综合医院住院患者口腔假丝酵母菌感染流行病学与药敏研究
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摘要
第一部分综合医院住院患者口腔假丝酵母菌感染流行病学和危险因素的研究
目的：对综合医院住院部多临床科室住院患者同时进行口腔真菌感染的流行病学调查,以获得综合医院口腔真菌感染现状,了解口腔真菌感染的危险因素。
方法：收集昆明医学院附属第一医院住院部患者临床资料及口腔分泌物标本,对口腔分泌物标本进行真菌镜检及培养。结合临床资料,分析流行病学特点及危险因素并进行多分类单因素回归分析。
结果：共收集了昆明医学院第一附属医院住院部16个科室579例患者有效样本,共培养获得228例阳性标本。其中,口腔真菌感染患者80例,占13.82%,口腔真菌带菌患者148例,占25.56%。口腔真菌感染危险因素分析结果显示：住院时间越长口腔真菌感染率越高；使用抗生素患者较不使用抗生素口腔者真菌感染率越高,抗生素使用疗程越长的患者口腔真菌感染率越高,多种抗生素联合或交替使用的患者较单一用药者口腔真菌感染率高；使用糖皮质激素患者较不使用者口腔真菌感染率高,其中使用倍他米松和地塞米松患者较使用其他种类糖皮质激素者口腔真菌感染率高,每日糖皮质激素用量越大口腔真菌感染率越高,糖皮质激素疗程越长口腔真菌感染率越高；住院期间手术后时间越长口腔真菌感染率越高,以上结果均有统计学意义(P<0.05)。而口腔真菌带菌危险因素分析则显示：1-10岁及50岁以上患者口腔真菌带菌率较其他年龄段高,其差异有显著性(P＜O.05)。患有呼吸系统疾病患者较未患呼吸系统疾病者口腔真菌带菌率高,其差异有统计学意义(P＜O.05)。
结论：住院时间、使用抗生素、糖皮质激素等多因素可增加口腔真菌感染的机率,住院时间及住院期间手术后时间越长,口腔真菌感染率越高；使用抗生素患者口腔真菌感染率高于不使用抗生素患者,抗生素使用越长,口腔真菌感染率越高,联合或交替使用多种抗生素均可提高口腔真菌感染率；使用糖皮质激素尤其是大剂量使用糖皮质激素是口腔真菌感染的危险因素,使用倍他米松和地塞米松较使用其他种类的糖皮质激素更易引起口腔真菌感染。1-10岁和50岁以上患者以及患有呼吸系统疾病的患者,口腔真菌带菌率高于其他年龄组及无呼吸系统疾病的患者。在临床时工作中,对住院时间长、使用抗生素尤其是抗生素使用疗程长、联合或交替使用多种抗生素,长期大剂量使用糖皮质激素的患者,要密切监测口腔真菌感染情况,并及时治疗。使用倍他米松和地塞米松明显增加真菌感染率,因此,建议临床在可替代条件下尽量使用其他种类的糖皮质激素。对1-10岁和50岁以上患者以及患有呼吸系统疾病患者,应定期检测口腔真菌带菌情况。
第二部分综合医院住院患者口腔真菌菌感染致病菌株病原学及药敏研究
目的：通过对培养获得菌株的菌种鉴定及体外抗真菌药物药敏实验,获得口腔真菌感染和带菌的病原学资料及不同菌株药敏情况,指导临床治疗口腔真菌感染的药物选择。
方法：运用CHROMagar Candida显色培养基对和法国梅里埃API 20 C AUX酵母菌菌种鉴定试剂条对口腔分泌物培养获得菌株进行菌种鉴定。按照美国国家实验室标准委员会NCCLS M27-A2(2002)方案推荐的微量液基稀释法,检测所分离菌株对氟康唑、伊曲康唑、伏立康唑和两性霉素B四种抗真菌药物的体外药敏情况。
结果：从228例患者口腔分泌物培养阳性标本中共分离出242株假丝酵母菌,其中13例有两种或两种以上的假丝酵母菌共存。242株假丝酵母菌中白假丝酵母菌174株,占71.90%,非假丝酵母菌珠菌共68株,占28.10%。非白假丝酵母菌以光滑假丝酵母菌为主,共31株占所有菌株12.81%。年龄、使用抗生素和糖皮质激素对非白假丝酵母菌的发生率无影响(P>0.05)。白假丝酵母菌组对氟康唑、伊曲康唑、伏立康唑及两性霉素B的耐药率分别为9.20%、10.34%、5.75%及0%,非白假丝酵母菌组对氟康唑、伊曲康唑、伏立康唑及两性霉素B的耐药率分别为39.70%、11.76%、7.35及1.47%。口腔真菌感染组和带菌组的白假丝酵母菌和非白假丝酵母菌的构成比无差异,对四种抗真菌药物的敏感性也无差异。
结论：白假丝酵母菌仍是住院患者口腔假丝酵母菌感染的主要致病菌,光滑假丝酵母菌是住院患者口腔假丝酵母菌感染的主要非白假丝酵母菌,口腔真菌感染和口腔真菌带菌患者白假丝酵母菌和非白假丝酵母菌的检出率无差异,白假丝酵母菌对氟康唑、伊曲康唑、伏立康唑和两性霉素B均敏感,非白假丝酵母菌对氟康唑敏感性差。少数非白假丝酵母菌对两性霉素B存在耐药性。
Part1 Status of oral fungal infection and the relative risk factors of oral fungal infection.
Objective To find out status of oral fungal infection and its relative risk factors
Metheds In this study 579 inpatients of 16 departments from the First Affiliated Hospital of Kunming Medical College were investigated,and their oral secretion samples and clinical information were collected, Identification of fungi was performed by direct microscopy, fungal culture.
