Fluconazole 첨가 사브로덱스트로오스 한천 배지를 사용한 Candida 종의 Fluconazole 내성 검색

이미경,김태형 대한의진균학회 2009 대한의진균학회지 Vol.14 No.1

Background: Antifungal susceptibility testing methods are relatively expensive and laborious and are not easily applicable for screening purposes in routine laboratories. Objective: We have developed a susceptibility screening method by adding fluconazole to Sabouraud dextrose agar (SDA) plate. In this study, SDA plates screening was compared with the Clinical and Laboratory Standards Institutes (CLSI) broth microdilution method for determining fluconazole susceptibility of Candida spp. Methods: A total 186 isolates of Candida spp. (134 C. albicans, 24 C. tropicalis, 15 C. glabrata, 13 C. parapsilosis) were tested with the CLSI document M27-A2 method and fluconazole-containing SDA plate (0, 8, 16 μg/mL of fluconazole). By this method, colony count and diameter were read after 24 hr of incubation. Results: Fluconazole-susceptible Candida spp. are significantly smaller (≤50%) on SDA with fluconazole than on fluconazole-free SDA. On SDA with 8 and 16 μg of fluconazole per mL, 80.7% (150/186) and 87.1% (162/186) of isolates were correctly predicted, respectively. Conclusions: These data suggest that the fluconazole-containing SDA plates can be used as a routine screening procedure for susceptibility of Candida spp. in clinical laboratories. Background: Antifungal susceptibility testing methods are relatively expensive and laborious and are not easily applicable for screening purposes in routine laboratories. Objective: We have developed a susceptibility screening method by adding fluconazole to Sabouraud dextrose agar (SDA) plate. In this study, SDA plates screening was compared with the Clinical and Laboratory Standards Institutes (CLSI) broth microdilution method for determining fluconazole susceptibility of Candida spp. Methods: A total 186 isolates of Candida spp. (134 C. albicans, 24 C. tropicalis, 15 C. glabrata, 13 C. parapsilosis) were tested with the CLSI document M27-A2 method and fluconazole-containing SDA plate (0, 8, 16 μg/mL of fluconazole). By this method, colony count and diameter were read after 24 hr of incubation. Results: Fluconazole-susceptible Candida spp. are significantly smaller (≤50%) on SDA with fluconazole than on fluconazole-free SDA. On SDA with 8 and 16 μg of fluconazole per mL, 80.7% (150/186) and 87.1% (162/186) of isolates were correctly predicted, respectively. Conclusions: These data suggest that the fluconazole-containing SDA plates can be used as a routine screening procedure for susceptibility of Candida spp. in clinical laboratories.

