Safety and Efficacy of Cefovecin (Convenia<sup>®</sup>) as an Adjunctive Treatment of Periodontal Disease in Dogs

doi:10.4236/ojvm.2012.23016

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Open Journal of Veterinary Medicine, 2012, 2, 89-97

http://dx.doi.org/10.4236/ojvm.2012.23016 Published Online September 2012 (http://www.SciRP.org/journal/ojvm)

Safety and Efficacy of Cefovecin (Convenia®) as an

Adjunctive Treatment of Periodontal Disease in Dogs

Henry Giboin, Csilla Becskei, Jacky Civil, Michael R. Stegemann*

Veterinary Medicine Research & Development, Pfizer Animal Health, Zaventem, Belgium

Email: *[email protected]

Received April 30, 2012; revised June 8, 2012; accepted June 15, 2012

ABSTRACT

This study was designed to determine the safety and efficacy of cefovecin (Convenia®; Pfizer Animal Health) when

compared to clindamycin (Antirobe®; Pfizer Animal Health) as an adjunctive therapy to periodontal scaling or surgery

for severe periodontal disease in dogs. A multi-centre, double-masked, randomised study was conducted in 299 dogs

with severe periodontal disease. Clindamycin, administered once daily at 11 mg/kg bodyweight orally for 10 days fol-

lowing dental surgery was compared with a single, subcutaneous injection of cefovecin (8 mg/kg bodyweight) adminis-

tered at the time of dental surgery. The primary efficacy parameter assessed was percentage of tooth-root sites bleeding

when probed (an indicator of gingival inflammation) 42 days after surgery. Two-hundred and ninety-one (291) dogs

were included in the efficacy assessments. Cefovecin was shown to be non-inferior to clindamycin. The percentage of

sites bleeding on probing was reduced from 54.3% to 20.3% for the cefovecin group (53.1% reduced to 17.4% for the

clindamycin group). There were no suspected adverse drug experiences attributed to treatment with cefovecin or clin-

damycin. Cefovecin was shown to be as effective and safe adjunctive treatment for severe periodontal disease in dogs

undergoing periodontal scaling and surgery as clindamycin.

Keywords: Canine; Antibiotics; Dentistry; Porphyromonas gulae; Prevotella intermedia

1. Introduction

Periodontal disease is the most common dental infection

in dogs [1]. It is caused by the accumulation of plaque

and an associated change in periodontal bacterial flora

(from commensal aerobic to pathogenic anaerobic bacte-

ria such as Porphyromonas spp. and Prevotella spp)

[2-5]. Periodontal disease is a collective term for a num-

ber of inflammatory conditions affecting the periodon-

tium around the tooth (attached gingiva, periodontal liga-

ment, cementum of the root and alveolar bone). It pro-

gresses from reversible gingivitis, characterised by in-

flamed and often bleeding gingiva, to periodontitis with

the associated inflammatory tissue damage, the formation

of deep periodontal pockets or gingival recession, loss of

epithelial attachment and bone resorption. The end result

of periodontitis is loss of the tooth due to progressive

destruction of its periodontium [6].

As periodontal disease disturbs the integrity of mucous

membranes, periodontal pathogens can be exported via

the blood stream. In severe periodontal disease, bacte-

raemia may even occur during minimal mechanical dis-

turbance, such as normal mastication, without any pro-

fessional tooth cleaning or surgery [7,8]. Periodontal dis-

ease is associated with myocardial infarction and stroke

in humans [9] and with abscesses in organs, endocarditis

and glomerulonephritis in dogs [10,11].

In dogs, prevention of periodontal disease by home

applied hygiene as in humans is rarely possible and the

effect of poor plaque control is often only managed by

periodontal treatment (e.g. debridement, scaling, polish-

ing). However, mechanical periodontal therapy alone

will not adequately reduce the periodontopathogen load

[12,13]. In severe and progressive cases adjunctive anti-

biotic treatment is justified to augment a reduction in

periodontopathogens and physiological bacterial flora,

thereby facilitating detoxification of the periodontium

from detrimental bacterial toxins and aiding gingival

healing [13-16]. Results from clinical studies in dogs

support this notion, as systemic treatment with clinda-

mycin in periodontal disease significantly decreased

plaque scores, gingivitis and pocket depths compared to

placebo when used as adjunctive therapy to ultrasonic

scaling, root planing and polishing [17-19].

