot-on preparation to provide a mini-
mum dose of 6 mg/kg). All dogs in multi-pet homes were treated
with the same product. Cats in participating households received
selamectin irrespective of the dog treatment (since no spinosad for-
mulation suitable for cats was available and flea-control in the home
depends on all pets being treated). The use of any other medicament,
shampoo, food supplement, environmental treatment etc contain-
ing any ingredient efficacious against fleas was prohibited during the
course of the trial.
After the initial flea-count and allocation, recruited dogs were
dosed on day 0 in the one-month study (study 4) and at monthly
intervals on days 0, 30 and 60 in the three-month study (study 5).
Flea-counts
A standardised flea-combing procedure taking at least 15 minutes was
performed by trained practice staff using a separate flea-comb for each
dog. Only live, viable fleas were recorded (ie, those demonstrating nor-
mal movement and behaviour, with an ability to maintain an upright
posture and cling onto hair). In study 4, flea-counts were performed
on days 14 and 30 (with a discretionary period of ±2 days to encour-
age owner compliance) and on days 14, 30, 60 and 90 (±three days)
in study 5. Observations were completed before dosing on treatment
es within strictly defined limits. This paper describes laboratory and
field investigations evaluating a dose range of 45 to 70 mg spinosad/
kg bodyweight for the oral treatment and control of flea infestations
on dogs in Europe.
Materials and methods
Three laboratory and two multicentric field studies are reported.
They complied with internationally accepted guidelines and stand-
ards for trial design and animal welfare (EMEA/CVMP 2000, 2007,
Marchiondo and others 2007) as well as all relevant local regulations
and ethical requirements.
Laboratory studies
Study design
Laboratory investigations included a preliminary dose-demonstration
study using unformulated spinosad powder and two dose-confirma-
tion studies with chewable tablets. All were designed as randomised
complete block studies and partly blinded to minimise the risk of
unintentional bias. The dose-confirmation studies were conducted
independently at separate locations.
Animals and infestations
Individually housed laboratory beagles with bodyweights between
10 and 17 kg were used. As part of the allocation procedure, all dogs
were infested with 100 newly emerged unfed fleas about one week
before the scheduled treatment date to account for variation in indi-
vidual susceptibility. Insecticidal activity was evaluated by a similar
application of fleas on the days indicated for each study. Fleas were
counted and removed 48 hours after each infestation. To do this, dogs
were combed systematically with a fine-toothed comb until no more
fleas were detectable. Personnel conducting flea-counts were unaware
of which treatment had been given.
Treatment
An earlier observation (Snyder and others 2007) had suggested that
feeding around the time of dosing improves spinosad bioavailability.
On the day of treatment, therefore, all dogs were offered 25 per cent of
their daily canned ration no more than 30 minutes before they were
dosed. Control dogs received a placebo identical to the spinosad pres-
entation but without an active ingredient. To ensure that the whole
dose was swallowed, the capsule or tablet was placed over the back of
the tongue with a small volume of water. The remainder of the daily
meal was given after dosing.
Statistical analysis
Before each analysis of results, a logarithmic transformation
(ln(count+1)) was applied to the live flea-counts for each animal at
each scheduled time point. This transformation addressed the skew-
ness of the data and also allowed for zero counts. Back-transformed
geometric means were calculated as
e
x
–1
, where x was the arithme-
tic treatment mean of log-transformed counts at a given time point.
Efficacy based on the reduction of flea-counts attributable to treatment
was calculated using the following formula:
Efficacy (per cent) = CT
C x 100
Where, C is the geometric mean of the flea-counts of the con-
trol group and T is the corresponding geometric mean for the treated
group.
Preliminary study
The preliminary dose-demonstration study (study 1) employed two
groups of six dogs, each comprising four males and two females. The
purpose was to confirm the residual insecticidal efficacy of spinosad at
the proposed European minimum dose rate of 45 mg/kg. For this, each
dog was treated on day 0 with an exact dose, based on its bodyweight
of unformulated spinosad powder in a gelatine capsule. Control dogs
received empty capsules. Fleas were applied on days 21 and 28.
Dose-confirmation studies
The first dose-confirmation trial was conducted in Germany (study 2)
and included two groups of eight dogs with equal numbers of males
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days. In the case of multi-pet homes, flea-count data were collected
from only one designated dog.
Statistical analysis
The prescribed spinosad dosage used in these trials was based on
results from early studies (Snyder and others 2007) and as a conse-
quence spanned a broader dose range (30 to 90 mg/kg) than that sub-
sequently selected for European registration (45 to 70 mg/kg). To fulfil
the objective of the current publication, therefore, data from spinosad-
treated dogs receiving less than 45 mg/kg or more than 70 mg/kg were
rejected from the analysis. This constrained the numbers of eligible
spinosad-treated dogs to 93 (of 197) and 43 (of 130) in studies 4 and
5, respectively. These restrictions did not affect the statistical power
or validity of the analysis. The full set of positive control (selamectin)
dogs was kept for comparison.
In the absence of negative (untreated) controls, efficacy values were
calculated by comparing post-treatment flea-counts with baseline data
collected immediately before the first treatment. For reasons outlined
above for the laboratory studies, geometric means were used for this
purpose. Further analysis on the log-transformed (flea-count+1) data
used a repeated measures mixed effects linear model for values on suc-
cessive observation days. In addition to estimating reduction in flea
populations on treated dogs, the proportion of dogs in each treatment
group on which no fleas could be found (the ‘zero-flea’ percentage)
was also recorded.
Results
Laboratory studies
In all cases, pretreatment observations confirmed that flea infestations
could be established on all animals in sufficient numbers to allow valid
statistical analysis. Feeding and treatment procedures were completed
without problem and all animals received their full dose, which in
the dose-confirmation trials ranged from 45.9 to 54.0 mg/kg. Efficacy
values for each observation-point in the three studies are displayed
in Table 1. Flea populations established on dogs in study 3 one day
before treatment were completely eliminated. Residual efficacies in
all three studies were greater than 99 per cent up to three weeks post-
treatment, while day 30 values of 96.5, 96.5 and 97.8 per cent were
recorded in studies 1, 2 and 3, respectively.