한천희석법을 이용한 Candida species의 fluconazole 내성선별

신종희,김민,김종필,서순팔,양동욱 대한화학요법학회 1999 대한화학요법학회지 Vol.17 No.3

배경 : 칸디다 감염의 빈도가 증가함에 따라 Candida species의 fluconazole 내성은 점차 중요한 관심이 되고 있다. 그러나 NCCLS법은 fluconazole 내성균을 선별하는데 다소 복잡하고 trailing endpoint도 있어 보통 검사실에서 사용하기 어렵다. 저자들은 fluzonazole이 포함된 한천배지를 이용하여 fluconazole 내성 선별검사를 실시하여 보았다. 방법 : 혈액에서 분리된 총 47주의 Candida species를 대상으로 하였다. 한천희석법은 0, 8 및 16g/mL 농도의 fluconazole이 첨가된 Castione agar와 CHROMagar Candida의 두 종류의 평판 배지를 이용하였다. 한천희석법에서의 fluconazole 내성 성적은 NCCLS법의 결과와 비교하였다. 성적 : NCCLS법에 의해 MIC 16g/mL 이상였던 9주는 Castione 배지를 사용한 한천 희석법의 경우 모두 24시간과 48시간에 100% 내성이 검출되었고, CHROMagar Candida를 이용한 한천 희석법에서는 48시간 배양시에는 모두 내성이 검출되었으나 24시간 배양시엔 1주를 제외한 8주(89%)에서 내성이 검출되었다. NCCLS법에 의한 MIC 1g/mL이하인 33주는 두 종류의 한천희석법에 의해 모두 감수성으로 판정되어 NCCLS법의 성적과 100% 일치하였다. 그러나 MIC 2-8g/mL인 C. guilliermondii등의 5주에서는 두 배지에서의 한천희석법 성적이 다소간의 차이를 보였다. 전체적으로 fluconazole 내성 선별에 있어 한천희석법의 NCCLS법과의 일치율은 Castione agar의 경우 24시간 배양 후 98%(46/47), 48시간 배양 후 94%(44/47)이었고 CHROMagar Candida의 경우, 24시간 배양 후 96%(45/47) 및 48시간 배양 후 91%(43/47)이었다. C. albicans 4주에서 NCCLS 검사에서 trailing endpoint가 관찰되었는데 이 균주들은 fluconazloe이 포함된 평판배지에서는 모두 감수성을 보였다. 결론 : 한천희석법은 간단하며 fluconazole 내성 검출에 있어 NCCLS법과 높은 일치율을 보이며 동시에 trailing endpoint를 보이는 균에서 감수성을 확인할 수 있어 Candida species의 fluconazole에 대한 내성 선별에 좋은 방법으로 생각되었다. Background : With the widespread use of fluconazole in treating and preventing Candida infections, detection of Candida with fluconazole resistance is becoming increasingly important. However, the laborious procedure and trailing endpoints remain problems in fluconazole susceptibility testing by the National Committee for Clinical Laboratory Standards(NCCLS) method. We evaluated simple agar dilution methods for the determining fluconazole resistance of Candida species. Method : A total of 47 isolates of Candida species isolated from blood cultures was tested. Fluconazole susceptibility testing by the agar dilution method was performed using Casitone agar(AD-Casitone) or CHROMagar Candida (AD-CHROM) wllich contained 0. 8. and 16 g of fluconazole per mL. The results were compared with those by the NCCLS broth macrodilution method. Results : All nine Candida isolates having fluconazole MICs of > 16 g/mL were correctly determined as > 16 g/mL by AD-Casitone (at 24h and 48h) and AD-CHROM (at 48h). Thrity three isolates with NCCLS MIC (1 g/mL were successfully determined as MIC < 8 g/mL with both AD-Casitone and AD-CHROM. However, five Candida isolates with MIC 2-8 g/mL showed variable results by both agar dilution methods. Overall agreements with the NCCLS method for the screen of fluconazole susceptibility was 98% (46/47) at 24h and 94% (44/47) at 48h in AD-Casitone, and 96% (45/47) at 24h and 91% (43/47) at 48h in AD-CHROM. Testing by both agar dilution method revealed all four isolates which showed trailing-endpoint by the NCCLS, to be susceptible (MIC < 8 g/mL). Conclusion : The agar dilution method appears to be simple and highly correlate with the NCCLS method and gives a clear MIC endpoint for isolates for which trailing endpoints are found. These suggest that agar dilution method can be an effective screen for determining of fluconazole susceptibility for Candida species.

임상분리 효모균주에 대한 항진균제의 시험관내 감수성양상

김의종,김재석,정현진 대한화학요법학회 1998 대한화학요법학회지 Vol.16 No.3

배경 : 최근 진균감염증 환자의 수가 증가하면서 항진균제의 사용량도 증가하였고, 항진균계에 대한 내성균주의 출현이 우려된다. 따라 현재 임상에서 가장 많이 사용하는 항진균제인 amphotericin B와 fluconazole에 대한 감수성양상을 파악할 필요가 있다. 방법 : 서울대학교병원 환자의 검체에서 분리한 총 200주의 임상분리효모균을 대상으로 National Committee for Clinical Laboratory Standards에서 권장하는 microdilution broth법을 실시하여 균종별로 amphotericin B 및 fluconazole의 최소억제농도분포를 조사하였다. 결과 : Candida albicans의 fluconazole과 amphotericin B에 대한 최소억제농도분포를 보면 MIC_(50)이 각각 0.5 ug/mL과 0.25 ug/mL이었으며, MIC_(90)는 각각 >16 ug/mL과 0.5 ug/mL이었다. Candida albicans의 경우 amphotericin B에 대한 최소억제농도가 2 ug/mL이상인 균주는 관찰되지 않았다. Torulopsis glabrata, Cnndida krusei와 Trichosporon beigel??의 경우 fluconazole에 대한 최소억제농독 amphotericin에 비하여 높았다. Candida albicans의 fluconazole에 대한 내성율은 15.3%이었다. 결론 : C. albicans에서 fluconazole에 대한 내성율이 높고, 일부 효모균은 fluconazole에 대해 내성이므로, 진균감영증 환자를 적절하게 치료하기 위하여 임상미생물검사실에서는 분리된 균주를 정확하게 동정하고 항진균제감수성검사를 실시해야 한다. Background : Recently the number of patients with fungal infection has been increased and the antifungal agents have been prescribed more than the past. The emergence of the resistant strain against antifungal agents may be expected. It is necessary that antifungal susceptibility patterns of amphotericin B and fluconazole, those are commonly used by clinicians in Korea, are evaluated. Methods : The minimal inhibitory concentrations of total 200 strains of yeast isolated from Seoul National University Hospital were measured against amphotericin B and fluconazole by microdilution broth method of National Committee for Clinical Laboratory Standards. Results : MIC?? and MIC?? of Candida albicans against fluconazole and amphotericin B were 0.5 ug/ml and 0.25 ug/ml, >16 ug/ml and 0.5 ug/ml, respectively. There was no strain of C. albzcans with MIC of more than 1 ug/ml against am photericin 3. The MICs of Torulopszs glabrata, Candida krusez, and Trichosporon beigelrz against fluconazole were higher than those against amphotericin 3. The resistant rate of C. albzcans against fluconazole was 15.3%. Conclusion : The resistant rate of C. albicans IS high against fluconazole and some species of yeast are resistant to fluconazole. It is recommended that the exact identification and antifungal susceptibility tests are performed in clinical microbiology laboratory for the adequate treatment of patients with fungal infection.