Neither in human nor in veterinary dentistry is there a

consensus in the choice of antimicrobial agent or in the

minimum duration required to successfully treat perio-

*Corresponding author.

H. GIBOIN ET AL.

dontal infections [13]. Here we show that in a large

clinical study, a single subcutaneous administration of

cefovecin at 8 mg/kg effectively aided healing of the

periodontal tissues after professional periodontal treat-

ment and surgery in dogs.

Cefovecin is an extended-spectrum cephalosporin, ap-

proved for veterinary use in dogs and cats. It is formu-

lated as an injectable solution containing 80 mg/ml cefo-

vecin sodium. Following subcutaneous administration in

dogs, cefovecin has a long elimination half-life (5.5

days), low clearance (0.76 ml/hour/kg) and therapeutic

tissue concentrations are maintained for approximately

14 days [20]. As a consequence, prolonged therapeutic

efficacy can be maintained through injections adminis-

tered at 14-day intervals. Cefovecin, administered as a

subcutaneous injection at 14-day intervals, was highly

effective in the treatment of both superficial and deep

canine pyoderma [21,22] and also of wounds and ab-

scesses in both cats [23,24] and dogs [21,22]. Further-

more, cefovecin was demonstrated to be an effective and

safe treatment for urinary tract infections in dogs [25]

and cats [26].

2. Materials and Methods

2.1. General Study Design

This multi-centre study was conducted in compliance

with VICH guidelines for Good Clinical Practice [27]

(International Co-operation on Harmonisation of Tech-

nical Requirements for Registration of Veterinary Medi-

cal Products) in veterinary practices in Belgium (n = 5)

and France (n = 15). At each site one veterinarian, ex-

perienced in veterinary dentistry made all the observa-

tions, who received training in the procedures before

study start. Approval was obtained from the appropriate

regulatory authorities and the study conformed to local

animal welfare standards. Informed consent was obtained

from the owners of all dogs participating in the study.

Dogs were randomised in a 1:1 ratio to treatment with

either cefovecin or clindamycin in a double-masked

study.

2.2. Selection of Animals

Only dogs, which were assessed by the veterinarian to

have advanced severe periodontal disease requiring sys-

temic antimicrobial therapy for at least 10 days as an

adjunct to professional periodontal treatment, were con-

sidered for the study. Inclusion also required that dogs

had at least one tooth site of gingival bleeding in addition

to either a gingival pocket of at least 4.0 mm deep and/or

a gingival recession of at least 1.0 mm. Pocket depth was

defined as the distance (mm) between the margin of the

gingiva and the bottom of the deepest pocket at that site.

Gingival recession was defined as the distance (mm)

from the gingival margin to the associated tooth’s apical

cemento-enamel junction.

Dogs that had been treated with local or systemic an-

timicrobial agents or long acting corticosteroids within

the previous 4 weeks, with short acting corticosteroids

within the previous week, and dogs being treated with an

oral antiseptic or an anti-plaque agent were excluded.

Concomitant administration of local or systemic anti-

microbials or corticosteroids was not permitted.

2.3. Clinical Examination and Parameter

Measurements

Prior to treatment (day 0) and at study completion (day

42) all dogs were subjected to a detailed mouth examina-

tion under general anaesthesia. First halitosis and general

oral health were assessed on a visual analogue scale

(VAS, healthy to extremely unhealthy). Then before any

invasive procedures, any two most severely affected

teeth (i.e. not necessarily the same teeth on day 0 and 42)

were selected for subgingival bacteriological sampling

using sterile paper points (Nº. 40, Roeko, Dentsply Bel-

gium). The 2 samples from the same dog were pooled

and later analyzed together.

Following sampling, the Gingival Bleeding Index

(GBI) was assessed whilst probing the tooth-root sites

with a pressure sensitive probe (Florida Probe, Florida

Probe Corporation, Gainesville, Florida) to measure the

gingival pocket depth and to identify any evidence of

gingival recession. For each site, normal gingiva was gi-

ven a GBI score of 0, mild inflammation without bleeding

was scored 1, moderate inflammation with bleeding with-

in 30 seconds was scored 2, whilst severely inflamed

gingiva which spontaneously bled on probing scored 3.