Field studies
The clinical phase of each field study was completed between May
and November and encompassed a wide range of geographical, social
and climatic regions. Data from 34 veterinary clinics qualified for
inclusion in study 4, and from 21 clinics in study 5. The test popu-
lation in study 4 comprised female and male dogs in almost equal
proportions (54.5 v 45.5 per cent). They belonged to no fewer than
52 breeds. Longhaired varieties were, however, in a minority (9.6 per
cent). Bodyweight ranged from 1.3 to 65 kg and age from seven weeks
to 17 years. Homes with a single dog, with more than one dog (but
no cat) or with at least one cat were almost equally represented (32.6,
37.9 and 29.5 per cent, respectively). Most (82.7 per cent) lived partly
or fully outdoors. Study 5 was similarly diverse, although a larger pro-
portion (69.3 per cent) was kept indoors.
Flea populations at the time of recruitment were often substantial
and were comparable between treatment groups. The largest initial
flea infestations recorded for spinosad- and selamectin-treated groups,
respectively, were 560 and 229 in the first trial; they were 437 and
394, respectively, in the second trial (Table 2). Pretreatment geometric
mean flea-counts for spinosad- and selamectin-treated groups, respec-
tively, were 36.7 and 29.7 in study 4, and 40.7 and 33.5 in study 5.
At both 14 and 30 days post-treatment, flea burdens of spinosad-
treated dogs were reduced by about 97 per cent compared with
pretreatment values (Table 2), while corresponding figures for sela-
mectin were significantly lower (90.7 and 88.5 per cent on day 14;
89.4 and 91.0 per cent on day 30 in studies 4 and 5, respectively). At
the end of the second and third months, reductions of 99.6 per cent
were recorded for the spinosad group, while selamectin values were
again significantly lower at 97.8 and 98.2 per cent on days 60 and 90,
respectively.
The proportion of spinosad-treated dogs on which no fleas could
be found (Table 2) varied during the first month from a low of 39.5
per cent (study 5, day 14) to a high of 59.1 per cent (study 4, day 14).
Corresponding figures for the selamectin animals were 28.6 per cent
(study 5, day 14) to 34.1 per cent (study 4, day 30). Following the sec-
ond monthly dose, the figures for spinosad and selamectin increased
to 77.5 and 62.9 per cent, respectively. By day 90, they had become
significantly different (P=0.042) at 85 and 67.1 per cent, respectively.
Discussion
Laboratory studies are usually designed to isolate and define single
aspects of the biological activity of an experimental compound. They
provide essential building blocks for knowledge and understanding
but rarely do they fully reproduce or reflect the complexities of natural
disease. In this respect, domestic flea infestations present a particu-
larly challenging therapeutic problem (Rust and Dryden 1997). Only
a small part of the total flea population resides on the host animal.
In much greater abundance are off-host life cycle stages such as eggs,
larvae, pupae and newly emerging adults found in locations such as
carpets, furniture and bedding. Flea-control therefore depends on the
overall impact of veterinary and other interventions on the dynam-
ics of this ecological system. Modern veterinary pulicides can influ-
ence this process in a number of ways depending upon their particu-
lar biological characteristics, the nature and spectrum of which vary
between products. Such attributes can include their short-term effect
on adult fleas (knockdown), longer-term residual activity, speed of kill,
TABLE 1: Laboratory studies: percentage reduction in flea-counts
comparing spinosad-treated dogs with placebo-treated controls
48 hours after each infestation
Study Formulation Actual dose given
% Reduction in flea-count
measured on day
mg/kg 1 9 16 23 30
1 Powder 45 - - - 99.8 97.8
2 Tablet 45.9-54.0 - 99.9 100 99.4 96.5
3 Tablet 48.2-53.0 100 100 100 99.1 96.5
TABLE 2: Field trial data: percentage reduction in flea-counts of spinosad and selamectin-treated dogs (compared with pretreatment values
on day 0) and the proportion of flea-free dogs at each observation day
Treatment*
Total number
of dogs
Number of fleas
on day 0
% Reduction in flea-counts on day % Dogs with zero fleas on day
14 30 60 90 14 30 60 90
Study 4
Spinosad 93 36.7 (11-560) 97.5 97.2 - - 59.1 54.5 - -
Selamectin 93 29.7 (10-229) 90.7 89.4 - - 33.7 34.1 - -
P values
§
0.001 0.003 - - 0.001 0.006 - -
Study 5
#
Spinosad 43 40.7 (10-437) 97.3 97.4 99.6 99.6 39.5 50.0 77.5 85.0
Selamectin 71 33.5 (10-394) 88.5 91.0 97.8 98.2 28.6 31.4 62.9 67.1
P values
§
<0.001 0.005 0.01 0.035 NS NS NS 0.042
* Spinosad 45 to 70 mg/kg; selamectin 6 to 11.8 mg/kg
Geometric mean and range
Treated day 0
#
Treated days 0, 30, 60
§
Comparing spinosad and selamectin groups
NS Not significant (P>0.05)
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anti-feeding potential, repellency and larvicidal effects (Carlotti and
Jacobs 2000). Furthermore, these properties can be modified by factors
such as formulation, dose and method of application. Consequently,
field studies play a particularly important role in evaluating prospec-
tive flea-control agents as they come closest to encompassing the full
scope of these ecological and therapeutic complexities.
Effective flea-control is a three-stage process (Carlotti and Jacobs
2000). First, the removal of fleas from an already infested host pro-
vides relief from discomfort and aids the resolution of skin lesions due
to self-trauma or allergy. Secondly, the animal must be protected from
re-infestation since the household environment is likely to be con-
taminated and therefore a continuing source of hungry host-seeking
fleas. Thirdly, the reservoir of off-host life cycle stages must be elimi-
nated as this is the only way a long-term solution can be provided.
Traditionally, this was achieved by the direct application of chemicals
onto flea development ‘hotspots’ around the home (Rust and Dryden
1997). More recently, however, this approach has been largely super-
seded by long-acting animal treatments that halt the deposition of
viable flea-eggs. With no new eggs entering the system, the domestic
reservoir of developing fleas becomes progressively depleted and is
eventually driven towards extinction (Dryden 2009).
Under most household conditions, fleas originating from eggs
deposited before the start of a control programme will have completed
their development and emerged from their cocoons within three to five
weeks, but this process can in some cases be delayed by up to 174 days
(Dryden and Rust 1994) and may influence the results of clinical trials.
Nevertheless, in the current field investigation, a 99.6 per cent reduction
in flea burdens on dogs was observed in spinosad households 60 days
from the start of the monthly dosing programme and the ‘zero-flea’
data suggested that fleas had been eliminated from up to 85 per cent of
these homes by day 90 (Table 2). This compared favourably with the
selamectin controls in which a 97.8 per cent reduction in flea-count
was recorded at day 60 and a ‘zero-flea’ value of 67 per cent at day 90.
