Azithromycin as an adjunct to scaling and root planing in the treatment of porphyromonas gingivalisassociated periodontitis: a pilot study
J Clin Periodontol 2010; 37: 1005–1015 doi: 10.1111/j.1600-051X.2010.01607.x
Alfonso Oteo1, David Herrera2,Elena Figuero1,3, Ana O’Connor3,
Itziar Gonza´lez3 and Mariano Sanz21Section of Graduate Periodontology, Facultyof Odontology; 2Etiology and Therapy of
Periodontal Disease (ETEP) ResearchGroup; 3Laboratory of Microbiology,Complutense University, Madrid, Spain
gingivalis-associatedperiodontitis: a pilot study
Oteo A, Herrera D, Figuero E, O’Connor A, Gonza´lez I, Sanz M. Azithromycin as anadjunct to scaling and root planing in the treatment of Porphyromonas gingivalis-associated periodontitis: a pilot study. J Clin Peridontol 2010; 37: 1005–1015. doi: 10.1111/j.1600-051X.2010.01607.x.
AbstractObjective: To evaluate the clinical and microbiological effects of systemicazithromycin as an adjunct to scaling and root planing (SRP) in the treatment ofPorphyromonas gingivalis-associated chronic periodontitis. Methods: Twenty-nine patients harbouring P. gingivalis were randomized into testand placebo groups. Test patients received SRP plus 500 mg of azithromycin per day(3 days), and control patients received SRP plus placebo. Clinical [plaque and bleedingindexes, probing pocket depth (PPD), clinical attachment level (CAL)] andmicrobiological data (four-sites pooled samples, processed by culture) were collectedat baseline, and 1, 3 and 6 months, post-therapy. Clinical variables were compared byANOVA, and microbiological variables by chi-square, signed-rank and Wilcoxon tests. Results: Fifteen test and 11 placebo patients completed the study. Mean PPDdecreased 0.34 mm [95% confidence interval (CI) 0.19–0.49] in the placebo and0.80 mm (CI 0.57–1.04) in the test group after 6 months. For mean CAL gain, thecorrespondent figures were 0.29 (CI 0.08–0.49) and 0.76 (CI 0.46–1.05), respectively. The frequency of detection of P. gingivalis decreased significantly (p40.01) in the testgroup after 1, 3 and 6 months.
Key words: azithromycin; periodontitis;P. gingivalis; microbiology; scaling and root
Conclusions: Within the limitations of this study, the adjunctive use of systemic
azithromycin in the treatment of P. gingivalis periodontitis demonstrated significantclinical and microbiological benefits when compared with SRP plus placebo.
porting tissues caused by specific micro-
as the most relevant species, due to their
pathology and their pathogenic potential.
aetiology of periodontitis is multi-factor-
ial, but it is an infection and bacterial
pills were provided by Pfizer, Alcobendas,
microbial spectrum with in vitro activity
attachment loss (Winkel et al. 1997).
elimination of these bacterial species is
et al. 1987, Willians et al. 1992, Muller
University Complutense, Madrid, Spain.
Winkelhoff et al. 1996, Herrera et al.
as a result of chemotactic effects exerted
sites. Different in vitro (Pajukanta 1993)
specific microbiological profiles, it has
and in vivo (Herrera et al. 2000) studies
mitans can be predictably eradicated with
the adjunctive administration of amoxicil-
In the last years, different studies have
lin plus metronidazole (Pavicic & van
is not frequent, and this bacterial species
periodontitis. Conversely, P. gingivalis is
et al. 2008, Pradeep et al. 2008, Yashima
et al. 2009) reporting different clinical
periodontitis, and it has also been found
tal diseases, (vii) HIV infection, (viii)
pared with other European (Sanz et al.
patients. Our hypothesis is that patients
patients, the eradication of the pathogen
with P. gingivalis will benefit, in terms
tion of P. gingivalis from the adjunctive
use of azithromycin, because this drug is
selected. Clinical variables (presence of
choice, due to its anti-microbial spectrum.
on P. gingivalis are not predictable.
days (Herrera et al. 2002), and the lack of
et al. 1993). In addition, adverse effects,
including the interference with alcoholic
controlled, randomized clinical trial.
ethical committee at the Hospital Clı´n-
were transferred to the microbial labora-
days) and limited side effects. This short
et al. 1990), and serially diluted in PBS.
they were positive for P. gingivalis.
et al. 2001). These plates were incubated
for 3 days in air with 5% CO2 at 371C.
