Article Type : Review Article
Authors : Muthuraj MSA, Janakiram S and Chithresan K
Keywords : Metronidazole; Nitroimidazole; Periodontitis; Scaling and root planning
Periodontitis is a bacterial plaque induced
inflammatory disease of periodontium. Some of the bacterial pathogens evade
host defence mechanism and diligent periodontal therapy. Antimicrobials when given as an adjuvant play
a major role in such situations. Many antimicrobials were used before, but only
some showed efficacy against most putative pathogens with significant
advantages. Metronidazole is one such
antimicrobial which is effective against various anaerobic periodontal
pathogens, with minimal side effects and least bacterial resistance. Here in
this review we are going to discuss about metronidazole and its application in
treatment of periodontitis.
Periodontitis is a
bacterial plaque induced inflammatory disease of periodontium characterised by
inflammation of gingiva and adjacent attachment apparatus, along with loss of
attachment [1]. Some of
the bacterial pathogens in dental plaque are tissue invading and evades host
defence mechanism. Such pathogens reside and repopulate even after diligent
non-surgical and surgical periodontal therapy [2,3]. In such cases
antimicrobials as an adjuvant to periodontal therapy will play a role. Many
antimicrobials have been employed as an adjuvant to periodontal therapy.
Metronidazole (MTZ), a 5-nitroimidazole
compound and amoebicide exerts its anti-bacterial activity on gram-negative
obligate anaerobes such as Porphyromonas gingivalis, Prevotella intermedia, Fusobacterium, Selenomonas sputigin and Tannerella
forsythia. Gram-positive obligate
anaerobes such as Peptostreptococcus are also susceptible to MTZ. C rectus, a facultative anaerobe
and probable periodontal pathogen, is also susceptible to low concentration of MTZ
[4]. The main advantage of MTZ is that it is least
affected by drug resistance [5]. Here in this mini review we will
discuss about important aspects of MTZ and its application as systemic drug in
treatment of periodontitis.
The metabolites of MTZ are cytotoxic, and they directly interact
with bacterial DNA, and other macromolecules, resulting in cell death. Upon
entry into an anaerobic organism, MTZ is reduced at the 5-nitro position by
electron transport proteins that are part of anaerobic metabolic
energy-yielding pathways. Alteration of the MTZ molecule creates a continuous
concentration gradient favouring diffusion of additional MTZ into the cell. The
above process generates free radicals which react with macromolecules such as
DNA, resulting in cell death [4].
MTZ is
completely and rapidly absorbed after oral administration. MTZ distributes well throughout body
tissues and fluids. Therapeutic levels can be found in various body fluids. The serum half-life is between 5.2 to 8.6 hours (mean-
7.3hours). Its bactericidal effect is not altered by pH changes within the
range 5.5 to 8.33. The drug is primarily metabolized in the liver and its
metabolites are excreted in the urine and faeces [6]. MTZ penetrates well into
gingival fluid achieving levels comparable to serum levels but not
demonstrating the concentration effect exhibited by the tetracyclines. For
Actinomyces species, a single dose of MTZ does not appear to produce minimal inhibitory drug
concentrations in gingival crevicular fluid. A single oral dose of
metronidazole would seem to deliver drug levels in serum and gingival crevicular
fluid that would not totally inhibit Eikenella
corrodens and Actinobacillus actinomycetemcomitans [7]. Levels achieved in
the gingival fluid following multiple doses (approximately 14 ?g/ml with
considerable variability) are sufficient to inhibit anaerobic periodontal
organisms like B. gingivalis, F. nucleatum Treponema etc in-vivo. In serum it
will inhibit the same suspected periodontopathogens for 6 to 7 hours [8].
Resistance
to MTZ is very rare, although
strains of trichomonads resistant to the drug have been reported. Two mechanisms were proposed to account for rare
instances of acquired resistance: lowered ability to reduce MTZ and decreased
drug absorption.
Metronidazole resistance is
uncommon and some reports on laboratory findings may be the result of
incomplete anaerobiosis. However, when present it is most likely to be the
result of a lack of reducing potential through, by implication, a lack of
pyruvate– ferredoxin oxidoreductase complex activity, leading to impairment of
pro-drug activation [5].
