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In vitro synergistic activity of lidocaine and miconazole against Candida albicans/Atividade sinergica in vitro de lidocaina e miconazole contra Candida albicans.

Introduction

Candida albicans is the leading yeast involved in fungal infections in the world, though other species start to detach, this species still remains isolated from samples of urine, blood, secretions, among other biological samples (Quindos, 2014).

The treatment of infections caused by C. albicans is performed using systemic and topical antifungal, mainly from the group of azole drugs, the main representatives are ketoconazole, miconazole, itraconazole, fluconazole, voriconazole and posaconazole, which have the same mechanism of action, inhibiting the synthesis of ergosterol. The foremost differences of this group of drugs are pharmacokinetic and toxicity (Guinea et al., 2014).

C. albicans is the most commonly isolated yeast vulvovaginal candidiasis (VVC). Treatment of VVC is usually accomplished by use of antifungal creams. The miconazole (MZ) is the active ingredient in vaginal cream used in the treatment of (VVC) and Candida spp. already show reduced sensitivity to this drug (Liu, Fan, Peng, & Zhang, 2014; Sobel, 2013).

Lidocaine (LD) is an anesthetic used in clinical medicine, which showed antifungal activity has already been described, alone or in synergy with antifungal agents like amphotericinB, itraconazole, voriconazole, and caspofungin, however it is important to emphasize that the use must be topical due to toxicity (Judd & Martin, 2009; Palmeira-de-Oliveira et al., 2012; Rodrigues, Araujo, & Pina-Vaz, 2006).

The aim of this study was to evaluate in vitro synergy between lidocaine(LD) and miconazole (MZ) against C. albicans, this combination has not been tested in previous works.

Material and methods

In this study, 19 strains of Candida albicans isolated from vaginal secretion cultures were selected, these strains are the most commonly isolated fungal infections in Ceara, Northeast Brazil. The identification was performed by micromorphology on rice agar Tween 80, germ tube production, fermentation and assimilation of carbohydrates and molecular biology (Menezes, Cunha, & Cunha 2009).

The test sensitivity and synergism of LD and MZ was performed according to the protocol M27-A3 by method the microdilution in broth RPMI (pH 7.0), and by checkerboard method, the range of LD used was 2,500 to 15.0 [micro]g [mL.sup.-1] and MZ 32.0 to 0.015 [micro]g [mL.sub.-1]. The MIC was the lowest concentration that inhibited 50% of fungal growth. The tests were performed with drugs alone (MZ and LD) and also combined at fixed concentrations. The synergistic effect of MZ and LD was calculated based FICI (fractional inhibitory concentration index), (FICI = [MZC] x [[MZA].sup.-1] + [LDC] x [[LDA].sup.-1]), where [MZC] and [LDC] are the concentrations of miconazole and lidocaine that showed action when combined. [MZA] and [LDA] are the concentrations of the same drugs acting alone. The interpretation of results was performed according to the value of FICI < 0.5, synergism (SYN), 0.5 < FICI < 4.0--Indifferent (IND) and FICI > 4.0--antagonism (ANT) (Menezes et al., 2012; Menezes, Vasconcelos Junior, Angelo, Cunha, & Cunha, 2013).

Results

The Table 1 shows the results of the synergy between MZ and LD, 78.9% of the strains have sensitivity to combination of drugs and effect synergic was found.

The LD alone has antifungal action only at high doses, but when combined with MZ concentrations fall too, which shows the potential of this combination. The antifungal properties of anesthetics had already been presented in previous works (Judd & Martin, 2009; Wright, Durieux, & Groves, 2008).

Discussion

Fungal infections are increasing worldwide, affects all age groups, but especially seriously ill patients, HIV patients, transplant recipients and those using corticosteroids and they are associated with increased morbidity and mortality. Another important factor is fungal resistance a phenomenon has been detected in various parts of the world and worries, because the amount of antifungal agents available is very limited (Delaloye & Calandra, 2014; Dimopoulos, Antonopoulou, Armaganidis, & Vincent, 2013; Paramythiotou, Frantzeskaki, Flevari, Armaganidis, & Dimopoulos, 2014).