Suspected isolates were identified on the
adjunctive medication was prescribed.
border and a ‘‘star’’ or ‘‘crossed cigars’’
(1 mg/l) and 5% sterile horse blood.
After 7–14 days of anaerobic incubation
probe) and calibrated operator (A. O.).
in the test group received a blister con-
identical in colour, form and size. Codes
indole and trypsin-like activity). Counts
units per millilitre of the original sam-
sites selected at baseline), clinical para-
bacterial species were also calculated.
effects, the overgrowth of other species,
tored, especially in Dentaid-1 plates.
and inter-dental brushes (Vitis Accesssofts and Interproxs, Dentaid).
microbiological variables, especially the
sion/exclusion criteria and to select the
was evaluated as a control variable.
fulfilling the inclusion criteria, the pur-
patient and visit and then by group.
instructions were reinforced at each visit
calculated at each visit. After evaluating
statistically significant (p 5 0.009).
the normality of the distribution (asses-
40 patients, 29 patients were included in
baseline visit with the 1-, 3- and 6-month
in the test group, with statistically sig-
visit (see Fig. 1 for the flowchart of the
smokers; mean age 46.6, range 38–62).
for the clinical variables. Frequencies of
evaluation and the data were excluded.
square test in the inter-group assessment,
and follow-up visits. Proportions of flora
vided only data at the baseline visit (one
antibiotic due to another disease and one
visit, totaling a loss of 0.23 mm after 6
visit. An intention-to-treat analysis was
Statistically significant reductions were
fidence interval (CI) 0.59–0.97] after 6
The Consort E-Flowchart Enrollment Azithromycin group Placebo group Allocation
Lost to fol ow-up (n=2) One took antibiotics for other
One because of personal reasons One due to illness
Table 1. Demographic features of the selected sample
One patient in the test group reporteddiarrhoea probably associated with the
months. Out of the 13 placebo patients,13 samples were available at baseline,
(significantly different as compared with
baseline). No inter-group significant dif-
ferences were detected at any visit or in
at baseline in frequencies of detection of
as inclusion criteria). A. actinomycetem-
placebo and 13.3% in the test group.
rose again and were always over 80%.
Table 3. Mean values, standard error (SE) and 95% confidence intervals (CI) of changes of clinical variables between visits and inter-groupcomparison (ANCOVA, with treatment as factor and baseline value, smoking and gender as cofactors; significant cofactors are listed)
CAL, clinical attachment level; PPD, probing pocket depth in mm; % PPD 1–3 mm, mean proportion of pockets in the 1–3 mm category; % PPD 4–6 mm, mean proportion of pockets in the 4–6 mm category; PlI, plaque index; BoP, bleeding on probing; RAL, relative attachment level.
values were achieved at 3 and 6 months.
p 5 0.032) of P. intermedia. P. gingivalis
represented the highest proportion of the
with regard to other target pathogens.
flora in both groups (21.5% in placebo and
17.7% in test samples). Higher proportions
was initially observed, and then a return
(po0.001), and the 6-month visit for A.
other pathogens were similar at baseline.
