# Antibiofilm Potential of Natural Essential Oils
## 5 Synergistic Effect of EO and Antibiotics  
Bacteria in biofilm undergo phenotypic changes that make them several-fold more resistant to antimicrobials. Owing to the heterogeneous nature of the BF, it is likely that there are multiple resistance mechanisms at work within a single community [52]. Combining existing antimicrobials with any ingredient (synergistic interaction), which can be a compound, a mixture of compounds (EOs), an antibiotic, antimicrobial peptides, and even any other antimicrobial agent, can be an effective form of neutralization of the resistance mechanism. There are many synergistic combinations used to define MIC and to prevent drug resistance, as well as to reduce toxicity. An example is flavon baikalin, which reduced MIC of ampicillin, methylicins, and cefotaxis in _S. aureus_ (MRSA) resistant to many drugs, as well as in penicillin-resistant _S. aureus_[53]. [PERSON] et al. [54] found various interactions (synergistic and indifferent) between plant extracts and antibiotics. The best synergistic ability was demonstrated between erythromycincin and sesame EO. MIC values of each antibiotic were reduced by half when used in combination with the tested plant extracts. Therefore, comprehensive actions seem to be particularly interesting, especially when using multi-component products such as EOs. EOs in combination with antibiotics can prevent the transfer of resistance to AM agents due to the synergistic ABF effect [23]. In turn, certain phytontrients can influence the formation and development of bacterial BF by acting as factors controlling bacterial adhesion and QS [55]. Due to their amphipathic nature, menthol, thymol, and eucalypt can pervade the exopolysaccharideacharide matrix of BF and enhance the antibiotic's activity by disrupting membrane permeability. Dominant synergy was observed for mixtures of muiprocin and menthol or thymol, whereas the muiprocin-eucalypt mixture exerted a neutral or additive effect on the inhibition of BF formation by _S. aureus_. Monoterpenes probably inhibited Staphylococcus adherence, allowing muiprocin diffusion into bacteria. Considering the anti-inflammatory properties of monoterpenes, muiprocinmonoterpene combinations could have a dual benefit of reducing both BF growth and inflammation. Monoterpenes applied in sub-inhibitory concentrations prior to BF formation could interact with staphylococcal surface proteins, compromising the initial attachment phase as well as interfering with the QS system [48]. [PERSON] et al. [56] demonstrated the potential AM and ABF activities of carvacrol as well as its synergistic interaction with an antibiotic (cefixime) against _E. coli_. Carvacrol and cefixime significantly inhibited BF formation at MIC/2 (125 and 62.5 \(\upmu\)m/mL), MIC/4 (62.5 and 31.25 \(\upmu\)g/mL), and MIC/8 (31.25 and 15.625 \(\upmu\)g/mL), respectively. [PERSON] and [PERSON] [21] evaluated the ABF activity of three EOs: cinnamon EO, tea tree EO (TTO), and palmarosa EO, and the synergistic effect of TTO and its major component terpinen-4-ol in combination with ciprofloxacin (CIP) against 24 h BF formed by _P. aeruginosa_. They showed that _P. aeruginosa_ BF treatment with the EOs, T4 ol, and CIP individually promoted a significant reduction in BF biomass and cell count in BF (mainly in the case of the higher concentrations tested). The AM synergism of TTO or T4 ol with CIP proved to be more effective, causing a significant disruption of BF at lower concentrations. The enhancement of CIP anti-BF activity with TTO could be explained by a multi-target effect (cytoplasmic membrane, DNA synthesis inhibitors) or the reversal of antibiotic resistance, inhibiting active efflux pumps. In the authors' opinion, the combination of terpinen-4-ol and CIP may offer a useful therapeutic option in the treatment of infections associated with _P. aeruginosa_ BF. The synergistic inhibitory effects between EOs and drugs would aim to reduce the side effects of antibiotic therapy, such as decreased immunity, inflammation, diarrhea, mycosis, and thrush. [PERSON] et al.