These investigations were conducted over the summer season in
a variety of climatic regions including warm, humid areas favouring
flea reproduction. Thus, these results were obtained at a time when
flea populations would normally be increasing in magnitude. Indeed,
the day 14 zero-flea figures indicate the presence of heavy challenge in
many of the households in the early part of the two studies (Table 2)
with evidence of re-infestation taking place on 41 and 60 per cent of
spinsosad dogs, respectively, and on 66 and 71 per cent of the selamec-
tin groups. Nevertheless, the overall number of fleas on the animals
at day 14 had been reduced by 97 per cent in the case of spinosad and
by about 90 per cent for selamectin indicating a high level of protec-
tion in the face of continuing re-infestation. Similar results have been
reported from a comparable trial encompassing 14 sites in the USA
and two in Canada (Robertson-Plouch and others 2008).
The high-performance level of spinosad under challenging clinical
situations in both European and North American field trials can be
ascribed to the summation of its inherent pulicidal attributes, includ-
ing ‘knockdown’, duration of activity, speed of kill and the resultant
impact of these on flea-egg output. At dose rates of 30 mg/kg or more,
the ‘knockdown’ effect of spinosad against a previously established flea
population is virtually 100 per cent (Snyder and others 2007, Blagburn
and others 2010). Thereafter, a high level of residual protection against
re-infestation is maintained for a month (Snyder and others 2007). In
this study, where dose rates in individual dogs ranged from 45 to 54
mg/kg, values higher than 99 per cent were recorded up to day 23 and
of 96.5 per cent at day 30 (Table 1). The speed at which spinosad kills
fleas was investigated by Blagburn and others (2010) using a dose rate
of 30 to 60 mg/kg. Mortality was evident as early as 30 minutes after
treatment with a significant reduction (64.2 per cent, P<0.05) at one
hour. By two hours, efficacy had increased to 85.8 per cent and had
reached 100 per cent by four hours. This is of significance in control
programmes as newly acquired fleas must be killed before they start
to lay eggs, if recontamination of the household environment is to
be avoided. To measure the effect of spinosad-treatment on flea-egg
production, Blagburn and others (2010) collected eggs dropping from
treated dogs and untreated controls that had been infested with fleas at
intervals over a one-month period. They estimated that treatment had
reduced the number of eggs falling to the ground by at least 99.8 per
cent. Extrapolating this result to a domestic setting, monthly spinosad
treatments would therefore be expected to make a major contribution
towards the long-term objective of eliminating the environmental res-
ervoir of off-host life cycle stages. Complementary interventions such
as household vacuum cleaning, particularly of potential hotspots, are of
course invaluable adjuncts for accelerating progress towards this goal.
The fast onset of flea mortality following oral dosing observed by
Blagburn and others (2010) can be explained by rapid absorption of
spinosyns A and D from the canine gastrointestinal tract, with maxi-
mum plasma concentrations occurring about two to four hours after
treatment (Anon 2007). The systemic activity of spinosad has other
potentially beneficial consequences. For example, newly acquired fleas
start to feed within minutes of jumping onto their host (Dryden and
Gaafar 1991, Cadiergues and others 2000) and may thereby assimilate
a lethal dose of a systemic pulicide more quickly than by absorption
of a topical contact insecticide through the cuticle (McCoy and others
2008). Furthermore, as spinosad is not known to be present in sebum,
shed hair or skin flakes (Blagburn and others 2010), direct transfer
from treated animals onto animal handlers or into the household
environment is unlikely.
In conclusion, the rapid absorption and fast speed of kill of spinosad
ensure that infested dogs respond quickly to treatment and that fleas
acquired subsequently are killed before they start to lay eggs, thereby
breaking the flea life cycle in contaminated households. A monthly
dosing programme using client-owned dogs, many of which would
have been kept under conditions of heavy natural challenge, reduced
parasite burdens on dogs by 97 per cent during the first month and
drove the flea population close to extinction in the majority of homes
within 60 days. In comparative field studies, efficacy values for spinosad
were higher than those obtained for the reference product, selamectin.
Thus, laboratory and field trials have confirmed that spinosad chewable
tablets administered to dogs at a dose rate of 45 to 70 mg/kg are highly
effective for the treatment and control of flea infestations.
Acknowledgements
The authors express their gratitude to all personnel involved in the
independent laboratory studies and to the dog owners and staff of
veterinary clinics taking part in the field investigations. J. Stoker, A.
K. Nissen and other members of the Elanco team are thanked for
their participation, as is Dr Dan Snyder for his constant support and
encouragement.
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and control of flea infestations on dogs in
Evaluation of spinosad for the oral treatment
and D. E. Jacobs
S. Wolken, M. Franc, E. Bouhsira, S. Wiseman, B. Hayes, B. Schnitzler
doi: 10.1136/vr.100211
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... It is both a contact and stomach poison for many caterpillar species. Owing to its favorable environmental properties such as rapid degradation, low acute mammalian toxicity 15 , no carcinogenicity 16 , and no cross-resistance 14 , spinosad has been widely used to control a wide variety of pests, such as thrips, leafminers, mosquitoes, ants, fruit flies, as well as animal and human head lice [17][18][19] . It has been reported that the highly selective toxicity to insects may be related to its indirect interaction with acetylcholine receptor and gammaaminobutyric acid (GABA) receptor of insect central nervous system 20,21 . ...
... SPA and LM-2I interact with ASS1. SPA is one of the two components of spinosad, a natural substance that is very toxic to insects, but not to mammals 15,[17][18][19] . The highly selective toxicity to insects is related to its indirect interaction with GABA receptors of insect central nervous system 20,21 . ...
... SPA is one of the two components of the insecticide spinosad, a natural substance produced by Saccharopolyspora spinoza 17 . Because of its low mammalian toxicity, spinosad has been widely used to control a wide variety of pests [17][18][19] . Spinosad interrupts the function of nicotinic and GABA-gated ion channels, resulting in rapid excitation of the insect nervous system, leading to involuntary muscle contractions, tremors, paralysis, and death 28 . ...