Results The experiment collected 579 cases of inpatients' samples from 16 departments of the First Affiliated Hospital ofKunming Medical College. From 579 samples,228 strains of fungi were isolated including 80 patients with Oral fungal infection (13.82%),and 148 patients with oral fungi- carrying (25.56%). Analysis of risk factors for oral fungal infection showed:patients who had long hospital stay had higher rate of oral fungal infection than those who did not (P<0.05), usage of antibiotics had higher rate of oral fungal infection than those who did not (P<0.05), the longer course of antibiotic usage had higher rate of oral fungal infection (P<0.05), combined or alternative usage of antibiotics had higher rate of oral fungal infection (P<0.05), Thoes who used glucocorticoid, especially betamethasone and dexamethasone had higher rate of oral fungal infection, large daily dosage and long treatment of glucocorticoid would increase the rate of oral fungal infection,(P<0.05),Those who stay in hospital for a long time after surgery got oral fungal infection easily(P<0.05). Analysis of risk factors for oral fungal carriers showed:1-10 years old and above 50 years age inpatients had higher risk of oral fungi- carrying (P<0.05). Inpatients who had respiratory diseases were more likely to be oral fungal carrier(P<0.05).
Conclusion Unvaried logistic regression analysis showed that length of hospital stay, whether to use antibiotics, length of antibiotics treatment, combined or alternative antibiotics treatment, whether to use glucocorticoid, kinds of glucocorticoid, daily dosage of glucocorticoid treatment, length of glucocorticoid treatment, length of hospital stay after surgery were risk factors of oral fungal infections. Age and respiratory disease were risk factors of oral fungi-bearing. In clinical Practice,doctors should closely monitor the condition of patients who had risk factors mentioned before.
Part2 The distribution and drug susceptibility spectrum of oral fungi in in patients
Objectic:To investigate the distribution and drug susceptibility spectrum of oral fungi in inpatients.
Methods:The yeasts isolated from patients were cultured and purified routinely, then the species of isolates were indentified by CHROMagar culture media and API 20 C AUX. Sensitivity of the isolates to Fluconazole,Itraconazole, Voriconazole and Amphotericin B was detected with checkerboard micro dilution method based on M27-A2(2002) of NCCLS.
Result:In this part 242 srains were separated and identified,Among them,the most common specie was candida albicans (174srains 71.90%).There were 68 strains non-candida albicans in all the isolates (28.10%). The differences ofratio of non-candida albicans of groups of age,antibiotics treatment and glucocorticoid treatment did not have statistical significance (P>0.05). Most isolates were sensitive to Fluconazole, Voriconazole and Amphotericin B. Non-candida albicans likely had lower sensitivity to Fluconazole compared With candida albicans,The differences were significant (P<0.05).
