**5. Antibiotic compounds commonly used in implant dentistry**

Antibiotic compounds can be classified in a number of different ways: (a) by their origin (natural, semisynthetic or synthetic drugs); (b) by their mode of antibacterial activity as bacteriostatic (growth inhibiting), or bacteriocidal (drugs kill the bacteria); (c) by antibacterial spectrum (broad-spectrum or narrow-spectrum), or (d) by their cellular mechanism of action, for example:


responsible for the infection is treated on a presumptive basis, founded on probabilistic reasoning [90]. A wide range of antibiotic compounds and dose regiments is presented in the literature. Ideally, antibiotic treatment duration should include the shortest efficient cycle for preventing both clinical and microbiological relapse [91]. However, this short cycle should ideally have certain characteristics such as rapid onset of action; bactericidal activity; lack of propensity to promote resistant mutants; ease of invasion into tissues; activity against nondividing bacteria; unaffected by adverse infection conditions (low pH, presence of pus, etc.); administration at an optimal dose; and an optimal and convenient dosing regimen [92].

Local delivery facilitates the application of antimicrobial agents at levels that cannot be reached by the systemic route. However, these levels need to be maintained at a high local concentration for a long period of time, and the agents should reach the entire affected area, that is, the base of the pocket, in order to be efficient. This type of delivery varies from simple pocket irrigation and specifically placed drug-containing ointments and gels, to sophisticated tools for sustained release of antibacterial agents. However, it is unlikely that mouth rinse or supragingival irrigation could predictably deliver an agent to the deeper parts of the defect because the crevicular fluid rapidly washes out agents from the pockets [93, 94]. Nevertheless, there is a low incidence of side effects with locally applied antibiotics. The use of local antibiotics as an adjunctive in the treatment of peri-implantitis has shown no or limited effect on the reduction of periodontal pocket depth and gain in clinical attachment level [95, 96]. This lack of significant clinical additive effects of local antibiotic supplement is may be due to inadequate exposure

Systemic use of antibiotics is commonly recommended when the targeted bacteria are more widely spread, which is beyond the site of initial infection. The periodontal bacteria may be found throughout the whole oral cavity including on non-dental sites such as the dorsum of the tongue or tonsillary crypts [97–103]. However, this colonization of perio-pathogens at various oral ecological niches is not to be regarded as a systemic infection and does not call for systemic antimicrobial treatment. The drawback of systematic administration is the high rate of drug dissemination throughout the body, where only a small portion reaching the subgingival microflora in the periodontal pocket [104]. Moreover, adverse drug reactions are of greater concern. Systemic antibiotics should never be applied as compensation for inade‐

**5. Antibiotic compounds commonly used in implant dentistry**

Antibiotic compounds can be classified in a number of different ways: (a) by their origin (natural, semisynthetic or synthetic drugs); (b) by their mode of antibacterial activity as bacteriostatic (growth inhibiting), or bacteriocidal (drugs kill the bacteria); (c) by antibacterial

**4.1. Local use of antibiotics**

24 Dental Implantology and Biomaterial

of the subgingival bacteria to the compound.

**4.2. Systematic use of antibiotics**

quate oral hygiene.

**v.** Antibiotics that can damage the cell membrane, such as polymyxin B and daptomycin


**Table 1.** Summary of characteristics of the most common antibiotic compounds used in implant dentistry.

Although there are numerous antimicrobial agents available, only a limited number of systemic antibiotics such as amoxicillin; phenoxymethylpenicillin (PcV); clindamycin; metronidazole; and the combination of amoxicillin and metronidazole have been widely used in the implant dentistry field (**Table 1**).

#### **5.1. Amoxicillin**

Amoxicillin is derived from one of the oldest antibiotics, penicillin, which was discovered in 1928 by Alexander Fleming. It is a broad-spectrum antibiotic compound commonly used during invasive dental procedures as it shows a good and predictable absorption and bioa‐ vailability [106]. It has a bactericidal activity against gram-positive and gram-negative microorganisms. In addition, it is active against several members of the oral commensal microflora, such as viridans streptococci, and is thus expected to reduce the risk of local and systemic infection after dental procedures. The molecular structure of amoxicillin includes a β-lactam ring that may be cleaved by bacterial enzymes.

The combination of amoxicillin and clavulanic acid, the beta-lactamase inhibitors, is used to treat infections with β-lactamase producing bacteria. This combination results in an antibiotic with a broader spectrum of action and restored efficacy against amoxicillin-resistant bacteria, which produce β-lactamase.

## **5.2. Penicillin-V**

Penicillin-V is a widely used antibiotic in dentistry and possesses several beneficial charac‐ teristics. It achieves peak serum levels within 30 min, and persistent, detectable levels for up to 4 h after administration [106]. It has a bactericidal action with a narrow microbial spectrum, and it is highly effective against most *Streptococcus* species and oral anaerobes [106]. Penicillin-V is recommended as the drug of choice for the treatment of dental infections in Scandinavian countries. However, it is seldom used outside Scandinavia mainly because it is not available for purchase in many countries. The wide use of penicillin-V instead of broad-spectrum compounds is considered to be an important factor contributing to the low rates of antibiotic resistance seen in Scandinavian countries.

#### **5.3. Metronidazole**

Metronidazole has a unique bactericidal effect against anaerobic bacteria. It is a narrowspectrum antibiotic, which minimizes the risk of opportunistic pathogens among commensal microbiota and reduces the risk of developing a resistant species. There is no known allergic or hypersensitivity reactions to metronidazole, and it has limited side effects which are generally tolerable, transient, or reversible [107].