Article
Full-text available
Argininosuccinate synthase (ASS1) is a ubiquitous enzyme in mammals that catalyzes the formation of argininosuccinate from citrulline and aspartate. ASS1 genetic deficiency in patients leads to an autosomal recessive urea cycle disorder citrullinemia, while its somatic silence or down-regulation is very common in various human cancers. Here, we show that ASS1 functions as a tumor suppressor in breast cancer, and the pesticide spinosyn A (SPA) and its derivative LM-2I suppress breast tumor cell proliferation and growth by binding to and activating ASS1. The C13-C14 double bond in SPA and LM-2I while the Cys97 (C97) site in ASS1 are critical for the interaction between ASS1 and SPA or LM-2I. SPA and LM-2I treatment results in significant enhancement of ASS1 enzymatic activity in breast cancer cells, particularly in those cancer cells with low ASS1 expression, leading to reduced pyrimidine synthesis and consequently the inhibition of cancer cell proliferation. Thus, our results establish spinosyn A and its derivative LM-2I as potent ASS1 enzymatic activator and tumor inhibitor, which provides a therapeutic avenue for tumors with low ASS1 expression and for those non-tumor diseases caused by down-regulation of ASS1.
... Spinosad was introduced in 2007 as a highly effective orally-administered treatment for canine flea control and pioneered the move to monthly, systemic adulticide treatments for control programs. Early field studies with spinosad in the USA and Europe demonstrated excellent efficacy against existing flea infestations (Robertson-Plouch et al., 2008;Wolken et al., 2012;Dryden et al., 2013). Those studies and the recent isoxazoline-spinosad investigations have made spinosad one of the most field-tested flea control products, and the standard against which systemically active products are assessed. ...
... That speed of onset may have been a factor in our Week 1 finding of significantly more dogs being free of fleas in the spinosad group (88.9%) than in the lotilaner group (66.7%) (p = 0.025). The field efficacy of spinosad that we report aligns with findings over the years of other studies in the USA and Europe demonstrating that spinosad continues to be as effective now as when first made available in 2007 (Robertson-Plouch et al., 2008;Wolken et al., 2012;Dryden et al., 2013;Meadows et al., 2014;Freedom of Information Summary, NexGard, 2013;Hayes et al., 2015;Becskei et al., 2016;Cherni et al., 2016;Dryden et al., 2017). Nonetheless, the significant between-treatment differences at Week 4, both in owner scoring of the CPSS and in flea counts, merit further consideration, although these differences were not observed during the remainder of the study. ...
... From the many field reports describing comparisons of spinosad with other flea control products, our study is just the second to find a significant improvement over spinosad (Robertson-Plouch et al., 2008;Wolken et al., 2012;Dryden et al., 2013;Meadows et al., 2014;Freedom of Information Summary, NexGard, 2013;Hayes et al., 2015;Becskei et al., 2016;Cherni et al., 2016;Dryden et al., 2017). Meadows et al. (2014) found a significant difference in favor of fluralaner over spinosad in the proportion of flea-free dogs four weeks after each of the first and the third monthly spinosad treatments, but there was no evidence that this difference was clinically relevant. ...
Article
Full-text available
Post-launch field investigations of recently-approved flea control products establish an efficacy baseline and in subsequent years can detect any efficacy decline suggestive of emerging resistance. As part of a continuing program of yearly assessment of flea control products in west central Florida, this study, using client-owned dogs, investigated the efficacy of lotilaner and spinosad in controlling fleas and in alleviating dermatologic signs likely associated with flea infestations. Forty-four qualifying households were randomized to either a lotilaner (Credelio®) (minimum dose rate 20 mg/kg) or a spinosad (Comfortis®) (30 mg/kg) group, with 33 and 36 dogs in each group, respectively. On Days 0 and 28 (±2) all dogs in each household were treated with the allocated product according to label directions, and all household cats received spinetoram (Cheristin®). On Day 0 and at weekly intervals through Day 56 (±2), on-animal and premises flea burdens were enumerated, a veterinary dermatologist scored integumental changes using canine atopic dermatitis extent and severity index (CADESI)-4 and flea allergy dermatitis (FAD) scales, and owners scored pruritus using the validated canine pruritus severity scale (CPSS).At study entry geometric mean flea counts were 33.2 and 29.9 in the lotilaner and spinosad groups, respectively. For both groups, reductions in flea counts were > 99% at the first post-treatment assessment (Week 1), and 100% from Week 6 through the final assessment (Week 8) when all study dogs were flea-free. For both groups, at each timepoint, flea counts on dogs and in traps were significantly reduced compared to the initial assessment (p
... An oral dose of spinosad provided >95% kill for 30 days on dogs [285]. An oral dose of spinosad against C. felis on dogs provided >95% kill of fleas for 22 days compared with 100% kill with fipronil/methoprene at day 43 [295]. A combination spinosad/milbemycin oxime and spinosad applied to dogs provided 100% kill of fleas for at least 30 days [350]. ...
... Similarly, a clinical trial with selamectin and spinosad resulted in >95% reductions in flea counts at day 90. At day, 85% of the dogs treated with spinosad were flea free compared with 67% of dogs treated with selamectin [295]. ...
Article
Full-text available
The cat flea Ctenocephalides felis felis (Bouché) is the most important ectoparasite of domestic cats and dogs worldwide. It has been two decades since the last comprehensive review concerning the biology and ecology of C. f. felis and its management. Since then there have been major advances in our understanding of the diseases associated with C. f. felis and their implications for humans and their pets. Two rickettsial diseases, flea-borne spotted fever and murine typhus, have been identified in domestic animal populations and cat fleas. Cat fleas are the primary vector of Bartonella henselae (cat scratch fever) with the spread of the bacteria when flea feces are scratched in to bites or wounds. Flea allergic dermatitis (FAD) common in dogs and cats has been successfully treated and tapeworm infestations prevented with a number of new products being used to control fleas. There has been a continuous development of new products with novel chemistries that have focused on increased convenience and the control of fleas and other arthropod ectoparasites. The possibility of feral animals serving as potential reservoirs for flea infestations has taken on additional importance because of the lack of effective environmental controls in recent years. Physiological insecticide resistance in C. f. felis continues to be of concern, especially because pyrethroid resistance now appears to be more widespread. In spite of their broad use since 1994, there is little evidence that resistance has developed to many of the on-animal or oral treatments such as fipronil, imidacloprid or lufenuron. Reports of the perceived lack of performance of some of the new on-animal therapies have been attributed to compliance issues and their misuse. Consequentially, there is a continuing need for consumer awareness of products registered for cats and dogs and their safety.
... Sarolaner provided 99.3% (northern study) and 96.7% (southern study) mean efficacy at 14 days after the first treatment and these findings were consistent with previous data reported for field studies conducted in the United States and Europe [26,27]. At the same time point, spinosad provided 94.6 and 97.6% mean efficacy in the northern and southern studies, respectively, which is similar to that previously reported in other studies [26][27][28]. The efficacy of sarolaner at the end of the first monthly treatment was ≥ 99.2% compared to the spinosad efficacy of ≥ 89.7%. ...