Conclusion:Candida albicans was the most common specie in oral fungal infections and fungi-bearing. Most isolates were sensitive to Fluconazole, Voriconazole and Amphotericin B. Non-candida albicans likely had lower sensitivity to Fluconazole.
目的：对综合医院住院部多临床科室住院患者同时进行口腔真菌感染的流行病学调查,以获得综合医院口腔真菌感染现状,了解口腔真菌感染的危险因素。
方法：收集昆明医学院附属第一医院住院部患者临床资料及口腔分泌物标本,对口腔分泌物标本进行真菌镜检及培养。结合临床资料,分析流行病学特点及危险因素并进行多分类单因素回归分析。
结果：共收集了昆明医学院第一附属医院住院部16个科室579例患者有效样本,共培养获得228例阳性标本。其中,口腔真菌感染患者80例,占13.82%,口腔真菌带菌患者148例,占25.56%。口腔真菌感染危险因素分析结果显示：住院时间越长口腔真菌感染率越高；使用抗生素患者较不使用抗生素口腔者真菌感染率越高,抗生素使用疗程越长的患者口腔真菌感染率越高,多种抗生素联合或交替使用的患者较单一用药者口腔真菌感染率高；使用糖皮质激素患者较不使用者口腔真菌感染率高,其中使用倍他米松和地塞米松患者较使用其他种类糖皮质激素者口腔真菌感染率高,每日糖皮质激素用量越大口腔真菌感染率越高,糖皮质激素疗程越长口腔真菌感染率越高；住院期间手术后时间越长口腔真菌感染率越高,以上结果均有统计学意义(P<0.05)。而口腔真菌带菌危险因素分析则显示：1-10岁及50岁以上患者口腔真菌带菌率较其他年龄段高,其差异有显著性(P＜O.05)。患有呼吸系统疾病患者较未患呼吸系统疾病者口腔真菌带菌率高,其差异有统计学意义(P＜O.05)。
结论：住院时间、使用抗生素、糖皮质激素等多因素可增加口腔真菌感染的机率,住院时间及住院期间手术后时间越长,口腔真菌感染率越高；使用抗生素患者口腔真菌感染率高于不使用抗生素患者,抗生素使用越长,口腔真菌感染率越高,联合或交替使用多种抗生素均可提高口腔真菌感染率；使用糖皮质激素尤其是大剂量使用糖皮质激素是口腔真菌感染的危险因素,使用倍他米松和地塞米松较使用其他种类的糖皮质激素更易引起口腔真菌感染。1-10岁和50岁以上患者以及患有呼吸系统疾病的患者,口腔真菌带菌率高于其他年龄组及无呼吸系统疾病的患者。在临床时工作中,对住院时间长、使用抗生素尤其是抗生素使用疗程长、联合或交替使用多种抗生素,长期大剂量使用糖皮质激素的患者,要密切监测口腔真菌感染情况,并及时治疗。使用倍他米松和地塞米松明显增加真菌感染率,因此,建议临床在可替代条件下尽量使用其他种类的糖皮质激素。对1-10岁和50岁以上患者以及患有呼吸系统疾病患者,应定期检测口腔真菌带菌情况。
第二部分综合医院住院患者口腔真菌菌感染致病菌株病原学及药敏研究
目的：通过对培养获得菌株的菌种鉴定及体外抗真菌药物药敏实验,获得口腔真菌感染和带菌的病原学资料及不同菌株药敏情况,指导临床治疗口腔真菌感染的药物选择。
方法：运用CHROMagar Candida显色培养基对和法国梅里埃API 20 C AUX酵母菌菌种鉴定试剂条对口腔分泌物培养获得菌株进行菌种鉴定。按照美国国家实验室标准委员会NCCLS M27-A2(2002)方案推荐的微量液基稀释法,检测所分离菌株对氟康唑、伊曲康唑、伏立康唑和两性霉素B四种抗真菌药物的体外药敏情况。
结果：从228例患者口腔分泌物培养阳性标本中共分离出242株假丝酵母菌,其中13例有两种或两种以上的假丝酵母菌共存。242株假丝酵母菌中白假丝酵母菌174株,占71.90%,非假丝酵母菌珠菌共68株,占28.10%。非白假丝酵母菌以光滑假丝酵母菌为主,共31株占所有菌株12.81%。年龄、使用抗生素和糖皮质激素对非白假丝酵母菌的发生率无影响(P>0.05)。白假丝酵母菌组对氟康唑、伊曲康唑、伏立康唑及两性霉素B的耐药率分别为9.20%、10.34%、5.75%及0%,非白假丝酵母菌组对氟康唑、伊曲康唑、伏立康唑及两性霉素B的耐药率分别为39.70%、11.76%、7.35及1.47%。口腔真菌感染组和带菌组的白假丝酵母菌和非白假丝酵母菌的构成比无差异,对四种抗真菌药物的敏感性也无差异。
结论：白假丝酵母菌仍是住院患者口腔假丝酵母菌感染的主要致病菌,光滑假丝酵母菌是住院患者口腔假丝酵母菌感染的主要非白假丝酵母菌,口腔真菌感染和口腔真菌带菌患者白假丝酵母菌和非白假丝酵母菌的检出率无差异,白假丝酵母菌对氟康唑、伊曲康唑、伏立康唑和两性霉素B均敏感,非白假丝酵母菌对氟康唑敏感性差。少数非白假丝酵母菌对两性霉素B存在耐药性。
Part1 Status of oral fungal infection and the relative risk factors of oral fungal infection.
Objective To find out status of oral fungal infection and its relative risk factors
Metheds In this study 579 inpatients of 16 departments from the First Affiliated Hospital of Kunming Medical College were investigated,and their oral secretion samples and clinical information were collected, Identification of fungi was performed by direct microscopy, fungal culture.