No significant differences were detected at
baseline in proportions of flora of target
Table 4a. Mean values, standard error (SE) and 95% confidence intervals (CI) of log of colony-
forming units at study visits and intra-group comparison (ANOVA and multiple rank test)
were also detected, specifically thoserelated with P. gingivalis. Conversely,
7.18 0.15 6.88 7.47 po0.066, baseline 7.07 0.16 6.75 7.40 p 5 0.511,
relevant limitations. Only 15 patients in
placebo group provided data for 6-monthvisit, and this may be considered as a
Table 4b. Mean values, standard error (SE) and 95% confidence intervals (CI) of changes in log
of colony-forming units between visits and inter-group comparison (ANCOVA, with treatment as
factor and baseline value as cofactors; significant cofactors are listed)
ences in size between both groups. Also,the effect of smoking in the results could
control this variable was made by strati-
failed to find significant differences in
periodontal disease severity betweennon-smokers and patients who con-
Table 5. Frequency of detection (in percentage) and mean proportions of flora (in percentage) of
different periodontal pathogens in subgingival samples, at every study visit
nez-Canut et al. 1995). Moreover,smoking was included as a cofactor in
line (statistically significant, p 5 0.022)
gival plaque control is an essential factor
significant better clinical and microbio-
logical results, despite the fact that pla-
the plaque control was homogeneous inboth groups. Other baseline difference
Aa, Aggregatibacter actinomycetemcomitans; Pg, Porphyromonas gingivalis; Pi, Prevotella inter-media; Tf, Tannerella forsythia; Pm, Parvimonas micra; Cr, Campylobacter rectus; Fn, Fusobac-
terium nucleatum; Capno, Capnocytophaga sp.; Ec, Eikenella corrodens; Eu, Eubacterium sp.
levels in the test group (p 5 0.004).
the first study in which azithromycin has
of patients with a specific microbiologi-
between the test and the control groups.
(Loesche et al. 1984); presence of A.
visits on a quadrant/sextant basis within
nidazole (Flemmig et al. 1998); or A.
ridement is a matter of controversy. In a
results of the adjunctive use of systemic
anti-microbials (Herrera et al. 2008a).
resulting in different bacterial antibiotic
of clinical trials with the use of adjunc-
susceptibility profiles in different Eur-
versus ‘‘partial-mouth’’ (within 7 days)
off et al. 2005). In order to optimize the
need of periodontal surgery after SRP.
tive of the other bacteria detected. After
significantly reduced in the test group at
sites (Herrera et al. 2002, Guerrero et al.
positive results, and it seems reasonable
not find any significant impact (Haffajee
et al. 2008). With regard to T. forsythia,
found in periodontal tissues. In addition,
detected at any follow-up visit, as oppo-
failed to find significant clinical differ-
detected T. forsythia at all time periods
et al. 2007). In these two studies, debri-
defined in the literature; thus, it is not
et al. 2002) or 3 weeks (Haffajee et al.
tions and counts of different pathogens).
analysed (Casey & Pichichero 2005). As
Gomi, K., Yashima, A., Iino, F., Kanazashi, M.,
Malizia, T., Tejada, M., Ghelardi, E., Senesi, S.,
Nagano, T., Shibukawa, N., Ohshima, T., Maeda,
Gabriele, M., Giuca, M., Blandizzi, C., Danesi,
N. & Arai, T. (2007a) Drug concentration in
R., Campa, M. & Del Tacca, M. (1997) Periodontal
inflamed periodontal tissues after systemically
tissue disposition of Azithromycin. Journal of
administered azithromycin. Journal of Perio-
Martinez-Canut, P., Lorca, A. & Magan, R. (1995)
Gomi, K., Yashima, A., Nagano, T., Kanazashi, M.,
Smoking and periodontal disease severity. Journal
Maeda, N. & Arai, T. (2007b) Effects of full-mouth
of Clinical Periodontology 22, 743–749.
