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Regenerative endodontic procedures (REPs) are
biologically based procedures designed to replace damaged structures, including
dentin and root structures, as well as cells of the pulp–dentin complex i. In
cases of necrotic immature teeth with open apices, REPs promote root
development and apical closure. Most REPs include minimal-to-no mechanical
debridement ii, trusting on the chemical
debridement step and on the use of intracanal medicaments to achieve disinfection.
Therefore, intracanal medicaments have been used in almost all published REPs. In
the recent review carried out by Kontakiotis et al. iii
analyzing the protocols that have been used in regenerative endodontic therapy,
including 60 clinical studies, 49 studies used antibiotics, alone (n = 45) or
in combination with calcium hydroxide (n = 4).

The infection of the root canal system in
immature permanent teeth with open apices, and the following apical
periodontitis, are diseases caused by mixed bacterial communities consisting of
both aerobic and anaerobic bacteria iv. Therefore,
the use of a combination of antibiotics is more probable to achieve an
effective sterilization of the canal, also decreasing the likelihood of the
development of antibiotic resistance.

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The first reported clinical protocol v using
antibiotics as intracanal medicament in REPs, used a double antibiotic paste
(DAP) containing ciprofloxacin and metronidazole. Posteriorly, a triple
antibiotic paste (TAP) containing ciprofloxacin, metronidazole and a third
antibiotic such as minocycline vi, vii, viii, ix, x, xi, xii, xiii, cefaclor
xiv, xv, xvi or
clindamycin xvii,
has been used as intracanal medicament.

Nowadays, the antibiotic mixture composed of
ciprofloxacin, metronidazole, and minocycline, known as triple antibiotic paste
(TAP) or “3mix”, is the most widely used intracanal medicament in REPs 2.

The nitroimidazole compound metronidazole is
well known for its broad spectrum and strong antibacterial activity against
anaerobic cocci, as well as gram-negative and gram-positive bacilli.
Metronidazole permeates bacterial cell membranes, reaches the nuclei and binds
to the DNA, disrupting its helical structure, causing cell death. The in vitro
activity of metronidazole against clinical isolates from odontogenic abscesses
was investigated by Roche & Yoshimori xviii,
concluding that, although it has no activity against aerobes, metronidazole has
excellent activity against anaerobes isolated from odontogenic abscesses.
Moreover, the use of metronidazole has been advocated because of its low
induction of bacterial resistance xix.

Minocycline is a member of the bacteriostatic
and broad spectrum antimicrobials group of tetracyclines. They are effective
against both gram-positive and gram-negative microorganisms, including most
spirochaetes and many anaerobic and facultative bacteria. Minocycline is a
semisynthetic derivative of tetracycline with a similar spectrum of activity.
Minocycline invades bacterial cells by passive diffusion through the outer
membrane followed by active transport through the inner membrane. Minocycline
reaches the surfaces of ribosomes and inhibits protein synthesis. Minocycline
has been used in periodontal therapy, being available in many topical forms.

The synthetic fluoroquinolone ciprofloxacin
inhibits DNA gyrase in bacterial nuclei, degrading the DNA by exonucleases and
resulting in a bactericidal effect. Ciprofloxacin has very potent activity
against gram-negative pathogens but its activity is limited against
gram-positive bacteria and most anaerobic bacteria are resistant to
ciprofloxacin. Consequently, ciprofloxacin is often combined with metronidazole
in the treatment of mixed infections. Although ciprofloxacin can cause side
effects, in low doses the drug is clinically safe xx. It
can be assumed that when low doses of ciprofloxacin are applied as intra-canal
medicament, adverse systemic side effects are minimal.

This review aims to analyze: 1) the scientific evidence
about the effectiveness of antibiotics used in REPs against bacteria implicated
in endodontic disease; 2) the scientific evidence supporting the use of
antibiotics in REPs; and 3) the clinical implications of their use, such as
possible side effects and their interactions with dental pulp stem cells.


i Murray PE,
Garcia-Godoy F, Hargreaves KM. Regenerative endodontics: a review of current
status and a call for action. J Endod 2007;33:377–90.

ii Diogenes A, Henry
MA, Teixeira FB et al. An update on clinical regenerative endodontics. Endod Topics 2013;28:2–23.

iii Kontakiotis EG,
Filippatos CG, Tzanetakis GN et al. Regenerative endodontic therapy: a data
analysis of clinical protocols. J Endod 2015;41:146–54.

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I. Present status and future directions in endodontic microbiology. Endod
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JD, Cohenca N. Pulp revascularization of necrotic bilateral bicuspids using a
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D, Loghin S, et al. Histologic study of a human immature permanent premolar with chronic
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xvi Bezgin T, Yilmaz
AD, Celik BN, et al. Efficacy of platelet-rich plasma as a scaffold in
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xvii Kahler B, Mistry S,
Moule A, et al. Revascularization outcomes: a prospective analysis of 16
consecutive cases. J Endod 2014;40:333–8.

xviii Roche Y, Yoshimori
RN. In-vitro activity of spiramycin and metronidazole alone or in combination
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of antimicrobial agents in periodontal therapy. J Periodontal Res 2002;37:389–98.

xx Black A, Redmond
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