Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / A coccidioidomicose e a histoplasmose sÃo micoses sistÃmicas que acometem o homem e animais, causadas por espÃcies de fungos dimÃrficos, com Ãnfase para Coccidioides posadasii e Histoplasma capsulatum var. capsulatum, respectivamente. SÃo consideradas doenÃas profundas importantes, podendo culminar em diversas complicaÃÃes secundÃrias. Nos Ãltimos anos, a melhoria dos mÃtodos de diagnÃstico micolÃgico e o aumento da ocorrÃncia de doenÃas imunossupressoras causaram grande impacto na incidÃncia das micoses profundas e oportunistas no mundo. Apesar da existÃncia de terapias eficazes com antifÃngicos contra a coccidioidomicose e a histoplasmose, a busca por novas drogas para o tratamento destas doenÃas se faz necessÃria. Ciprofloxacina à uma droga antibacteriana clÃssica do grupo das fluoroquinolonas, que inibe a atividade catalÃtica da DNA girase e topoisomerase IV, essenciais na replicaÃÃo e transcriÃÃo do DNA bacteriano. Estudos verificaram que ciprofloxacina pode atuar na DNA girase dos fungos. Assim, o presente estudo visou avaliar o efeito inibitÃrio in vitro de ciprofloxacina (CIP) isolada e em combinaÃÃo com os antifÃngicos anfotericina B (AMB), itraconazol (ITC), voriconazol (VRC) e caspofungina (CAS) frente à C. posadasii e Histoplasma capsulatum var. capsulatum. Foram utilizados 16 cepas de C. posadasii na fase filamentosa, 16 cepas de H. capsulatum var. capsulatum na fase filamentosa e 9 cepas de H. capsulatum var. capsulatum na fase leveduriforme. O estudo foi conduzido em ensaio de macrodiluiÃÃo e microdiluiÃÃo em caldo, descritos nos documentos M-38A e M-27A2, padronizados pelo Clinical Laboratory Standards Institute (CLSI), sendo utilizados para C. posadasii e Histoplasma capsulatum var. capsulatum, respectivamente. A interaÃÃo das drogas foi analisada atravÃs do cÃlculo do Ãndice da ConcentraÃÃo InibitÃria FracionÃria (FICI), definido como a soma das relaÃÃes entre a concentraÃÃo inibitÃria mÃnima (CIM) de cada droga em combinaÃÃo e a CIM da mesma droga isolada, considerando os valores menores ou iguais a 0,5 indicativos de sinergismo. Com relaÃÃo Ãs cepas de C. posadasii, foram observadas interaÃÃes sinÃrgicas em todas as combinaÃÃes, com destaque para as associaÃÃes de CIP (3,125≤CIM≤12,5 ug mL-1) com ITC (0,0078≤CIM≤0,125 ug mL-1) (n=13/16), CIP (3,125≤CIM≤12,5 ug mL-1) com VRC (0,0078≤CIM≤0,0312 ug mL-1) (n=13/16) e CIP (3,125≤CIM≤12,5 ug mL-1) com CAS (2≤CIM≤8 ug mL-1) (n=14/16). Para as cepas de H. capsulatum na fase filamentosa, tambÃm foram observadas interaÃÃes sinÃrgicas em todas as combinaÃÃes, com destaque para as associaÃÃes de CIP (3,906≤CIM≤62,5 ug mL-1) com ITC (0,00006≤CIM≤0,0078 ug mL-1) (n=14/16) e CIP (31,25≤CIM≤125 ug mL-1) com VRC (0,0156≤CIM≤0,125 ug mL-1) (n=16/16). No tocante Ãs cepas de H. capsulatum na fase leveduriforme, foram observadas poucas interaÃÃes sinÃrgicas nas combinaÃÃes de drogas testadas. Nenhuma das associaÃÃes de drogas testadas apresentou antagonismo. Os dados obtidos apontam uma nova alternativa para o tratamento da coccidioidomicose e da histoplasmose, sendo necessÃrios novos estudos que visem investigar os mecanismos de aÃÃo dessas combinaÃÃes de drogas no metabolismo celular fÃngico, bem como o delineamento de experimentos in vivo para confirmar a significÃncia desses achados. / Coccidioidomycosis and histoplasmosis are systemic mycoses that occur in humans and other animals and are caused by the dimorphic fungi Coccidioides posadasii and Histoplasma capsulatum var. capsulatum, respectively. They are considered important deep mycoses that can lead to several secondary complications. In the past years, the improvement of the techniques applied in mycological diagnosis and the increase in the occurrence of immunocompromising diseases have caused a great impact in the incidence of deep and opportunistic mycoses in the world. In spite of the existence of effective antifungal therapy against coccidioidomycosis and histoplasmosis, the pursue of new drugs to treat theses diseases is necessary. Ciprofloxacin is a classic antibacterial drug that belongs to the group of fluoroquinolones, which inhibit the catalytic activity of DNA gyrase and topoisomerase IV, which are essential in bacterial DNA replication and transcription. Some studies have shown that ciprofloxacin can act on fungal DNA gyrase. Thus, the present study aimed at evaluating the in vitro inhibitory effect of ciprofloxacin (CIP), when associated with amphotericin B (AMB), itraconazole (ITC), voriconazole (VRC) or caspofungina (CAS), on C. posadasii and H. capsulatum var. capsulatum. Sixteen strains of C. posadasii in the filamentous phase and 16 and 9 strains of H. capsulatum in the filamentous and yeast-like phase, respectively, were used. Broth macrodilution and microdilution assays were performed, as described in the documents M38-A and M27-A2, respectively, of the Clinical Laboratory Standards Institute (CLSI). Drug interaction was analyzed by calculating the fractional inhibitory concentration index (FICI), which is defined as the sum of the ratios between the minimal inhibitory concentration (MIC) of each combined drug and the MIC of the same drug isolatedly. Values of FICI smaller or equal to 0.5 indicate the occurrence of synergy. Concerning the isolates of C. posadasii, synergistic interactions were observed for all combinations, especially for the associations of CIP (3.125≤CIM≤12.5 ug mL-1) with ITC (0.0078≤CIM≤0.125 ug mL-1) (n=13/16), CIP (3.125≤CIM≤12.5 ug mL-1) with VRC (0.0078≤CIM≤0.0312 ug mL-1) (n=13/16) and CIP (3.125≤CIM≤12.5 ug mL-1) with CAS (2≤CIM≤8 ug mL-1) (n=14/16). For the isolates of H. capsulatum in the filamentous phase synergistic interactions were also observed for all combinations, with emphasis to the associations of CIP (3.906≤CIM≤62.5 ug mL-1) with ITC (0.00006≤CIM≤0.0078 ug mL-1) (n=14/16) and CIP (31.25≤CIM≤125 ug mL-1) with VRC (0.0156≤CIM≤0.125 ug mL-1) (n=16/16). For H. capsulatum in yeast-like phase, few synergistic interactions were observed for the tested drug combinations. None of the tested combinations presented antagonism. The obtained data may point at a new alternative for the treatment of coccidioidomycosis and histoplasmosis. Thus, it is necessary to investigate the mechanisms of action of these drug combinations on the fungal cellular metabolism and to perform in vivo experiments to confirm the relevance of these findings.