Study to compare the efficacy and safety of fluconazole cream with flutrimazole cream in the treatment of superficial mycosis: a multicentre, randomised, double-blind, phase III trial

Yim, S. M.,Ko, J. H.,Lee, Y. W.,Kim, H. W.,Lee, J. Y.,Kim, N. I.,Kye, Y. C.,Park, K. C.,Choi, J. H.,Lee, K. H.,Kim, M. N.,Kim, K. J.,Ro, Y. S.,Ahn, K. J. Blackwell Publishing Ltd 2010 Mycoses Vol.53 No.6

<P>Summary</P><P>Fluconazole, which is a drug of the azole family, is safely used in systemic treatment of oral and intravenous injection, but it is difficult to use fluconazole as a topical application because of its large molecular weight and strong hydrophilic property. This study is a multicentre, double-blind, randomised, non-inferiority study to compare the antifungal effect and safety of fluconazole cream 0.5% and 1% with flutrimazole cream 1% in superficial mycosis. A total of 162 subjects selected to participate in this study were equally divided into three groups and assigned to be given fluconazole cream 0.5%, fluconazole cream 1%, and flutrimazole cream 1% in the ratio of 1 : 1. The primary index of drug efficacy was determined by complete mycological cure in which no fungus was detected on KOH smear test 4 weeks after application of fluconazole. The secondary index of efficacy was defined as complete mycological cure 4 weeks after the application of fluconazole, improvement of clinical symptoms and overall effectiveness assessed by the research staff. According to this study, on comparing the efficacy of cure of superficial dermatomycosis after 4 weeks of application, both fluconazole 0.5% and fluconazole 1% cream were found to be equally effective and non-inferior to flutrimazole 1% cream. Given the effectiveness and safety of the drug, both fluconazole 0.5% and 1% cream might be said to be optimal concentration in the treatment of superficial dermatomycosis.</P>

The in vitro and in vivo efficacy of fluconazole in combination with farnesol against Candida albicans isolates using a murine vulvovaginitis model

Aliz Bozó,Marianna Domán,László Majoros,Gábor Kardos,István Varga,Renátó Kovács 한국미생물학회 2016 The journal of microbiology Vol.54 No.11

Farnesol is a quorum-sensing molecule that inhibits biofilm formation in Candida albicans. Previous in vitro data suggest that, in combination with certain antifungals, farnesol may have an adjuvant anti-biofilm agent. However, the in vivo efficacy of farnesol is very questionable. Therefore, the in vitro and in vivo activity of fluconazole combined with farnesol was evaluated against C. albicans biofilms using fractional inhibitory concentration index (FICI) determination, time-kill experiments and a murine vulvovaginitis model. The median biofilm MICs of fluconazole-sensitive C. albicans isolates ranged between 4 -> 512 mg/L and 150–300 μM for fluconazole and farnesol, respectively. These values were 512 -> 512 mg/L and > 300 μM for fluconazole-resistant clinical isolates. Farnesol decreased the median MICs of fluconazole by 2-64-fold for biofilms. Based on FICI, synergistic interaction was observed only in the case of the sessile SC5314 reference strain (FICIs: 0.16–0.27). In time-kill studies, only the 512 mg/L fluconazole and 512 mg/L fluconazole + 75 μM farnesol reduced biofilm mass significantly at each time point in the case of all isolates. The combination reduced the metabolic activity of biofilms for all isolates in a concentration- and time-dependent manner. Our findings revealed that farnesol alone was not protective in a murine vulvovaginitis model. Farnesol was not beneficial in combination with fluconazole for fluconazole-susceptible isolates, but partially increased fluconazole activity against one fluconazole- resistant isolate, but not the other one.