All measurements were undertaken at 50 pre-determined

tooth-root sites, which are reported to be most frequently

and most severely affected in dogs [6]. This included all

labial roots (both mesial and distal of multiple-rooted

teeth) of all investigated teeth and both labial and palatal

side of the upper canine teeth. No root-sites were consid-

ered for any of the first premolar, the second molar and

the third molar teeth. In addition, the height of the upper

canine tooth (mm) was recorded to allow adjustments of

the total mouth periodontal scores for periodontitis (TMPS-P)

for the size of the animal [28].

After all measurements taken on day 0, dental proce-

dures were completed as necessary, including ultrasonic

supragingival scale, subgingival debridement, dental po-

lish and extraction. Further VAS assessments of halitosis

and general oral health were recorded on day 14 on un-

anaesthetized animals. Veterinarians and owners were

requested to report all suspected adverse events for all

treated dogs.

H. GIBOIN ET AL. 91

2.4. Laboratory Examination

A single laboratory in Belgium (Katholieke Universiteit

Leuven, Leuven) was used to evaluate bacteriological

samples. These were transported by courier in a cool box

to the laboratory. Upon arrival, the samples were plated

on agar plates and incubated for growth. After incubation,

total aerobic colony forming units (cfu) and total anaero-

bic cfu were counted. In addition, within the anaerobic

strains, the black pigmented strains were identified mor-

phologically, and the Porphyromonas gulae and Prevotell a

intermedia were identified via enzymatic tests. All strain

identification was performed by the same laboratory

technician.

If present and identified, one strain per pre-treatment

sample of P. gulae and P. intermedia was tested for an-

timicrobial sensitivity using agar dilution minimum in-

hibitory concentration (MIC) methodology (supplement-

ed Brucella Blood agar) in accordance with CLSI guide-

lines M31-A3 and M11-A8. Antimicrobials tested were

cefovecin, clindamycin, metronidazole and amoxicil-

lin/clavulanate 2 to 1 ratio.

2.5. Investigational Treatment Administration

As 10 days of antimicrobial treatment was required, dogs

randomised to receive cefovecin received a single sub-

cutaneous injection of cefovecin (8 mg/kg bodyweight;

Convenia®, Pfizer Animal Health) followed by 10 days

of oral placebo capsules. Dogs randomised to receive

clindamycin capsules received a placebo subcutaneous

injection followed by 10 days of oral clindamycin cap-

sules (11 mg/kg bodyweight; Antirobe®, Pfizer Animal

Health). The veterinarian administered the subcutaneous

injections to dogs after periodontal treatment on day 0

and the owners administered the capsules once daily.

Owners kept a diary in which capsule administration was

recorded and compliance with treatment could then be

determined.

2.6. Assessment Criteria

The primary efficacy criterion was the percentage of

tooth sites which bled when probed (GBI > 1). This was

measured using a clear and reproducible, GBI scoring

system, validated for veterinary use [28]. Clinically,

bleeding on probing is a well accepted and objective

measure of active gingivitis and current periodontal

pocket inflammation. Statistically, because each dog is

assessed at numerous sites to generate an overall per-

centage, the power for comparison is superior to a vari-

able such as clinical success or bacteriological cure. Fur-

ther, the good reproducibility of the score between dogs

and clinics ensures that high quality data is generated,

permitting robust statistical comparison between treat-

ment groups. Therefore, for both clinical and statistical

reasons, percentage of bleeding on probing was consid-

ered the most suitable parameter for a primary efficacy

endpoint.

Gingival pocket depth, total mouth periodontal scores

(TMPS), the presence of pathogens before and after

treatment, halitosis and general oral health at each ex-

amination were considered as secondary efficacy end-

points.

TMPS for gingivitis (TMPS-G) was calculated ac-

cording Harvey et al. [28] and was a composite of all the

GBI scores for a particular dog, weighted according to

the circumference of the cemento-enamel junction at

each site, giving a final individual score for each dog of

between 0 and 3. TMPS-P was a composite of all the

pocket depth measurements for a particular dog, weight-

ed according to the root surface area at each site and

normalised according to the length of the upper canine.

This allowed comparison of periodontitis in dogs of dif-

ferent sizes.

2.7. Statistical Analysis

For each assessment criterion, two analyses were con-

ducted. One analysis included all treated dogs which

completed the study on day 42 (Intent to Treat analysis:

ITT). A second analysis (Per Protocol analysis: PP) ex-

cluded all animals for which procedures (including

treatment administration and efficacy measurements)

were not conducted to a sufficient standard to enable a

fair comparison. Results are presented for the PP analysis

only unless otherwise stated.