Mascarenhas, P., Gapski, R., Al-Shammari, K., Hill,
scaling and root planing in conjunction with sys-temically administered azithromycin. Journal of
R., Soehren, S., Fenno, J. C., Giannobile, W. V. &
Wang, H. L. (2005) Clinical response of azithro-
Guerrero, A., Griffiths, G. S., Nibali, L., Suvan, J.,
mycin as an adjunct to non-surgical periodontal
Moles, D. R., Laurell, L. & Tonetti, M. S. (2005)
therapy in smokers. Journal of Periodontology 76,
Adjunctive benefits of systemic amoxicillin and
metronidazole in non-surgical treatment of general-
McDonald, P. J. & Pruul, H. (1991) Phagocyte uptake
ized aggressive periodontitis: a randomized place-
and transport of azithromycin. European Journal of
bo-controlled clinical trial. Journal of Clinical
Clinical Microbiology and Infectious Diseases 10,
Haas, A. N., de Castro, G. D., Moreno, T., Susin, C.,
Muller, H. P., Holderrieth, S., Burkhardt, U. & Hoffler,
Albandar, J. M., Oppermann, R. V. & Rosing, C. K.
U. (2002) In vitro antimicrobial susceptibility of
(2008) Azithromycin as an adjunctive treatment of
oral strains of Actinobacillus actinomycetemcomi-
aggressive periodontitis: 12-months randomized
tans to seven antibiotics. Journal of Clinical Perio-
clinical trial. Journal of Clinical Periodontology
Pajukanta, R. (1993) In vitro antimicrobial suscept-
dontitis harbouring P. gingivalis in their
Haffajee, A. D., Patel, M. & Socransky, S. S. (2008)
ibility of Porphyromonas gingivalis to azithromy-
Microbiological changes associated with four dif-
cin, a novel macrolide. Oral Microbiology and
ferent periodontal therapies for the treatment of
chronic periodontitis. Oral Microbiology Immunol-
Pavicic, M. & van Winkelhoff, AJ. (1994) Microbio-
logical and clinical effects of metronidazole and
Haffajee, A. D., Socransky, S. S. & Gunsolley, J. C.
amoxicillin in Actinobacillus actinomycetemcomi-
(2003) Systemic anti-infective periodontal therapy.
tans associated periodontitis. A 2-year evaluation.
A systematic review. Annals of Periodontology 8,
Journal of Clinical Periodontology 21, 107–112.
Pradeep, A. R., Sagar, S. V. & Daisy, H. (2008)
Haffajee, A. D., Torresyap, G. & Socransky, S. S.
Clinical and microbiologic effects of subgingivally
(2007) Clinical changes following four different
delivered 0.5% azithromycin in the treatment of
Alsina, M., Olle, E. & Frias, J. (2001) Improved, low-
periodontal therapies for the treatment of chronic
chronic periodontitis. Journal of Periodontology 79,
cost selective culture medium for Actinobacillus
periodontitis: 1-year results. Journal of Clinical
actinomycetemcomitans. Journal of Clinical Micro-
Renvert, S., Wikstrom, M., Dahlen, G., Slots, J. &
Herrera, D., Alonso, B., Leon, R., Roldan, S. & Sanz,
Egelberg, J. (1990a) Effect of root debridement on
Armitage, G. C. (1999) Development of a classifica-
M. (2008a) Antimicrobial therapy in periodontitis:
the elimination of Actinobacillus actinomycetemco-
tion system for periodontal diseases and conditions.
the use of systemic antimicrobials against the sub-
mitans and Bacteroides gingivalis from periodontal
pockets. Journal of Clinical Periodontology 17,
Blandizzi, C., Malizia, T., Lupetti, A., Pesce, D.,
Gabriele, M., Giuca, M. R., Campa, M., Del, T.
Herrera, D., Contreras, A., Gamonal, J., Oteo, A.,
Renvert, S., Wikstrom, M., Dahlen, G., Slots, J. &
M. & Senesi, S. (1999) Periodontal tissue disposi-
Jaramillo, A., Silva, N., Sanz, M., Botero, J. E. &
Egelberg, J. (1990b) On the inability of root debri-
tion of azithromycin in patients affected by chronic
Leon, R. (2008b) Subgingival microbial profiles in
dement and periodontal surgery to eliminate Acti-
inflammatory periodontal diseases. Journal of
chronic periodontitis patients from Chile, Colombia
and Spain. Journal of Clinical Periodontology 35,
periodontal pockets. Journal of Clinical Perio-
Casey, J. R. & Pichichero, M. E. (2005) Higher
dosages of azithromycin are more effective in
Herrera, D., Rolda´n, S., O’Connor, A. & Sanz, M.