#### **5.4. Clindamycin**

Clindamycin is a broad-spectrum compound active against oral anaerobic and aerobic bacteria, such as streptococci and staphylococci, although its use in dentistry is recommended mainly in patients with a penicillin allergy [106]. It is bacteriostatic in normal concentrations and has good bone penetration [91]. Because of its broad-spectrum effect, it gives significant and long-term effects on the protective resident microflora and is associated with the devel‐ opment of *Clostridium difficile* gastroenteritis [108, 109].

#### **5.5. Antibiotic combination therapy**

metronidazole; and the combination of amoxicillin and metronidazole have been widely used

Amoxicillin is derived from one of the oldest antibiotics, penicillin, which was discovered in 1928 by Alexander Fleming. It is a broad-spectrum antibiotic compound commonly used during invasive dental procedures as it shows a good and predictable absorption and bioa‐ vailability [106]. It has a bactericidal activity against gram-positive and gram-negative microorganisms. In addition, it is active against several members of the oral commensal microflora, such as viridans streptococci, and is thus expected to reduce the risk of local and systemic infection after dental procedures. The molecular structure of amoxicillin includes a

The combination of amoxicillin and clavulanic acid, the beta-lactamase inhibitors, is used to treat infections with β-lactamase producing bacteria. This combination results in an antibiotic with a broader spectrum of action and restored efficacy against amoxicillin-resistant bacteria,

Penicillin-V is a widely used antibiotic in dentistry and possesses several beneficial charac‐ teristics. It achieves peak serum levels within 30 min, and persistent, detectable levels for up to 4 h after administration [106]. It has a bactericidal action with a narrow microbial spectrum, and it is highly effective against most *Streptococcus* species and oral anaerobes [106]. Penicillin-V is recommended as the drug of choice for the treatment of dental infections in Scandinavian countries. However, it is seldom used outside Scandinavia mainly because it is not available for purchase in many countries. The wide use of penicillin-V instead of broad-spectrum compounds is considered to be an important factor contributing to the low rates of antibiotic

Metronidazole has a unique bactericidal effect against anaerobic bacteria. It is a narrowspectrum antibiotic, which minimizes the risk of opportunistic pathogens among commensal microbiota and reduces the risk of developing a resistant species. There is no known allergic or hypersensitivity reactions to metronidazole, and it has limited side effects which are

Clindamycin is a broad-spectrum compound active against oral anaerobic and aerobic bacteria, such as streptococci and staphylococci, although its use in dentistry is recommended mainly in patients with a penicillin allergy [106]. It is bacteriostatic in normal concentrations and has good bone penetration [91]. Because of its broad-spectrum effect, it gives significant

in the implant dentistry field (**Table 1**).

β-lactam ring that may be cleaved by bacterial enzymes.

**5.1. Amoxicillin**

26 Dental Implantology and Biomaterial

which produce β-lactamase.

resistance seen in Scandinavian countries.

generally tolerable, transient, or reversible [107].

**5.2. Penicillin-V**

**5.3. Metronidazole**

**5.4. Clindamycin**

Peri-implant subgingival microbiota contains several putative periodontopathic species with different antimicrobial susceptibility. Therefore, antibiotic combination may be useful because of its wider spectrum of activity compared with a single agent. Combination drug therapy may reduce the possibility of developing bacterial resistance due to antimicrobial spectrum overlap, or it may be combined in a synergetic way when targeting organisms, allowing the dose of a single agent to be lowered [110]. However, such combinations may lead to increased adverse reactions. Recently, the combination of metronidazole and amoxicillin has become a popular treatment modality for many dentists and researchers.

## **6. Consequences of antibiotic treatment**

No antibacterial drug is completely nontoxic, and its use carries accompanying risks, which has to balance the benefits and risks of its use before prescribing. The most common side-effects are gastrointestinal, ranging in severity from frequent self-limiting gastrointestinal upset to rare life-threatening pseudomembranous colitis. Other relatively common adverse effects are hypersensitivity reactions ranging from mild to life-threatening anaphylactic reactions [110]. However, the majority of these reactions are mild and limited to a rash or skin lesions in the head or neck region. Another negative impact of the over prescription of antibiotics is the cost to the healthcare system. A survey performed in USA suggested that while the cost of antibiotic prophylaxis is low to the individual, the potential cost to the healthcare system may be well over \$150 million annually [111].

**Figure 2.** The effect of antibiotic treatment on the ecology of the normal microflora [112–114].

It is well known that the administration of antimicrobial agents causes a disturbance in the oropharyngeal and intestinal microflora, which is considered to be important for health maintenance. This disturbance is not only due to the spectrum of agents, but also to their degree of absorption, route of elimination, possible enzymatic inactivation and/or binding to human fluids and intestinal material [112]. Individual variations in normal microflora further determines the ecological outcome of antimicrobial therapy [112]. Selective pressure by the administration of antibiotics will decrease the number of microorganisms in the oral cavity. Consequently, this leads to a disturbance in human microbial ecology as shown in **Figure 2** [112–114].

Antibiotic resistance has become a global growing health problem. The golden age of antibiotic therapy is now coming to an end as stated in 2014 by WHO [115]. However, some researcher believes that we are already in the pre-antibiotic era. The Global Economic Forum reported that the development of antibiotic resistance has major societal risks and increases both morbidity and mortality of affected individuals [115, 116]. Each year there are thousands of deaths, and millions of dollars spent on healthcare costs due to resistant infections [117]. Therefore, a restrictive approach towards using antibiotics is mandatory in order to limit the development of microbial antibiotic resistance and avoid the risk of unwanted systemic effects of antibiotics for the treated individual.