As recommended by EMEA guidelines [29] a

non-inferiority approach to compare cefovecin with

clindamycin was selected for the primary efficacy crite-

rion. For each animal, the percentage of tooth sites with a

GBI > 1 was calculated for both day 0 and 42. Data were

analysed using a mixed linear model using the day 0 re-

sults as a covariate. For the non-inferiority test, the dif-

ference in the mean percentage between the two treat-

ments (cefovecin minus clindamycin) on day 42 was

calculated together with a 95 percent two-sided confi-

dence interval. Thus, if the upper confidence bound on

the difference was less than 10 percentage points, then

cefovecin was considered non-inferior to clindamycin.

The 10% margin was justified based on pilot data which

indicated that 4 weeks after adjunctive treatment with

cefovecin, the percentage of bleeding on probing was

reduced by a further 14% than for surgery alone (data not

shown). Thus it was reasoned that to be clinically rele-

vant, the non-inferiority margin should exclude the effect

of surgery alone; i.e. to be less than 14%. Power calcula-

tions based on preliminary data indicated that a mini-

mum of 50 dogs per treatment group were needed to

H. GIBOIN ET AL.

3.2. Gingival Bleeding Index

demonstrate non-inferiority with at least 90% power.

All secondary parameters were assessed via the calcu-

lation of the treatment difference and 95% confidence

intervals.

The mean percentages of the GBI scores per animal are

summarized on Figure 1. Before treatment more than

half of the sites bled when probed, and less than 20% of

the sites were considered normal. More than 20% of all

sites had the highest GBI score of 3 in both groups. On

day 42, the number of sites with normal gingiva had

more than doubled in both treatment groups, whilst the

number of most severely affected sites (GBI = 3) was

reduced by more than 75%. Overall, there was a reduc-

tion in the number of bleeding sites in both treatment

groups with no significant difference between cefovecin

and clindamycin (Table 1). Therefore, cefovecin suc-

cessfully achieved non-inferiority to clindamycin.

3. Results

3.1. Evaluation and Completion of Dogs

In total 308 dogs were evaluated for inclusion in the

study. Four dogs were excluded before dental treatment

as they were unsuitable for anaesthesia (n = 2) or their

owners did not want to proceed (n = 2). After periodontal

treatment and bacteriological sampling, 5 dogs did not

continue (2 did not meet inclusion criteria, the probe

failed in 2 and 1 dog did not recover from anaesthesia).

Following periodontal treatment, 150 dogs received

cefovecin and 149 clindamycin. One dog did not com-

plete the study due to owner non-compliance (clindamy-

cin group) and one other dog was excluded because of

concomitant antimicrobial therapy for a non-study re-

lated adverse event (cefovecin group). Hence 297 dogs

completed the study on day 42 and were included for the

ITT analyses. Six further dogs were excluded from all PP

analyses; four dogs were underdosed during the study (1

in cefovecin and 3 in clindamycin group), one dog re-

ceived an unauthorised concomitant therapy, whilst data

was missing for another (both clindamycin group). A

further 25 dogs (14 in cefovecin and 11 in clindamycin

group) were excluded from PP analyses of pocket depth

and TMPS-P due to incorrect probe usage.

3.3. Gingival Pocket Depth

Before treatment, the mean gingival pocket depth was

2.48 mm (cefovecin group) and 2.39 mm (clindamycin

group). Of the total number of tooth root sites measured,

19% had a pocket depth between 3 - 5 mm in both groups

and the proportion of pocket depth larger than 5 mm was

5.3% and 3.9% in the cefovecin and clindamycin group

Of the 299 dogs enrolled into the study, 240 were pu-

rebred (wide range of small, medium and larger breeds)

and the remaining were crossbred. The ages of the dogs

in both groups ranged from 2 to 17 years (mean: 9.3 and

9.2 years for the cefovecin and clindamycin group, re-

spectively). The mean body-weights were 11.6 kg and

11.0 kg for the cefovecin and clindamycin group, respec-

tively. There were 161 female dogs (81 intact and 80

neutered) and 138 male dogs (99 intact and 39 neutered).

In Belgium, 72 dogs were enrolled from 5 practices, and

in France, 227 dogs were enrolled from 15 practices.

Figure 1. Mean percentage of 0, 1, 2 or 3 Gingival Bleeding

Index (GBI) scores per animal in each treatment group be-

fore treatment (day 0) and at the end of the study (day 42).