Retsema, J., Girard, A., Schelkly, W., Manousos, M.,
treatment of group A streptococcal tonsillopharyn-
(2000) The periodontal abscess: II. Short-term
Anderson, M., Bright, G., Borovoy, R., Brennan, L.
gitis. Clinical Infectious Diseases 40, 1748–1755.
Contopoulos-Ioannidis, D. G., Ioannidis, J. P., Chew,
clinical and microbiological efficacy of two sys-
& Mason, R. (1987) Spectrum and mode of action
P. & Lau, J. (2001) Meta-analysis of randomized
temic antibiotics regimes. Journal of Clinical
of azithromycin (CP-62,993), a new 15- membered-
controlled trials on the comparative efficacy and
ring macrolide with improved potency against
safety of azithromycin against other antibiotics for
Herrera, D., Sanz, M., Jepsen, S., Needleman, I. &
gram-negative organisms. Antimicrobial Agents
lower respiratory tract infections. Journal of Anti-
Roldan, S. (2002) A systematic review on the effect
microbial Chemotherapy 48, 691–703.
of systemic antimicrobials as an adjunct to scaling
Sanz, M. & Teughels, W. (2008) Innovations in non-
Dahlen, G., Renvert, S., Wikstrom, M. & Egelberg, J.
and root planing in periodontitis patients. Journal of
surgical periodontal therapy: consensus report of
(1990) Reproducibility of microbiological samples
Clinical Periodontology 29 (Suppl. 3), 136–159.
the sixth european workshop on periodontology.
from periodontal pockets. Journal of Clinical
Kornman, K. S., Newman, M. G., Moore, D. J. &
Journal of Clinical Periodontology 35, 3–7.
Singer, R. E. (1994) The influence of supragingival
Sanz, M., van Winkelhoff, AJ., Herrera, D., Dellemijn-
Dastoor, S. F., Travan, S., Neiva, R. F., Rayburn, L.
plaque control on clinical and microbial outcomes
Kippuw, N., Simo´n, R. & Winkel, EG. (2000)
A., Giannobile, W. V. & Wang, H. L. (2007) Effect
following the use of antibiotics for the treatment of
Differences in the composition of the subgingival
of adjunctive systemic azithromycin with perio-
periodontitis. Journal of Periodontology 65, 848–
microbiota of two periodontitis populations of
dontal surgery in the treatment of chronic perio-
different geographic origin. A comparison between
dontitis in smokers: a pilot study. Journal of
Lindhe, J. & Palmer, R. (2002) Group C Summary.
Spain and The Netherlands. European Journal of
Journal of Clinical Periodontology 29 (Suppl. 3),
Flemmig, T. F., Milian, E., Karch, H. & Klaiber, B.
Saxen, L. & Asikainen, S. (1993) Metronidazole in the
(1998) Differential clinical treatment outcome after
Loesche, W. J., Grossman, N. & Giordano, J. (1993)
treatment of localized juvenile periodontitis. Jour-
systemic metronidazole and amoxicillin in patients
Metronidazole in periodontitis (IV). The effect of
nal of Clinical Periodontology 20, 166–171.
harboring Actinobacillus actinomycetemcomitans
patient compliance on treatment parameters. Jour-
Schentag, J. J. & Ballow, C. H. (1991) Tissue-directed
and/or Porphyromonas gingivalis. Journal of Clin-
nal of Clinical Periodontology 20, 96–104.
pharmacokinetics. American Journal of Medicine
Loesche, W. J., Syed, S. A., Morrison, E. C., Kerry, G.