시플로덱으트린류를 이용한 새로운 플루코나졸 수성 주사제의 설계

이소윤(So Yun Lee),전인구(In Koo Chun) 大韓藥學會 2001 약학회지 Vol.45 No.4

The purpose of this study is to investigate the inf1uence of cyclodextrins (CDs): and different acids on the solubility of fluconazole, and to formulate its more concentrated parenteral aqueous solution. Solubility studies of fluconazole with β- CD, 2-hydroxypropyl-β-CD (HPCD), sulfobutyl ether β-CD (SBCD) and dimethyl-β-CD (DMCD) were performed. The aqueous solubility of fluconazole was measured in different concentrations of different acids with or without addition of CDs. Solubility of fluconazole increased in the rank order of β-CD 1H-NMR studies confined the formation of an inclusion complex of fluconazole with HPCD. It was also shown by the NMR studies that the complex formed was a 1:1 complex. Among the different acids used, maleic acid and phosphoric acid increased solubility of fluconazole. The lower the pH of solution is, the more fluconazole dissolved, regardless of acids. Addition of HPCD (50 mM) to acid solutions increased the solubility about two times. New fluconazole injections at a dose of 10 mg/ml could be prepared in aqueous solutions containing 10% HPCD or 15% SBCD. These parenteral solutions did not form any precipitates at 4oC and was very stable at elevated temperatures. These results demonstrate that it is possible to develop a parenteral aqueous solution of fluconaEole with a smaller injection volume using HPCD or SBCD.

Fluconazole 지연형 과민반응에 대한 성공적인 탈감작 사례 1예

허연정,박승우,이규선,강혜련,권재우 대한 소아알레르기 호흡기학회 2018 Allergy Asthma & Respiratory Disease Vol.6 No.1

Fluconazole is a triazole-based first-generation antifungal agent and has excellent effects on candidiasis and cryptococcosis. Hypersensitivity has been reported as a side effect of fluconazole. A 76-year-old female patient used fluconazole for consolidation therapy for cryptococcal meningitis, but showed delayed hypersensitivity with skin rashes and itching sensation of the whole body. For desensitization, was attempted by administering 12-step, 1:1 fluconazole solutions were administered intravenously at sequentially increasing infusion rates. After successful quick desensitization to fluconazole, fluconazole was continuously used as a consolidation therapy for cryptococcal meningitis. We herein report a case of delayed hypersensitivity reaction to fluconazole in consolidation therpy with cryptococcal meningitis who successfully completed desensitization.

임상 ; 고위험 미숙아에서 칸디다 감염관리에 대한 Fluconazole 예방요법의 효과

김천수 ( Chun Soo Kim ),홍승아 ( Seung Ah Hong ),이상락 ( Sang Lak Lee ),김흥식 ( Heung Sik Kim ) 대한주산의학회 2010 Perinatology Vol.21 No.4