Results The experiment collected 579 cases of inpatients' samples from 16 departments of the First Affiliated Hospital ofKunming Medical College. From 579 samples,228 strains of fungi were isolated including 80 patients with Oral fungal infection (13.82%),and 148 patients with oral fungi- carrying (25.56%). Analysis of risk factors for oral fungal infection showed:patients who had long hospital stay had higher rate of oral fungal infection than those who did not (P<0.05), usage of antibiotics had higher rate of oral fungal infection than those who did not (P<0.05), the longer course of antibiotic usage had higher rate of oral fungal infection (P<0.05), combined or alternative usage of antibiotics had higher rate of oral fungal infection (P<0.05), Thoes who used glucocorticoid, especially betamethasone and dexamethasone had higher rate of oral fungal infection, large daily dosage and long treatment of glucocorticoid would increase the rate of oral fungal infection,(P<0.05),Those who stay in hospital for a long time after surgery got oral fungal infection easily(P<0.05). Analysis of risk factors for oral fungal carriers showed:1-10 years old and above 50 years age inpatients had higher risk of oral fungi- carrying (P<0.05). Inpatients who had respiratory diseases were more likely to be oral fungal carrier(P<0.05).
Conclusion Unvaried logistic regression analysis showed that length of hospital stay, whether to use antibiotics, length of antibiotics treatment, combined or alternative antibiotics treatment, whether to use glucocorticoid, kinds of glucocorticoid, daily dosage of glucocorticoid treatment, length of glucocorticoid treatment, length of hospital stay after surgery were risk factors of oral fungal infections. Age and respiratory disease were risk factors of oral fungi-bearing. In clinical Practice,doctors should closely monitor the condition of patients who had risk factors mentioned before.
Part2 The distribution and drug susceptibility spectrum of oral fungi in in patients
Objectic:To investigate the distribution and drug susceptibility spectrum of oral fungi in inpatients.
Methods:The yeasts isolated from patients were cultured and purified routinely, then the species of isolates were indentified by CHROMagar culture media and API 20 C AUX. Sensitivity of the isolates to Fluconazole,Itraconazole, Voriconazole and Amphotericin B was detected with checkerboard micro dilution method based on M27-A2(2002) of NCCLS.