C. albicans is yeast that has several virulence factors and is the main agent isolated from VVC, with about 70-75% of the isolates. Antifungal drugs available for the treatment of VVC are generally for topical use and may cause local toxic effects, such as burns and irritation, in addition, the sensitivity of the strains to these drugs is becoming less (Liu et al., 2014). In our study, we used 19 strains of C. albicans isolated from vaginal secretion cultures; samples were identified and used in the tests.

Drugs without antifungal effects known have been associated with traditional antifungal agents with the goal of increasing their activity and diminish the toxic effects. The various associations tested the most common are those where fluconazole is used as a prototype (Liu et al., 2014; Stylianou et al., 2014). In our work we used a widely used antifungal miconazole and rarely described when evaluating synergy.

LD is a drug used as a local anesthetic and has no antifungal indication and its association with miconazole shows that this drug can be potentiated in the presence of an antifungal agent (Table 1). Due to some mechanism not yet fully elucidated synergy occurs between LD and MZ (Palmeira-de-Oliveira et al., 2012).

In a study using 10 strains of Candida spp. was evaluated and observed the antifungal effect of lidocaine; however the synergistic antifungal effect was not assessed (Palmeira-de-Oliveira et al., 2012). We observed an antifungal effect of LD alone and combined with the MZ (Table 1).

Conclusion

In conclusion, the synergistic activity of the combination of LD and MZ was observed in vitro, new studies with a larger number of strains should be used to confirm the results, and this combination could be an alternative in the production of vaginal cream for the treatment of VVC.

Doi: 10.4025/actascihealthsci.v39i2.32413

Acknowledgements

The financial support received from the CNPq, Capes and Funcap (Brazilian agencies).

References

Delaloye, J., & Calandra T. (2014). Invasive candidiasis as a cause of sepsis in the critically ill patient. Virulence, 5(1), 161-169.

Dimopoulos, G., Antonopoulou, A., Armaganidis, A., & Vincent, J. L. (2013). How to select an antifungal agent in critically ill patients. Journal of Critical Care, 28(5), 717-727.

Guinea, J., Zaragoza, O., Escribano, P., Martin-Mazuelos, E., Peman, J., Sanchez-Reus, F., & Cuenca-Estrella, M. (2014). Molecular identification and antifungal susceptibility of yeast isolates causing fungemia collected in a population-based study in Spain in 2010 and 2011. Antimicrobial Agents and Chemotherapy, 58(3), 1529-1537.

Judd, W. R., & Martin, C. A. (2009). Antifungal activity of nontraditional antifungal agents. Current Fungal Infection Reports, 3(2), 86-95.

Liu, S., Hou, Y., Chen, X., Gao, Y., Lia, H., & Sun, S. (2014) Combination of fluconazole with nonantifungal agents: a promising approach to cope with resistant Candida albicans infections and insight into new antifungal agent discovery. International Journal of Antimicrobial Agents, 43(5), 395-402.

Liu, X. P., Fan, S. R., Peng, Y. T., & Zhang, H. P. (2014). Species distribution and susceptibility of Candida isolates from patient with vulvovaginal candidiasis in Southern China from 2003 to 2012. Journal of Medical Mycology, 24(2), 106-111.

Menezes, E. A., Cunha, M. D. C. S. O., & Cunha, F.A. (2009). Identificacao preliminar de algumas especies do genero Candida spp. em meio cromogeno: resultados de dois anos de um estudo multicentrico realizado no Ceara. Revista de Patologia Tropical, 40(4), 297-303.

Menezes, E. A., Vasconcelos Junior, A. A., Angelo, M. R. F., Cunha, M. D. C. S. O. & Cunha, F. A. (2013). Correlation between microdilution, Etest, and disk diffusion methods for antifungal susceptibility testing of fluconazole against Candida sp. blood isolates. Revista da Sociedade Brasileira de Medicina Tropical, 46(1), 106-107.

Menezes, E. A., Vasconcelos Junior, A. A., Silva, C. L. F., Plutarco, F. X., Cunha, M. C. S .O., & Cunha, F. A. (2012). In vitro synergism of simvastatin and fluconazole against Candida species. Revista do Instituto de Medicina Tropical, 54(4), 197-199.

Palmeira-de-Oliveira, A., Ramos, A. R., Gaspar, C., Palmeira-de-Oliveira, R., Gouveia, P. & Martinez-de-Oliveira, J. (2012). In vitro anti-Candida activity of lidocaine and nitroglycerin: alone and combined. Infectious Diseases in Obstetrics and Gynecology, 727(1), 1-4.