목적: 신생아 집중치료실에서 칸디다는 병원감염을 일으키는 가장 흔한 원인 균주 중의 하나이다. 본 연구는 고위험 미숙아에서 칸디다 감염관리에 대한 fluconazole 예방요법의 효과를 알아보고자 시행하였다. 방법: 2008년 8월부터 2009년 12월까지 계명대학교 동산의료원 신생아 집중치료실에 입원한 출생체중 1,500 g 미 만의 극소 저체중 출생아 중 출생 초기부터 인공환기요법이나 중심정맥도관의 유치, 정맥영양 등을 받은 55명의 고 위험 미숙아를 대상으로 하였다. 대상 환아는 생후 3일 내 적용군과 대조군으로 무작위로 분류한 후 전향적으로 조사 하였으며, 적용군은 fluconazole을 체중(kg) 당 3 mg 용량으로 출생 후 4-6주간 정주하였다. 모든 환아에게 주 1회 칸 디다 집락형성에 대한 감시 배양검사를 시행하였다. 결과: Fluconazole 예방요법 적용군(28명)과 대조군(27명) 사이에 재태연령, 출생체중, 산전 스테로이드 사용 등의 주산기 인자는 두 군간 유사한 분포를 보였고, 칸디다 침습감염의 흔한 위험인자의 동반율도 양 군간 비슷하였다. 위 장관이나 피부에서 칸디다 집락형성은 대조군에서 15명(55.6%), 적용군에서 5명(17.9%)이 발생하여 대조군에서 유 의하게 높았다(P<0.005). 칸디다 패혈증도 대조군에서 발생률이 높았으나 통계학적 유의성은 없었다. 예방요법 후 시행한 간 기능검사에서 양 군간 유의한 차이는 없었다. 재원기간이나 동반질환, 사망률 등의 예후인자에 대해서 두 군간 차이가 없었다. 결론: 고위험 미숙아에서 fluconazole 예방요법은 칸디다 감염관리에 도움이 될 수 있으나 일상 적용에 앞서 내성균 출현에 대한 조사를 포함하는 대규모의 다기관 연구가 필요하다고 사료된다. Objective: Candida species are becoming one of the most common pathogens associated with nosocomial infection in the neonatal intensive care units (NICU). This study was undertaken to evaluate the efficacy of fluconazole prophylaxis (FP) to control candida infection in high-risk preterm infants. Methods: A prospective, randomized clinical trial was conducted over a 17-month period (Aug. 2008- Dec. 2009) in very low birth weight (VLBW) infants who were admitted to NICU of Dongsan Medical Center, Keimyung University. The 55 VLBW infants with mechanical ventilation, central vascular access and parenteral nutrition at early time of life were enrolled for this study. The infants were randomly assigned to FP and control group in the first three days of life. Fluconazole was administered by intravenous route for 4- to 6-week after birth at dose of 3 mg per kilogram of body weight. All enrolled infants underwent weekly surveillance culture for candida colonization. Results: The 28 infants with FP and the 27 control infants were similar in comparison of the perinatal parameters such as gestational age, birth weight and antenatal steroid therapy. And also, there were no differences between the two groups in terms of presence of common risk factors for invasive candida infection. During prophylactic period, candida colonization was identified in 5 infants of the fluconazole group and 15 infants of the control group (17.9% vs. 55.6%; P <0.005). And also candida sepsis was more frequently developed in the control group, but the result was not significant. No differences in liver function tests after prophylactic period were noted. Between two groups, prognostic factors such as duration of stay in hospital, combined diseases and mortality were not different. Conclusions: FP may help to control candida infection in high-risk preterm infants, but large scaled multicenter studies including development of resistant strains are necessary before initiation of routine prophylaxis.

출생 체중 1 kg 미만의 초 극소 저 체중 출생아에서 침습성 진균 감염증에 대한 Fluconazole 예방 요법의 효과 분석

임혜민,양사미,박윤희,한혜원,곽혜선,김재연 한국병원약사회 2014 病院藥師會誌 Vol.31 No.4

Background : An invasive fungal infection (IFI) is an important cause of morbidityand mortality in preterm infants with immature immune systems. In the present study, we evaluatedthe efficacy in preventing IFI and adverse effects of prophylactic fluconazole in extremelylow birth weight infants (ELBWIs). Methods : From January 2010 to July 2012, we conducted a chart review in a total of 106preterm infants with a birth weight less than 1 kg that were hospitalized in the neonatal intensivecare unit (NICU) of the Asan medical center. In May 2011, an unit policy on fluconazole prophylaxishad been implemented (3 mg/kg twice a week intravenous infusion) and we classified thestudy population into two groups; control group (admitted before the introduction of fluconazoleprophylaxis, n=71) and study group (admitted after the introduction of fluconazole prophylaxis,n=35). The incidence of IFI and the strains of infection were investigated and other outcome variables including mortality, morbidity, and adverse effects of fluconazole were also collected. Results : The incidence of IFI was 2.9% in the study group versus 19.7% in the control group(p<0.05). Logistic regression revealed that fluconazole prophylaxis significantly decreased therates of IFI (Odds ratio 0.082, p<0.05). There was no difference in the incidence of cholestasisbetween two groups and there was no evidence of hepatotoxicity of fluconazole. Conclusion : The prophylactic administration of fluconazole in ELBWIs revealed its effectivenessin preventing IFI without significant adverse effects.

캔디다뇨증 환자에서 Fluconazole 경구투여와 Amphotericin B 지속적 방광세척의 치료 효과 비교

김형남,오봉렬,박양일 大韓泌尿器科學會 1998 Korean Journal of Urology Vol.39 No.9