Result:In this part 242 srains were separated and identified,Among them,the most common specie was candida albicans (174srains 71.90%).There were 68 strains non-candida albicans in all the isolates (28.10%). The differences ofratio of non-candida albicans of groups of age,antibiotics treatment and glucocorticoid treatment did not have statistical significance (P>0.05). Most isolates were sensitive to Fluconazole, Voriconazole and Amphotericin B. Non-candida albicans likely had lower sensitivity to Fluconazole compared With candida albicans,The differences were significant (P<0.05).
Conclusion:Candida albicans was the most common specie in oral fungal infections and fungi-bearing. Most isolates were sensitive to Fluconazole, Voriconazole and Amphotericin B. Non-candida albicans likely had lower sensitivity to Fluconazole.
引文
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[19]Wilkieson C,Samaranayake LP,MacFarlane TW,et al.Oral candidosis in the elderly in long term hospital care[J] J Oral Pathol Med.1991;2O(1):13-16.
[20]inghoff H,Bischoff T,Tal lent SM,et al.Nosocomial bloodstream infections in US hospitals analysis of 24179 cases from a prospective nationwide surveillance Study[J].Clin Infect DiS 2004;39:309-317.
[21]景炳文.危重患者医院真菌感染的原因及对预后的影响[J].中华医院感染学杂志,2002；12(10)：748-749.
[22]ay E.Timsit JF,Tafflet M,et al.Candida Colonization of the respiratory tract and subsequent pseudomonas ventilator-associated pneumonia[J].Chest.2006;129(1):110-117.
[23]Brown RE,Overview of fungal infection in cancer patients[J].Seminoncol,1990; 17(36): 2-5.
[24]李从荣,彭少华,李栋.深部真菌医院感染的临床调查与耐药现状研究[J].中华医院感染学杂志,2002；12(7)：485-487.
[25]李景苏,蔡长春.78例应用抗菌药物继发真菌感染的临床分析[J].中华医院感染学杂志,.2002：12(12)：888-889.
[26]Masakazu Niimi,Norman A,Firthl,Richard D.Cannonl. Antifungal drug resistance of oral fungi[J].Odontology,2010;98(1):15-25.
[27]Samaranayake LP,Keung Leung W,Jin L.Oral mucosal fungal infections[J]. Periodontology 2000,2009;49:39-59.
[28]周正任.医学微生物学(第六版)[M].北京：卫生出版社,2003.
[29]Fekety R.Infections associated with corticosteroids and immunosuppressive therapy. In:Gorbach SL, Bartlett JG,Blacklow NR,eds [J].Infectious Diseases. PhiladeIphia: W BSaunders Company 1992;1050-1051.
[30]周正任.医学微生物学(第六版).[M].北京：卫生出版社,2003.
[31]Joel B. Epstein, DMD, MSD, et al. Essentials of Oral Medicine[M].2002: 170-179.
[32]陈方淳,林梅.口腔假丝酵母菌病患者口内菌株的检出和药敏性观察[J].华西口腔医学杂志,2007：25(1)：37-41.
[33]Muzyka BC,Glick M. Areview of oral fungal infections and appropriate therapy[J].J Am Dent Assoc,1995;126:63-72.
[34]Naglik J,Albrecht A,Bader o, et al.Candida albicans proteinases and host/pathogen interactions[J].Cell Microbiol,2004;6(10):915-926.
[35]Cotter G,Kavanagh KAdherence mechanisms of Candida albicans[J].Br J Biomed Sci,2000;57(3):241-249.
[36]Mathias L,Richard, Armel Plaine. Comprehensive Analysis of Glycosylphosphatidylinositol-Anchored Proteins in Candida albicans[J]. Eukaryotic Cell,February 2007;6(2):119-133.
[37]Louise A, Carol A,Irene de Bruijn,et al.Stimulation of Chitin Synthesis Rescues Candida albicans from Echinocandins [J].PLoS Pathogens,2008;4(4):1-12.
[38]Denning DW.Munozp Advances in invasive fungal infectionand antifungal therapy: Introduction [J]. ClinMicrobiol Infect,2001;7(suppl 2):6.
[39]Fatema Nomanbhoy, Chad Steele, Junko Yano, et al.Vaginal and Oral Epithelial Cell Anti-Candida Activity[J].Infect Immun.2002 December; 70(12):7081-7088.