Table 1. Summary of percentage of sites bleeding on probing before treatment (day 0) and after treatment (day 42).

Treatment

Cefovecin Clindamycin

Treatment Comparison

Day 0* Day 42* Day 0* Day 42* Difference day 42 [95% CI] Non-inferiority demonstrated?

PP1 54.3% 20.3% 53.1% 17.4% 2.91% [−0.65 to 6.48] Yes (<10%)

ITT2 54.5% 20.5% 52.7% 17.4% 3.16% [−0.35 to 6.67] Yes (<10%)

*Day 0 is presented as a Mean and day 42 as a Least Square (LS) Mean because day 0 datum is used as a covariate in the model to compare the results from day

42. 1PP: per protocol analysis; Number of dogs in the cefovecin group: 148 and 143 in the clindamycin group. 2ITT: intent to treat; Number of dogs in the cefo-

vecin group: 149 and 148 in the clindamycin group.

H. GIBOIN ET AL. 93

respectively (Figure 2). On day 42, a reduction in pocket

depth of 0.51 mm and 0.40 mm was observed for cefo-

vecin and clindamycin, respectively. For the deepest

pockets (≥5.0 mm) measured on day 0, there appeared to

be a proportionally greater reattachment (approximately

30%) following treatment than for less severe pockets.

There was no statistically significant difference in any

subgroup analysis between treatment groups. Similar

results were obtained for the ITT analysis.

3.4. Total Mouth Periodontal Scores

Dogs in both treatment groups exhibited a very similar

mean score for both TMPS-G and TMPS-P at the begin-

ning of the study (Tab le 2). The high mean pre-treatment

scores corroborate that the study population had moder-

ate to severe periodontal disease, as required by the in-

clusion criteria. On day 42, the TMPS-G score for both

groups was approximately halved whilst the TMPS-P

score for both groups was reduced by approximately

20%. The difference between treatments for both scores

was not statistically significant.

3.5. General Oral Health and Halitosis

General oral health and halitosis improved by more than

80% after treatment for both the cefovecin and clinda-

mycin groups. There was no statistically significant dif-

ference between treatments on days 14 and 42 (p ≥ 0.09

at all time points). Similar results were found in the ITT

population.

3.6. Bacteriology

From the 304 dogs assessed for inclusion, 301 bacterial

strains were isolated. Porphyromonas gulae was identi-

fied in the majority of samples collected on day 0 (272

strains), with Prevotella intermedia being identified less

frequently (29 strains). MIC90 values for these strains to

various antimicrobials are presented in Table 3. The P.

gulae strains were highly susceptible to cefovecin, with a

slightly wider susceptibility range for P. intermedia.

After treatment, there was a reduced recovery of both

bacterial species (see Table 4). For P. gulae, the odds

ratio comparing the two treatments was 0.334, indicating

that P. gulae was less likely to be isolated on day 42

from dogs treated with cefovecin than those treated with

clindamycin (p < 0.0001). For P. intermedia this odds

ratio was 0.379, indicating that this species was also less

likely to be isolated on day 42 from dogs treated with

cefovecin. This difference was not statistically significant

(p = 0.25).

Aerobic and anaerobic bacteria were identified in all

isolates. On day 0, anaerobic black pigmented bacteria

were recorded in 145 out of 151 samples in the cefovecin

and in 146 out of 150 in the clindamycin group. On day

42, this ratio was 110 out of 149 and 110 out of 145

samples, respectively.

3.7. Safety Assessments

All dogs that received medication were included in the

Figure 2. Changes in pocket depth during the study period

in all pockets and in the most severely affected pockets. The

top of the black bars shows the pocket depth on day 0, the

top of the white bars shows the pocket depth after treat-

ment on day 42. The black shaded area shows the reduction

n the pocket depth between day 0 and 42. i

Table 2. Summary of Total Mouth Periodontal Scores (TMPS) on day 0 and day 42.

TMPS——Gingivitis TMPS——Periodontitis

Cefovecin Clindamycin Cefovecin Clindamycin

Number of animals 148 143 133 133

Mean day 0* 1.65 ± 0.57 1.61 ± 0.60 1.99 ± 0.87 1.96 ± 0.71

LS Mean day 42 0.83 0.77 1.54 1.60

% reduction 49.7% 52.2% 22.6% 18.4%

Treatment comparison (CI, p-value) 0.065 (–0.02 to 0.15, p = 0.12) –0.056 (–0.15 to 0.04, p = 0.22)

*± standard deviation.