... The efficacy of sarolaner at the end of the first monthly treatment was ≥ 99.2% compared to the spinosad efficacy of ≥ 89.7%. The observed differences in the efficacy between sarolaner-and spinosad-treated dogs following the first monthly treatment were consistent with previous reports [27][28][29]. ...
Article
Full-text available
Background: The efficacy and safety of a novel isoxazoline compound, sarolaner (Simparica®, Zoetis) and spinosad (Comfortis®, Elanco) as a positive control were evaluated for the treatment and control of natural flea infestations on dogs in two randomised, blinded, multi-centric clinical trials conducted in 11 veterinary clinics in northeastern and southeastern states of Australia. Methods: A total of 162 client-owned dogs (80 in northern study and 82 in southern study) from 105 households were enrolled. Each household was randomly allocated to receive either sarolaner (Simparica®, Zoetis) or spinosad (Comfortis®, Elanco). Dogs were dosed on Days 0, 30 and 60 and physical examinations and flea counts were conducted on Days 0, 14, 30, 60 and 90. Efficacy assessments were based on the percentage reduction in live flea counts post-treatment compared to Day 0. Results: In the northern study, at enrolment, primary dogs had flea counts ranging from 5 to 772. At the first efficacy assessment on Day 14, sarolaner resulted in 99.3% mean reduction in live flea counts relative to Day 0, compared to 94.6% in the spinosad group. On Day 30, the sarolaner-treated group had mean efficacy of 99.2% compared to 95.7% in the spinosad-treated group, and on days 60 and 90, both groups had mean efficacies of ≥ 98.8%. In the southern study, at enrolment, primary dogs had flea counts ranging from 5 to 156. Both sarolaner and spinosad resulted in ≥ 96.7% mean reduction in live flea counts on Day 14. On Day 30, the sarolaner-treated group had mean efficacy of 99.5% compared to 89.7% in the spinosad-treated group, and on days 60 and 90, both groups had mean efficacies of ≥ 98.6%. No treatment-related adverse events were observed in either study. Conclusions: A single monthly dose of sarolaner (Simparica®) administered orally at 2-4 mg/kg for three consecutive months was well tolerated and provided excellent efficacy against natural infestations of fleas under a range of Australian field conditions including different climatic and housing conditions. Similar efficacy was observed with spinosad (Comfortis®) after the second and third monthly treatments.
... By comparison, Comfortis® is a mixture of two spinosyns (spinosyn A and D), which preferentially binds to nicotinic acetylcholine receptors (nAChRs), with secondary activity against GABA-receptors [29]. This drug can also be a potent pulicide, reducing C. felis burdens by >99 and 97-98% three and four weeks post-treatment in laboratory infestations, respectively, and by >99% after a 90 day multi-country community trial [30]. Other investigators have presented more variable residual activities against fleas over 28 days [31,32]. ...
... Other investigators have presented more variable residual activities against fleas over 28 days [31,32]. In contrast to our results, previous studies have reported complete knockdown of established flea populations [33] and 100% mortality within 4 h [31], coinciding with peak canine spinosad plasma levels, between 2 to 4 h post-treatment [30]. Spinosyns have also demonstrated high levels of efficacy against Phlebotomus papatasi feeding on treated hamsters (5000 mg/kg), producing 100% sand fly mortality for one week; mortality declined to 14.2% by day 14 [34]. ...
Article
Full-text available
Background: Despite large-scale reductions in Chagas disease prevalence across Central and South America, Trypanosoma cruzi infection remains a considerable public health problem in the Gran Chaco region where vector-borne transmission persists. In these communities, peridomestic animals are major blood-meal sources for triatomines, and household presence of infected dogs increases T. cruzi transmission risk for humans. To address the pressing need for field-friendly, complementary methods to reduce triatomine infestation and interrupt T. cruzi transmission, this study evaluated the systemic activity of three commercial, oral, single dose insecticides Fluralaner (Bravecto®), Afoxolaner (NexGard®) and Spinosad (Comfortis®) in canine feed-through assays against Triatoma infestans, the principal domestic vector species in the Southern Cone of South America. Methods: Twelve healthy, outbred dogs were recruited from the Zoonosis Surveillance and Control Program in Santa Cruz, Bolivia, and randomized to three treatment groups, each containing one control and three treated dogs. Following oral drug administration, colony-reared second and third stage T. infestans instars were offered to feed on dogs for 30 min at 2, 7, 21, 34 and 51 days post-treatment. Results: Eighty-five per cent (768/907) of T. infestans successfully blood-fed during bioassays, with significantly higher proportions of bugs becoming fully-engorged when exposed to Bravecto® treated dogs (P < 0.001) for reasons unknown. Exposure to Bravecto® or NexGard® induced 100% triatomine mortality in fully- or semi-engorged bugs within 5 days of feeding for the entire follow-up period. The lethality effect for Comfortis® was much lower (50-70%) and declined almost entirely after 51 days. Instead Comfortis® treatment resulted in substantial morbidity; of these, 30% fully recovered whereas 53% remained morbid after 120 h, the latter subsequently unable to feed 30 days later. Conclusions: A single oral dose of Fluralaner or Afoxolaner was safe and well tolerated, producing complete triatomine mortality on treated dogs over 7.3 weeks. While both drugs were highly efficacious, more bugs exposed to Fluralaner took complete blood-meals, and experienced rapid knock-down. Coupled with its longer residual activity, Fluralaner represents an ideal insecticide for development into a complementary, operationally-feasible, community-level method of reducing triatomine infestation and potentially controlling T. cruzi transmission, in the Gran Chaco region.
... Two studies used a negative control (Saridomichelakis et al, 2015;Otranto et al, 2017), with the remainder using positive controls. Although using an untreated group might have provided a better comparison, withholding treatment in cases of severe flea infestation raises ethical issues (Wolken et al, 2012). This was reflected in the Otranto et al (2017) study where 16 out of 100 cats in the negative control group presented with flea allergy dermatitis. ...
Article
Successful flea control relies mainly on the use of effective anti-flea products and the adherence of pet owners to treatment recommendations. When flea infestations continue to persist, despite the application of a potent flea product, lack of efficacy may be suspected. This study evaluated whether common flea products are still effective. As compliance is also critical, the impacts of owners' adherence on treatment success were also investigated, with a view to giving recommendations for improvement. The authors tested the hypothesis that when treatment failure occurs, perceived inefficacy of anti-flea products is caused by poor compliance. Searches were carried out in PubMed and CAB Abstracts, with abstracts screened against predetermined inclusion and exclusion criteria. In total, eleven studies on efficacy and seven studies on adherence were included in the analysis. All anti-flea products included in the study, with the exception of fipronil-S methoprene and possibly selamectin, appear to be effective in treating and preventing flea infestations in dogs and cats. With the majority of pet owners failing to adhere to recommendations, all veterinary staff should be proactive in providing rationale for the use of anti-flea products and reassure owners of their effectiveness to maximise compliance.