[40]Milens AR,et al.Normal Microbiota on the Teeth of Preschool children[J].Microbial Ecology in Health and Disease,1993;6:213.
[41]Kleinegger CL,Lockhard SR,Vargas l,et al.Frequency, Intensity Speciesand Strains of Oral Candida Vary a8 a Function of Host Age[J].J Clin Micrcbiol,1996;30(9):2246.
[42]Ugun B,Kadir T,Akytiz S.Oral candidal carriage in children with andwithout dental caries[J].Quintessence Int,2007,38(1);45.
[43]Zaremba ML,Daniluk T,Rozkiewicz D,et al.Incidence rate of Candida species in the oral cavity of middle-aged and elderly subjects[J].Adv Med Sci,2006;51(1):233.
[44]Marsh PD,Percival RS,Challacombe SJ.The influence of denturewearing and age on the oral microflora[J].J Dent Res,1992;71:1374.
[45]Edgerton M,Levine MJ.Ch aracterization of acquired denure pellicle from healthy and stomatitis patients[J].J ProsthetDent,1992;68(6):683.
[46]Jennifer K,Chow,Yoav Golan,et al.Factors Associated with Candidemia Caused by Non-albicans Candida Species Versus Candida albicans in the Intensive Care Unit [J].CID,2008;46:1206-1213.
[47]Pfaller MA, Diekema DJ.Epidemiology of invasive candidiasis:a persistent public health problem[J]Clin Microbiol Rev,2007;20:133-63.
[48]C Vaishnavi,S Kaur,S Prakash.Speciation of Fecal Candida Isolates in Antibiotic-Associated Diarrhea in Non-HIV Patients[J].J Infect Dis,2008;61:1-4.
[49]MS Lionakis, DP Kontoy iannis.Glucocorticoids and invasive fungal infections [J].The Lancet,2003;362:1828-1838.
[50]Fridkin SK.The changing face of fungal infections in health care settings [J].Clin Infect Dis,2005;41:1455-1460.
[51]H Schacke, KAsadullah, WD Docke. Side Effects of Topical and Oral Glucocorticoids [M]. Overcoming Steroid Ins ens itivity in Respiratory Disease,2008.
[52]Van den Bossche H, Willemsen G, Cools W, et al. Hypothesis on the molecular basis of the antifungal activity of N-substituted imidazoles and trizaoles[J]. Biochem Soc Trans 1983;(11):665-667.
[53]National Committee for Clinical Laboratory Standards. Reference method for broth, dilution antifungal susceptibility testing of yeasts. Approved standard-Second Edition[S].National Committee for Clinical Laboratory Standards,2002;22(15):1-30.
[54]Morschhauser J.The genetic basis of fluconamle resistance development in Candida albicans[J].Biochim Biophys Acta,2002;1587(2-3):240-248.
[55]Riccardo Torelli, Brunella Posteraro,Selene Ferrari,et al.The ATP-binding cassette transporter-encoding gene CgSNQ2 is contributing to the CgPDR1-dependent azole resistance of Candida glabrata[J].Molecular Microbiology,2008;68(1):186-201.
[56]Kumamoto CACandida biofilms[J] Curr Opin Microbiol,2002,5(6):608-611.
[57]Anna Selmecki,Maryam Gerami-Nejad,Carsten Paulson,et al.An isochromosomeconfers drug resistance in vivo by amplification of two genes, ERG11 and TAC1[J]. Molecular Microbiology,2008;68(3):624-641.
[58]Henry KW,CruzMC,KatiyarSK,et al. Antagonism of azole activity against Candida albicans following induction of multidrug resistance genes by selected antimicrobial agents[J].Antimicrob Agents Chemother,1999;43(8):1968-1974.
[59]Hubert Wolfger,Yasmine M Mamnun,Karl Kuchler.Fungal ABC proteins:pleiotropic drug resistance, stress response and cellular detoxification[J]. Research in Microbiology,2001; (15):375-389.
[60]Georgiev VS.Membrane transporters and antifungal drug resistance[J].Curr Drug Target,2000;1(3):261-284.