W.J. Loesche in
1981 and 1984 reported that MTZ along with scaling and root planing (SRP) significantly
reduced B. assacharolyticus, spirochetes and B.
gingivalis, but MTZ as a monotherapy hadn’t
demonstrated long standing effect on reducing periodontal pathogens and
creating healthy microflora [9,10]. Gusberti
et al. demonstrated statistically significant decrease of gram-negative rods, Fusobacteria and B. gingivalis over 6 months following
SRP along with MTZ [11]. Loesche WJ et al. demonstrated clinical
improvements accompanied by significantly lower proportions of spirochetes,
motile rods, selenomonads and P. intermedia along with increase in the
proportions of cocci in the subgingival flora [12]. Saxen
et al. had shown that Actinobacillus
actinomycetemcomitans was suppressed to below detection level at all
test sites only in the MTZ group and was more effective than tetracycline when
given as an adjuvant to modified Widman flap in patients with localised
juvenile periodontitis [13]. Carvalho LH et al.
observed reduction in counts of Porphyromonas gingivalis, Tannerella forsythia,
and Treponema denticola in subgingival; microflora of subjects received scaling
and root planing plus professional cleaning and scaling and root planing plus
professional cleaning plus systemic metronidazole 400 mg tid for 10 days [14].
Soder
et al. demonstrated a reduction in number of active sites in patients
recalcitrant to SRP after giving MTZ 400 mg TDS for 8 days as an adjuvant to
SRP [15].
Loesche WJ
et al. conducted a clinical study to determine the efficacy of metronidazole
(250 mg TDS) for one week, after the completion of scaling and root planing in
33 patients with advanced adult periodontitis.
The investigators observed a reduction in the need for periodontal surgery in
the metronidazole-treated group of 8.4 teeth per patient versus 2.6 teeth per
patient in the control group, a relative reduction of approximately 6 teeth.
Significant improvement in clinical parameters was noted in test group [16]. Carvalho et al. observed a significant improvement in
clinical parameters after giving MTZ 400 mg TDS for
10 days as an adjuvant to SRP. SRP plus periodical scaling and MTZ showed more
significant reduction [17].
Combination therapy extends the
antimicrobial spectrum and lowers the antimicrobial dose by exploiting possible
synergy between two drugs against targeted organisms.
The disadvantages of combination drug
therapy are increased drug interactions with improperly selected antibiotics. A
bactericidal antibiotic (?-lactam drug or metronidazole) should not be used
simultaneously with a bacteriostatic agent (tetracyclines) because the
bactericidal agent exerts activity during cell division that is impaired by the
bacteriostatic drug [18].
Effective combination therapies include MTZ +
amoxicillin (AMX) for A.
actinomycetemcomitans and various anaerobic periodontal infections, and
MTZ + ciprofloxacin (CPX) for mixed anaerobic and enteric rod/pseudomonas
periodontal infections
Primarily, amoxicillin–metronidazole had been introduced as a specific
treatment for periodontal infections with a detected presence of the
periodontal pathogen Aggregatibacter
actinomycetemcomitans (previously Actinobacillus
actinomycetemcomitans). However, this drug regimen is more efficacious
than the respective single drugs or placebo, even if empirically prescribed
without diagnostic identification of detectable pathogens in patients
exhibiting advanced periodontal disease. Accordingly,
amoxicillin+metronidazoleis considered to be an antibiotic regimen of first
choice and are used widely.
Many studies support the use of AMX + MTZ in treatment
of various forms of periodontitis. A study investigated the interactions between MTZ and
AMX, MTZ and its hydroxymetabolite, and AMX and the hydroxymetabolite of MTZ
using checkerboard titrations in combination with accurately determined Minimal
Inhibhitory Concentration (MIC) and Minimal Bactericidal Concentration (MBC).
Actinobacillus actinomycetemcomitans was used as the test organism. Synergism
was found for all three combinations. The synergistic interactions between
these antibiotics may explain the efficacy of the combination of metronidazole
and amoxicillin in periodontitis [20]. MTZ plus AMX therapy (Van
Winkelhoff cocktail) as an adjuvant to periodontal therapy eliminated A.
actinomycetemcomitans in 114 of 118 patients with clinically different forms of
periodontitis along with significant improvement in clinical parameters [21].
A controlled, randomized clinical trial involving advanced adult
periodontitis reported that 1-week-course of MTZ 250 mg plus AMX 250 mg as a
monotherapy, given 3 times every 4 months achieved reduction in active sites
and bleeding on probing along with improvement in overall attachment level.