... This excellent flea effectiveness is similar to what has been reported for the lotilaner mono product (Credelio ™ ) in laboratory studies with induced infestations as well as in clinical field studies with natural flea burdens [14,18,19]. Flea effectiveness results from this field study are similar to other studies that assessed an oral systemic isoxazoline or spinosyn containing mono-or combination drug products [18,[29][30][31][32]. Onset of action as well as speed of kill for adult fleas of the mono product of lotilaner (Credelio ™ ) has been previously reported [11,14]. ...
Article
Full-text available
Background A pivotal randomised, blinded, positive-controlled, multicentre, European field study was conducted to evaluate the effectiveness and safety of a novel combination tablet of lotilaner and milbemycin oxime (Credelio ® Plus) administered orally to client-owned dogs naturally infested with fleas and/or ticks. Methods In this field study, households with flea- or tick-infested dog(s) were enrolled on Day 0 into the study to provide data for either the tick or flea infestation cohorts. Households were randomised in a 2:1 ratio to receive either the combination investigational product (IP, Credelio Plus ® tablets) or the control product (CP: Nexgard Spectra ® tablets). Dogs were administered IP (flea cohort n = 135; tick cohort: n = 147) or CP (flea cohort: n = 67; tick cohort: n = 74) once every 4 weeks for a total of three times at a dose rate of 20.0–41.5 mg/kg bodyweight lotilaner and 0.75–1.53 mg/kg bodyweight milbemycin oxime (IP) or as recommended (CP). Percentage reduction was calculated by comparing individual dog flea and tick counts at each assessed post-treatment time point to their respective baseline (pre-treatment) infestation. Resolution of the clinical signs of flea allergy dermatitis (FAD) was assessed in flea-allergic dogs on the days that flea counts were performed. Results Flea effectiveness of Credelio Plus ® after 3 consecutive monthly treatments was 100% against Ctenocephalides felis , C. canis and Pulex irritans . Tick effectiveness of Credelio Plus ® over the same time frame was 99.3% for Ixodes ricinus and 100% against Rhipicephalus sanguineus ( s.l. ). Flea effectiveness of the CP after three consecutive monthly treatments was 100% against C. felis , C. canis and P. irritans . Tick effectiveness of the CP over the same time frame was 99.8% for I. ricinus and 100% against R. sanguineus . Credelio Plus ® was well tolerated based on the safety assessments in all treated dogs in this field study. Within both treatment groups there was a reduction in total FAD scores from baseline. Conclusions This pivotal European field study demonstrated the excellent effectiveness and safety of a combination of lotilaner and milbemycin oxime (Credelio Plus ® ) administered orally to dogs naturally infested with fleas and/or ticks. Graphic Abstract
... In the flea study, live flea counts for all species combined were reduced by 97.9% within two weeks after treatment, and this efficacy persisted through the end of the recommended monthly treatment interval with 98.6% reduction 30 days after treatment. These results are comparable to the efficacy reported previously for other orally administered pulicidal medications belonging to both the isoxazoline [13][14][15] and spinosyn class [16] in dogs. This high level of flea control is consistent with the adulticidal activity and breaking of the flea life-cycle through the cessation of flea reproduction that was seen in Simparica Trio ™ laboratory efficacy studies [17]. ...
Article
Full-text available
Background: A novel chewable oral tablet containing sarolaner, moxidectin and pyrantel (Simparica Trio™) has recently been developed to provide persistent protection against flea and tick infections for a month, treatment of hookworm and roundworm infections and prevention of heartworm and lungworm disease in dogs. Two field studies were conducted to evaluate the safety and efficacy of Simparica Trio™ against natural flea and tick infestations on dogs in Europe. Methods: Dogs with natural flea or tick infestations were allocated randomly to treatment on Day 0 with either Simparica Trio™ tablets (flea study: n = 297; tick study: n = 189) to provide 1.2-2.4 mg/kg sarolaner, 24-48 µg/kg moxidectin and 5-10 mg/kg pyrantel (as pamoate salt) or with NexGard® Spectra (afoxolaner + milbemycin oxime) according to the label instructions (flea study: n = 164; tick study: n = 91). Efficacy was calculated based on the mean percent reduction in live parasite counts compared to the respective pre-treatment counts on Days 14 and 30 in the flea study and on Days 7, 14, 21 and 30 in the tick study. To count the fleas, the dog's entire coat was systematically combed using an extra fine-tooth flea comb until all fleas were removed. For the tick counts, the dog's entire coat was searched manually. Resolution of the clinical signs of flea allergy dermatitis (FAD) was assessed in flea allergic dogs in the flea study. Palatability was assessed in both studies. Results: Simparica Trio™ was well tolerated in both studies. Efficacy against fleas was ≥ 97.9% in the Simparica Trio™ group and ≥ 96.1% in the NexGard® Spectra group. Efficacy against ticks was ≥ 94.8% in the Simparica Trio™ group and ≥ 94.4% in the NexGard® Spectra group. Clinical signs of flea allergy dermatitis improved following treatment with Simparica Trio™. Simparica Trio™ tablets were voluntarily and fully consumed on ≥ 78% of the 485 occasions they were offered. Conclusions: A single oral dose of Simparica Trio™ was safe and highly efficacious against naturally occurring flea and tick infestations for 1 month on dogs. Clinical signs of FAD improved following treatment. Simparica Trio™ was voluntarily and readily consumed by most dogs.
... In both laboratory and field tests on larvae of Rhipicephalus turanicus Pomerantsev and Argas persicus (Oken), the efficacy of spinosad was equivalent to that of conventional chemical acaricides; therefore, it is a usable alternative (Cetin et al. 2009, Brito et al. 2011. Spinosad is also effective against fleas, mites, mosquitoes, ticks, and pediculosis in other animal species and man (Davey et al. 2001, Snyder et al. 2009, Darriet et al. 2010, George et al. 2010, Wolken et al. 2012. ...
... The literature including the actual ingredient showed only effectiveness with dose twice that recommended for dogs [40][41][42][43][44]87] Milbemycin oxime/Spinosad 980 mg/kg 3600 mg/kg Well tolerated by dogs. Increased odds of effectiveness on sand flies with the action of both drugs together No literature regarding its antiphlebtomine effect and dogs should be tested for existing heartworms [41,[88][89][90] Fluralaner 2000 mg/kg Proven efficacy in killing flea adults and larvae using only one dose per season No literature regarding fluralaner antiphlebtomine effect. ...