H. GIBOIN ET AL.

Table 3. Summary of activity of antimicrobials against the strains isolated in dogs with periodontal disease, before antimicro-

bial treatment.

Value (µg/ml) for each antimicrobial agent

Bacterial species

(number of strains)

Summary MIC

parameters Cefovecin Clindamycin Metronidazole

Amoxicillin/Clavulanate

2 to 1 ratio

MIC range ≤0.008 to 1 ≤0.008 to >128 ≤0.008 to >128 ≤0.008 to 2

MIC50 0.031 ≤ 0.008 0.031 0.125

MIC90 0.062 ≤ 0.008 0.062 0.25

Porphyromonas gulae (272)

Geo. Mean 0.029 0.011 0.027 0.088

MIC range ≤0.008 to 4 ≤0.008 to >128 0.016 to 1 ≤0.008 to 2

MIC50 0.125 ≤ 0.008 0.5 0.062

MIC90 1 >128 1 0.5

Prevotella intermedia (29)

Geo. Mean 0.15 0.053 0.30 0.083

MIC range ≤0.008 to 4 ≤0.008 to >128 ≤0.008 to >128 ≤0.008 to 2

MIC50 0.031 ≤0.008 0.031 0.125

MIC90 0.125 ≤0.008 0.25 0.25

Total (301)

Geo. Mean 0.034 0.013 0.035 0.087

Table 4. Summary of the number and percentage of samples where Porphyromonas gulae or Prevotella intermedia were iden-

tified before treatment on day 0 and at the end of the study on day 42.

Treatment Treatment comparison

Cefovecin* Clindamycin** 95% confidence interval

Day 0 (%) Day 42 (%) Day 0 (%) Day 42 (%) Odds ratio (p-value) Lower Upper

Porphyromonas gul ae 126 (83.4%) 32 (21.5%) 117 (78.0%) 65 (44.8%) 0.334 (p < 0.0001) 0.20 0.56

Prevotella intermedia 10 (6.6%) 2 (1.3%) 13 (8.7%) 5 (3.5%) 0.379 (p = 0.25) 0.07 2.01

*total number of samples on day 0 = 151; on day 42 = 149; **total number of samples on day 0 = 150; on day 42 = 145.

safety assessments. One dog (clindamycin group) died

before antimicrobial therapy due to post-anaesthetic

complications. There were no abnormal injection sites

reported in any dogs administered either active cefovecin

or placebo. There was no notable difference in the inci-

dence of adverse events between the two treatment

groups. Two dogs in the cefovecin group vomited during

the study period, on a total of 3 occasions; one dog

showed inappetence in the clindamycin group and one

dog was lethargic and had modified feces on one occa-

sion in the cefovecin group. None of these events was

considered to be related to the administration of the me-

dications by the veterinarians.

4. Discussion

Periodontal disease is a very common and potentially

serious infectious dental disease in dogs [1]. Here we

investigated the efficacy and safety of the only veterinary

approved long-acting injectable antimicrobial, cefovecin

in the adjunctive treatment of severe periodontal disease

in dogs.

It has to be noted that the assessment of antimicrobial

efficacy for periodontal treatment is hampered by the

complexity of the disease. While the primary treatment is

professional periodontal therapy, the inclusion of such

therapy could be considered a confounding factor for

antimicrobial treatment comparisons. Nevertheless, ap-

plication of antimicrobials alone is not recommended

[16]. Further, EMEA guidelines recommend that when

assessing a new compound for treatment of a potentially

serious condition, a non-inferiority approach comparing

to a reference product is preferable to a conventional

hypothesis test for superiority using a placebo [29]. Es-

sentially this is designed to demonstrate that the new

compound is “at least as good as” the reference product

by a predefined margin. Here clindamycin (Antirobe®

capsules) was selected as reference product, because it

has been shown to effectively reduce the signs of perio-

dontal disease, including gingivitis and pocket depths

compared to placebo, when used adjunctive to profes-

sional periodontal treatment in dogs [17-19]. It was used

at the recommended European dosage of 11 mg/kg body-

weight orally once a day for at least 10 days.