Foulds, G., Shepard, R. M. & Johnson, R. B. (1990)
A., Higgins, T. & Stoll, J. (1984) Metronidazole in
Sefton, A. M., Maskell, JP., Beignton, D., Whiley, A.,
The pharmacokinetics of azithromycin in human
periodontitis. I. Clinical and bacteriological results
Shain, H., Foyle, D., Smith, S., Smales, F. &
serum and tissues. Journal of Antimicrobial Che-
after 15 to 30 weeks. Journal of Periodontology 55,
Willians, J. D. (1996) Azithromycin in the treat-
ment of periodontal disease. Effect on microbial
flora. Journal of Clinical Periodontology 23, 998–
van Winkelhoff, A. J., Herrera, D., Oteo, A. & Sanz,
Winkel, E. G., van Winkelhoff, A. J., Timmerman, M.
M. (2005) Antimicrobial profiles of periodontal
F., Vangsted, T. & van der Velden, U. (1997)
Sharma, V., Sharma, A., Kumar, V. & Aggarwal, S.
pathogens isolated from periodontitis patients in
Effects of metronidazole in patients with ‘‘refrac-
(2009) Disulfiram-like reaction with ornidazole.
The Netherlands and Spain. Journal of Clinical
tory’’ periodontitis associated with Bacteroides
Journal of Postgraduate Medicine 55, 292–293.
forsythus. Journal of Clinical Periodontology 24,
Smith, S. R., Foyle, D. M., Daniels, J., Joyston-Bechal,
van Winkelhoff, A. J., Rams, T. E. & Slots, J. (1996)
Yashima, A., Gomi, K., Maeda, N. & Arai, T. (2009)
S., Smales, F. C., Sefton, A. & Williams, J. (2002)
Systemic antibiotic therapy in periodontics. Perio-
One-stage full-mouth versus partial-mouth scaling
A double-blind placebo-controlled trial of azithro-
and root planing during the effective half-life of
mycin as an adjunct to non-surgical treatment of
Wikstrom, M., Renvert, S., Dahlen, G. & Johnsson, T.
(1991) Variance in recovery of periodontitis-asso-
systemically administered azithromycin. Journal of
periodontitis in adults: clinical results. Journal of
ciated bacteria caused by sampling technique and
Clinical Periodontology 29, 54–61.
laboratory processing. Oral Microbiology and
Socransky, S. S. & Haffajee, A. D. (1997) Microbiol-
ogy of periodontal disease. In: Lindhe, J., Karring,
Willians, J. D., Maskell, J. P., Shain, H., Chrysos, G.,
T. & Lang, NP. (eds). Clinical Periodontology and
Sefton, A. M., Fraser, H. Y. & Hardie, J. M. (1992)
Etiology and Therapy of Periodontal Disease
Implant Dentistry, pp. 138–188. Copenhagen:
Comparative in-vitro activity of azithromycin,
macrolides (erythromycin, clarithromycin and spir-
Syed, S. A. & Loesche, W. J. (1972) Survival of
amycin) and streptogramin rp 59500 against oral
human dental plaque flora in various transport
organism. Journal of Antimicrobial Chemotherapy
media. Applied Microbiology 24, 638–644.
Our Amazing Planet Outline script for PowerPoint presentation [Show first screen.] We live on an amazing planet. We’re going to look at some pictures and listen to some music now, that show us some amazing places on our planet. [Click to show the next screen, and start music playing. The next few slides will progress automatically.] [Although we can’t include songs on our CD for cop
Ordinance Amending the Drinking Water Ordinance of 21 May 2001 Article 1 ORDINANCE ON THE QUALITY OF WATER INTENDED FOR HUMAN CONSUMPTION (DRINKING WATER ORDINANCE - TRINKWASSERVERORDNUNG - TRINKWV 2001 ) CHAPTER ONE GENERAL PROVISIONS Section 1 Purpose of the Ordinance The purpose of this Ordinance shall be to protect human health from the adverse ef-fects of any