Sites exhibiting ? 2 mm of attachment loss in 2 successive or alternate
evaluations, and periodontal abscess were noticed only in the placebo group
[22].
The combination
of mechanical therapy and systemic
application of AMX + MTZ has been shown to resolve periodontal
inflammation effectively in generalized aggressive periodontitis patients, with
stability of the improved clinical attachment for up to 5 years [23]. Herrera et al (2002) in a
systemic review reported that SRP plus systemic antimicrobial
groups demonstrated an improvement in clinical attachment level and probing
depth than SRP alone; with a statistically significant additional improvement
for amoxicillin/metronidazole in deep pockets [24]. A 6-month
double-blind, placebo-controlled, randomized clinical trial assessed the
adjunctive clinical effect of systemic antibiotic consisting of 500 mg AMX and
500 mg MTZ three times a day for 7 days to non-surgical treatment in patients
with generalized aggressive periodontitis (GAP). All clinical parameters
improved at 2 and 6 months in both groups. In test group with deep pockets (?7
mm), treatment resulted in an added 1.4mm full-mouth probing pocket depth (PPD)
reduction and 1mm of life cumulative attachment loss (LCAL) gain at 6 months
[25]. SRP combined with MTZ (400 mg three times daily) and AMX (500
mg three times daily) for 14 days reduced orange complex organisms in
non-smokers along with increase in proportions of Actinomyces. But smokers with
chronic periodontitis benefitted less [26]. Kelly McGowan et al.
conducted a systematic review to determine the optimum dose
and duration of AMX + MTZ prescribed as an adjunct to non-surgical treatment of
periodontitis. Periodontal pocket depth and clinical attachment level were
evaluated at 3 months. Secondary outcomes assessed were adverse events and
compliance. He concluded that a 7-day regimen of 500/500 mg or 500/400 mg of
AMX and MTZ would be most appropriate for treatment of patients with
periodontitis [27]. Gómez-Sandoval JR
et al. compared the efficacy of clindamycin versus AMX +
MTZ, as an adjuvant to SRP in patients
with periodontitis and type 2 diabetes mellitus. Both groups showed same
efficacy for the reduction of probing depth, plaque index, and bleeding on
probing in patients with periodontitis and type 2 diabetes [28].
Rams et al. conducted
a clinical study to evaluate the effect of a combined systemic CPX+MTZ therapy (500
mg of each for 8 days) on 17 adults with recurrent periodontitis despite prior
mechanical/surgical therapy, plaque control and systemic maintenance care.
Clinical and microbiological parameters were evaluated before therapy and 6 to
18 months after therapy. Ciprofloxacin/metronidazole therapy eliminated or
significantly suppressed sub gingival putative periodontal pathogens.
Streptococci
and occasionally Actinomyces
species were the predominant cultivable subgingival microorganisms up to
6–18 months post treatment. Significant improvements in probing depth, clinical
attachment loss and bleeding on probing, paralleled elimination or suppression
of suspected periodontal pathogens was reported in all patients, with no
additional periodontal disease activity detected at any site post treatment
[29].
The
combination of CPX+MTZ has
been suggested as adjunctive therapy for periodontal infections when enteric
rods, pseudomonads or A.
actinomycetemcomitans are present. Metronidazole-ciprofloxacin combination
is effective against A. actinomycetemcomitans. Obligate anaerobes are more
susceptible to metronidazole and facultative anaerobes to ciprofloxacin. This
is a powerful combination against mixed infections. Studies of this drug
combination in the treatment of refractory periodontitis with enteric rods have
documented marked clinical improvement [30].
Metronidazole is a cheaper antimicrobial
effective against protozoa as well as anaerobic bacteria. In treatment of
periodontitis, it is very effective against most of periodontal pathogens with
least antimicrobial resistance. On combination with amoxicillin, it can be used
as an empirical drug in periodontal therapy, as it has a good track record.
When combined with ciprofloxacin it is very effective against cases refractory
to periodontal treatment by acting against enteric rods. Thus metronidazole is
a wonder drug in treatment of periodontitis when prescribed individually as
well as in combination, with Amoxicillin and metronidazole combination (AMX
3x375-500mg /day and MTZ 3x250-500 mg for eight days) being the most
effective.