The dogs included in this study represented a diverse

population encompassing many breeds and a wide age

range. The mean bodyweight suggested that there was a

tendency towards smaller dogs. Indeed, small breed dogs

H. GIBOIN ET AL. 95

are considered to be particularly susceptible to naturally

occurring periodontal disease. It has been reported that

by the age of 3 years more than 85% of the small dog

population has alterations in their vital organs due to pe-

riodontitis-associated recurrent bacteraemia [11]. As in-

clusion in this study required that the dogs had severe

periodontal disease, it is likely that many also had sys-

temic consequences of their periodontal disease. There is

consensus amongst veterinary and human dentists that

antimicrobial treatment as an adjunct to periodontal

therapy for severe conditions and in patients with sys-

temic diseases is fully justified [13-16]. Not only does

this help to restore the non-pathogenic flora and promote

gingival healing, but also minimises any associated bac-

teraemia.

The primary efficacy endpoint was percentage of

pre-defined tooth-root sites bleeding on probing six

weeks after the initial surgery. At the end of the study the

percentage of sites bleeding on probing was more than

halved in both treatment groups. Further, cefovecin suc-

cessfully met the stringent a priori criteria and efficacy

can be claimed.

Periodontal pocket depth was also considered as a

clinically relevant endpoint for the efficacy analysis,

however, assessment of depth using a probe is by nature

prone to large error and individual variation thereby re-

ducing the power of the study. Further, pocket depth does

not specifically assess current active inflammation, but

rather measures the extent of established damage histori-

cally caused by ongoing periodontal disease. Therefore,

pocket depth was included as a secondary efficacy crite-

rion. Subset analysis of the pocket depth data revealed

that whilst there were no significant treatment differences,

there was proportionally a larger reduction in pocket

measurement in the deepest pockets, with a trend in fa-

vour of cefovecin. This might be due to creating a more

favourable environment for re-attachment of the perio-

dontal membrane by maintaining low supragingival bac-

terial flora following periodontal therapy.

The bacterial species identified during this study were

typical of those associated with canine periodontal dis-

ease [3-5]. There was a high recovery of pathogens be-

fore treatment, with P. gulae being the most frequently

isolated species. After periodontal and antimicrobial

treatment, dogs treated with cefovecin were less likely to

be infected than those treated with clindamycin, although

for both groups there was a reduction in recovery of

pathogens. All P. gulae isolates tested were susceptible

to cefovecin. Whilst fewer P. intermedia strains were

collected, cefovecin still exhibited good in vitro activity

although a few isolates were resistant as defined in the

existing summary of product characteristics (sensitive ≤2

μg/mL).

There is always the potential for the development of

resistance when using antimicrobial drugs. The suscepti-

bility to cefovecin of pathogens isolated in this study was

very similar to previous results [30]. This indicates that

despite exposure of periodontal pathogens to cefovecin

since its approval in 2006, no MIC shift has occurred.

Therefore, it is likely that the risk of resistance develop-

ment of Porphyromon as spp. and Prevotella spp. through

the use of cefovecin as an adjunctive treatment to perio-

dontal therapy is minimal. Although clindamycin, met-

ronidazol and amoxicillin/clavulanic acid have been used

for a longer period against periodonthopathogens, the

susceptibility of the tested strains to these drugs does not

seem to have changed when compared to previous re-

ports [31,32].

Other secondary parameters included the total mouth

periodontal scores. The scores for gingivitis were ap-

proximately halved after treatment, with no significant

difference between groups. The scores for periodontitis

(TMPS-P) were also reduced after treatment, with no

significant difference between groups. Similarly, general

oral health and halitosis, improved after treatment for

both the cefovecin and clindamycin groups.

Importantly, there were no adverse events reported due

to treatment for either group. While owner diaries docu-

mented a few adverse events, including gastrointestinal

symptoms, these were unrelated to treatment according

to the observing veterinarians. There was no injection-

site reaction reported.

In conclusion, cefovecin at a dose of 8 mg/kg body-

weight administered once subcutaneously was safe and

efficacious in the adjunctive treatment of severe perio-

dontal disease in dogs presented as veterinary patients.

As the only veterinary approved long-acting injectable

antimicrobial, cefovecin enables reliable treatment, espe-

cially in dogs where oral administration may be difficult

following periodontal surgery.

5. Acknowledgements

The authors acknowledge the assistance of the staff at the

clinics involved and the cooperation of the owners which

facilitated the smooth conduct of the studies.

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