Paramythiotou, E., Frantzeskaki, F., Flevari, A., Armaganidis, A., & Dimopoulos, G. (2014). Invasive fungal infections in the ICU: how to approach, how to treat. Molecules, 19(1), 1085-1119.

Quindos, G. (2014). Epidemiology of candidaemia and invasive candidiasis. A changing face. Revista Iberoamericana de Micologia, 31(1), 42-48.

Rodrigues, A. G., Araujo, R., & Pina-Vaz, C. (2006). Interaction of local anaesthetics with other antifungal agents against pathogenic Aspergillus. International Journal of Antimicrobial Agents, 27(4), 339-343.

Sobel, J. D. (2013). Factors involved in patient choice of oral or vaginal treatment for vulvovaginal candidiasis. Journal of Patient Preference and Adherence, 16(8), 31-34.

Stylianou, M., Kulesskiy, E., Lopes, J. P., Granlund, M., Wennerberg, K. & Urban, C. F. (2014). Antifungal application of nonantifungal drugs. Antimicrobial Agents and Chemotherapy, 58(2), 1055-1062.

Wright, J. L., Durieux, M. E., & Groves, D. S. (2008). A brief review of innovative uses for local anesthetics. Current opinion in anaesthesiology, 21 (5), 651-656.

Received on June 26, 2016.

Accepted on November 17, 2016.

Maria da Conceicao dos Santos Oliveira Cunha (1-2) *, Tarcisio Paulo de Almeida Filho (1), Francisco Afranio Cunha1, Ana Gesselena da Silva Farias (2), Ieda Pereira de Souza (1) and Everardo Albuquerque Menezes (1)

(1) Departamento de Analises Clinicas e Toxicologicas, Universidade Federal do Ceara, Rua Capitao Francisco Pedro, 1210, 60270-430, Rodolfo Teofilo, Fortaleza, Ceara, Brazil. (2) Universidade da Integracao Internacional da Lusofonia Afro-Brasileira, Acarape, Ceara, Brazil. * Author for correspondence. E-mail: cecinhya@gmail.com
Table 1. Synergistic Effect of miconazole (MZ) and lidocaine (LD)
Against Candida albicans.

Strain        [MZ.sup.a]     [LD.sup.a]     MIC            FICI   Int
              [MIC.sub.50]   [MIC.sub.50    MZ+LD          MZ +
              ([micro]g      ([micro]g      ([micro]g      LD
              [mL.sup.-1])   [mL.sup.-1])   [mL.sup.-1])

C. albicans   1.0            2,500          025/15         0.26   SYN
C. albicans   2.0            2,500          0.50/500       0.45   SYN
C. albicans   0.50           2,500          0.25/15        0.50   SYN
C. albicans   1.0            2,500          0.25/250       0.35   SYN
C. albicans   0.25           2,500          0.12/125       0.55   IND
C. albicans   0.50           2,500          0.03/500       0.26   SYN
C. albicans   0.50           2,500          0.06/250       0.22   SYN
C. albicans   0.50           2,500          0.25/15        0.53   IND
C. albicans   1.0            2,500          0.25/15        0.26   SYN
C. albicans   1.0            2,500          0.25/30        0.26   SYN
C. albicans   2.0            2,500          0.50/30        0.26   SYN
C. albicans   1.0            2,500          0.25/250       0.35   SYN
C. albicans   0.50           600            0.25/15        0.53   IND
C. albicans   0.50           600            0.25/15        0.53   IND
C. albicans   0.50           2,500          0.015/15       0.04   SYN
C. albicans   0.06           600            0.015/30       0.30   SYN
C. albicans   0.50           600            0.03/250       0.48   SYN
C. albicans   0.25           300            0.06/15        0.29   SYN
C. albicans   0.25           2,500          0.015/125      0.11   SYN

(a) MZ-Miconazole, LD-Lidocaine. Int-interpretation.
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Title Annotation:texto en ingles
Author:Cunha, Maria da Conceicao dos Santos Oliveira; Filho, Tarcisio Paulo de Almeida; Cunha, Francisco Af
Publication:Acta Scientiarum. Health Sciences (UEM)
Date:Jul 1, 2017
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