Article
Full-text available
Zoonotic Visceral Leishmaniasis (ZVL) is a public health problem endemic in some countries. Current control measures, in particular culling infected dogs, have not reduced ZVL incidence in humans. We evaluated the use of five systemic insecticides (spinosad, fluralaner, afoxolaner, sarolaner and moxidectin) currently used in dogs for other purposes (e.g. tick, flea control) in controlling ZVL transmission. The anti-phlebotomine capacity of these compounds confirmed in experimental studies makes their use in ZVL control programs very promising. Limitations and benefits of using this new control tool are compared to current practices. This article is protected by copyright. All rights reserved.
Article
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A survey was conducted in order to gain current information on flea species (Siphonaptera: Pulicidae) infesting dogs and cats living in urban and rural areas of Hungary, along with data on the factors that affect the presence, distribution and seasonality of infestation. In addition, owner awareness of flea infestation was evaluated. Practitioners in 13 veterinary clinics were asked to examine all dogs and cats attending the clinic and to collect fleas, when present, on 2 days in each month from December 2005 to November 2006. They also completed a questionnaire for each animal examined. A total of 319 dogs (14.1%) were found to be infested; the highest prevalence (27.1%) of infestation on dogs occurred in August and the lowest (5.4%) in May. Prevalence of fleas on cats was higher (22.9%); the highest (35.0%) and lowest (8.1%) prevalences occurred in July and April, respectively. Fleas were more prevalent in rural (387/1924 animals, 20.2%) than in urban (161/1343 animals, 12.0%) areas. Three species, Ctenocephalides felis (Bouché), Ctenocephalides canis (Curtis) and Pulex irritans L., were found. On dogs, the prevalence of C. canis alone was 53.0%, whereas that of C. felis alone was 36.0%. Only 19 specimens of P. irritans were found on 14 dogs from rural habitats only. Prevalence of C. felis only on cats was 94.3%; the remaining cats were infested with either C. canis or with mixed infestations of C. felis and C. canis. More than half (51.4%) of the owners of infested dogs and cats had not used flea control products in the past year or more, and five times as many owners in rural than urban areas had not used flea control products in the same period. Very few owners reported having attempted to kill fleas in their animals' environment; instead, they believed that fleas were acquired from other cats or dogs.
Article
This article reviews contemporary concepts underlying the design of control strategies for the management of flea allergy dermatitis in dogs and cats. The limitations of palliative symptomatic approaches are noted, as is the fundamental requirement to differentiate simple pulicosis from true hypersensitivity. In the latter case, eradication of fleas from the affected animal and its surroundings has to be an essential aim. The different biological properties offered by modern chemotherapy are defined and the range of techniques for applying active compounds to the animal and its environment described. Factors for consideration when formulating control strategies and selecting chemotherapeutic agents are discussed in the context of the complexities of the flea life-cycle, the host-parasite relationship and client concerns.
Article
Control failures and recurrences of infestation of dogs, cats and their home environment with the cat flea, Ctenocephalides felis felis are common. Attempts to control these infestations are often impaired by an inadequate understanding of the interaction of the cat flea with its hosts and environment. This review presents information on the medical and veterinary importance of the cat flea and discusses recent information on the environmental and host factors that effect its development and survival. Additionally, information is presented on the use and effectiveness of various insecticides and insect growth regulators against the four life stages.
Article
Historically, veterinarians have told their clients that one flea is all that is necessary to produce and maintain the clinical signs of flea allergy dermatitis (FAD). Newer adulticides, such as fipronil, imidacloprid, nitenpyram and selamectin, have had a positive clinical effect on dogs and cats with FAD. However, data on flea feeding and the effect of these products on flea feeding bring into question the once perceived dogma of the single flea bite concept. Current data would indicate that the primary role of these insecticides in managing FAD is in rapidly reducing flea numbers and reducing flea feeding rather than preventing flea bites. Controlling tick infestations is important not only because ticks are nuisance parasites of dogs and cats, but also because they are vectors of a variety of bacterial and protozoal diseases. Achieving satisfactory tick control is often difficult due to unrealistic expectations of pet owners, to residual acaricidal properties of products that are often less than 100% and because of constant re-infestation pressure. Some of the most important factors veterinarians must be aware of are regional changes in tick distributions, our inability to control wildlife tick hosts and expectation differences between flea and tick control. These factors probably cause most real and perceived product failures.
Article
The efficacy of spinosad against adult fleas (Ctenocephalides felis) on dogs was evaluated in three controlled, blinded studies. One study was conducted to determine speed of kill on experimentally infested dogs. Two additional studies were designed to assess the efficacy of spinosad in preventing environmental contamination with flea eggs (USA study and EU study). An additional objective of the USA study was to assess the effects of skin and hair-coat debris from spinosad-treated dogs on eggs and larvae of C. felis. Dogs were randomly allocated to treatment with beef-flavored spinosad tablets, administered orally at a minimum dosage of 30mg/kg, or placebo. In the first study, speed of kill was determined by flea comb counts performed at 0.5, 1, 2, 4, 8, 12, 24 and 48h after spinosad treatment. Reductions in geometric mean flea counts for spinosad-treated dogs, compared to placebo were 53.7% at 0.5h, 64.2% at 1h, 85.8% at 2h and 100% at 4 through 48h post-treatment (p<0.05 at 1h and beyond). In the 2 flea egg production studies, dogs were treated (spinosad or placebo) once on day 0, infested with 600 fleas approximately 3h post-treatment and reinfested with approximately 600 fleas at intervals over 1 month. Flea eggs were collected starting at approximately 72h after each infestation. Eggs were examined for any effects of spinosad on egg viability. Efficacy of spinosad was also evaluated against environmental eggs and larvae exposed to canine hair-coat debris collected on days 3, 7, 14, 21, and 30. Spinosad was highly effective in reducing flea egg production (>99.8% across the entire study period) compared to control dogs in both egg collection studies. Insufficient numbers of eggs were recovered from spinosad-treated dogs to determine the viability of those eggs. There was no evidence of any effect on environmental flea stages, indicating that spinosad was not present in the skin debris of spinosad-treated dogs. The capability of spinosad to quickly kill adult fleas, and to greatly reduce egg production following challenge with high numbers of adult fleas is important in breaking the flea life cycle and preventing the introduction and establishment of new flea infestations in the household.
Article
The volume of blood consumed by actively reproducing female cat fleas, Ctenocephalides felis (Bouché), while feeding in confinement feeding chambers on cats for 3 h, was investigated using two radionuclide blood tags (51Cr-erythrocyte and 125I-albumin) and the gravimetric method. Female fleas consumed an average of 0.110 ml (+/- 0.026 ml) of blood per 100 females in 3 h as determined using the dual radionuclide system. The single 51Cr-erythrocyte tag overestimated blood consumption by 11.3% and the single 125I-albumin tag underestimated blood consumption by 6.4%. The gravimetric method underestimated blood consumption by 72.2% compared with the dual radionuclide value. Investigations of blood consumption of nonconfined female fleas were conducted with cats housed in metabolic cages and restricted from grooming. These investigations were conducted using the single 51Cr-erythrocyte tag, and the data obtained were corrected to compensate for using a single erythrocyte tag. Female cat fleas consumed an average of 13.6 microliters (+/- 2.7 microliters) of blood per day, which was equivalent to 15.15 times their body weight. In an additional study, direct exposure to 40 kHz ultrasound did not reduce blood consumption by the fleas.
Article
The cat flea, Ctenocephalides felis felis, is the most important ectoparasite of domestic cats and dogs worldwide. In addition to its annoyance to pets and humans, C. felis felis is responsible for flea bite allergy dermatitis and the transmission of dog tapeworm. The abiotic and biotic factors that affect the development of immature stages are reviewed with special emphasis given to those aspects directly affecting control. Factors influencing host selection and feeding by adults are summarized. Recent studies concerning mating and oviposition, especially as they impact the likelihood of survival by immatures, are discussed. There has been an increase in the number of reports of insecticide resistance in the past ten years. Greater attention has been placed on disrupting larval development in modern IPM programs. The immature stages of the cat flea are extremely susceptible to environmental factors such as temperature and relative humidity and insect growth regulators (IGRs). In recent years, the control of cat fleas has increasingly relied on the use of IGRs applied to the host or to the indoor environment. Finally, we discuss advances in pesticide chemistry that provide tools for better control of adult fleas on the host.
Article
Three experiments were conducted on cats to evaluate precocity and duration of the first blood meal of Ctenocephalides felis felis (Bouché). Percentage of engorged fleas was calculated for fleas held on cats for 5, 15, 30, and 60 min. Duration of first blood meal was also measured for individual fleas confined on cats. When fleas are free in the hair coat, 24.9% are engorged after 5 min and 97.2% are engorged after 1 h. Fleas confined to a vial on the cats fed significantly sooner; 60% of females were engorged within 5 min. The mean delay between deposition and biting for fleas, which began feeding within 15 min, was 24 s +/- 31 s for females and 23 s +/- 44 s for males. The mean duration of meals was 25 +/- 18 min for females and 11 +/- 8 min for males.
Article
The spinosyns, a novel family of insecticidal macrocyclic lactones, are active on a wide variety of insect pests, especially lepidopterans and dipterans. The biological activity of a mixture (spinosad; Tracer, Spin-Tor, Success) of the two most abundant spinosyns (spinosyns A and D) against pest insects is on a par with that of many pyrethroid insecticides. The spinosyns also exhibit a very favorable environmental and toxicological profile, and possess a mode of action that appears unique, with studies to date suggesting that both nicotinic and gamma-aminobutryic acid receptor functions are altered in a novel manner. Compared to pyrethroids such as cypermethrin, spinosyn A is slow to penetrate into insect larvae such as tobacco budworm larvae (Heliothis virescens); however, once inside the insect, spinosyn A is not readily metabolized. To date, more than 20 spinosyns and more than 800 spinosoids (semi-synthetic analogs) have been isolated or synthesized, respectively. Artificial neural network-based quantitative structure activity relationship (QSAR) studies for the spinosyns suggested that modification of the 2',3',4'-tri-O-methylrhamnosyl moiety could improve activity and several spinosoids incorporating these modifications exhibited markedly improved lepidopteran activity compared to spinosad. Multiple linear regression-based QSAR studies also suggest that whole molecule properties such as CLogP and MOPAC dipole moment can explain much of the biological activity observed for the spinosyns and closely related spinosoids.
Article
Pharmacokinetics of selamectin following intravenous, oral and topical administration in cats and dogs. J. vet. Pharmacol. Therap.24, 265–272. The pharmacokinetics of selamectin were evaluated in cats and dogs, following intravenous (0.05, 0.1 and 0.2 mg/kg), topical (24 mg/kg) and oral (24 mg/kg) administration. Following selamectin administration, serial blood samples were collected and plasma concentrations were determined by high performance liquid chromatography (HPLC). After intravenous administration of selamectin to cats and dogs, the mean maximum plasma concentrations and area under the concentration–time curve (AUC) were linearly related to the dose, and mean systemic clearance (Clb) and steady-state volume of distribution (Vd(ss)) were independent of dose. Plasma concentrations after intravenous administration declined polyexponentially in cats and biphasically in dogs, with mean terminal phase half-lives (t½) of approximately 69 h in cats and 14 h in dogs. In cats, overall Clb was 0.470 ± 0.039 mL/min/kg (±SD) and overall Vd(ss) was 2.19 ± 0.05 L/kg, compared with values of 1.18 ± 0.31 mL/min/kg and 1.24 ± 0.26 L/kg, respectively, in dogs. After topical administration, the mean Cmax in cats was 5513 ± 2173 ng/mL reached at a time (Tmax) of 15 ± 12 h postadministration; in dogs, Cmax was 86.5 ± 34.0 ng/mL at Tmax of 72 ± 48 h. Bioavailability was 74% in cats and 4.4% in dogs. Following oral administration to cats, mean Cmax was 11929 ± 5922 ng/mL at Tmax of 7 ± 6 h and bioavailability was 109%. In dogs, mean Cmax was 7630 ± 3140 ng/mL at Tmax of 8 ± 5 h and bioavailability was 62%. There were no selamectin-related adverse effects and no sex differences in pharmacokinetic parameters. Linearity was established in cats and dogs for plasma concentrations up to 874 and 636 ng/mL, respectively. Pharmacokinetic evaluations for selamectin following intravenous administration indicated a slower elimination from the central compartment in cats than in dogs. This was reflected in slower clearance and longer t½ in cats, probably as a result of species-related differences in metabolism and excretion. Inter-species differences in pharmacokinetic profiles were also observed following topical administration where differences in transdermal flux rates may have contributed to the overall differences in systemic bioavailability.