[61]Chia-Geun Chen, Yun-Liang Yang, Kuo-Yun Tseng.et al.Replp negatively regulating MDR1 efflux pump involved in drug resistance in Candida albicans[J].Fungal Genetics and Biology,2009;46(9):714-720.
[62]Chandra J,Kuhn DM,Muukherjee PK,el al.Biofilrn formation by the fungal pathogen Candida albicans:development,architecture,and drug resistance[J].J Bacteriol, 2001;183(18):5385-5394.
[1]Arkel S.Shinnick A.Update on oral candidosis[J]. Nurs Times.2003;99:52-53.
[2]吴安华,任南,文细毛,等.全国医院感染监控网1998-1999年监测资料分析[J].中华医院感染学杂志,2000：10(6)：401-403.
[3]尹有宽,张继明,黄玉仙,等.医院内深部真菌感染的前瞻性调查[J].中华医院感染学杂志,2004：14(11)：1308-1310.
[4]曹鸿玮,王瑞,于建斌.50例深部真菌感染病例回顾性分析[J].中外健康文摘,2008；5(1)：48-51.
[5]李春阳,刘方,郭淑兰,等.医院内真菌感染的调查分析临床皮肤科杂志[J].2002；31(2)：121-122.
[6]Benjamin DK Jr,Stoll BJ,Fanaroff AA,et al.Neonatal candidiasis among extremely low birth weight infants:risk factors,mortality rates,and neurodevelopmental outcomes at 18 to 22 months[J].Pediatrics.2006;117(1):84-92.
[7]Joel B.Epstein,MD, et al.Oral Fungal Infections[M]. Essentials of Oral Medicine.2002: 170-179.
[8]Odds FC.Candida and candidosis:Areview and bibliography[J].London:Bailliere Tindall,1998;10:124-135.
[9]孟小斌,曾黄辉,林建昌.453例院内真菌感染致病菌分布及药物治疗分析[J]中国现代药物应用,2009：3(8)：17-19.
[10]Kuriyama T, Williams DW, Bagg J,et al.In vitro antifungal resistance in Candida albicans from HIV-infected patients with and without oral[J].Oral Microbiology Immunology 2005;20:349-353.
[11]KJ Verstrepen. MicroReview Flocculation, adhesion and biofilm formation in yeasts [J]. Molecular Microbiology,2006;60(1):5-15.
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[13]Hube B,Nik JR.Extracellular hydrolases In:Calderone RA,ed.[M] Candida and candidasis.Washington.DC:American Society for Microbiology Press,2002:107-122.
[14]Hube B,Naglik J.Candida albicans protelnase:resolving the mystery of a gene family.[J]Microbiology,2001;147:1997-2005.
[15]Schaller M,Schackert C,Korting HC,et al.Invasion of Candida albicans correlates with expression of secreted asparfic proteinases during expe rimental infection of human epiderm is[J].Invest Derm atol,2000;114:712.
[16]Sommebom A,Bockmubh DP,Gerads M,et al.Protein kinase A encoded by TPK2 regu lated dimorphism of Can dida albicans[J].Mol Microbiol,2OOO;35(2):386-396.
[17]周正任.医学微生物学(第六版)[M].北京：卫生出版社,2003.
[18]Ueta E,Tanida T,Doi S,et al.Regulation of Candida albicans growth and adhesion by salive[J].Lab Clin IVied,2000;136(1):66-731
[19]MS Lionakis, DP Kontoyiannis.Glucocorticoids and invasive fungal infections [J].The Lancet,2003;362:1828-1838.
[20]Fridkin SK.The changing face of fungal infections in health care settings [J].Clin Infect Dis,2005;41:1455-1460.
[21]H Schacke, K Asadullah, WD Docke. Side Effects of Topical and Oral Glucocorticoids [M].Overcoming Steroid Insensitivity in Respiratory Disease,2008.
[22]Abu-Eheen KH,Abu-Aheen RM.111 prevalence of Canclida albicans populations in the mouths of complete denture wearers[j].New Microbiol,1998;21(1):41-48.
[23]Brown RE,Overview of fungal infection in cancer patients[J].Seminoncol,1990;17(36): 2-5.
[24]李从荣,彭少华,李栋.深部真菌医院感染的临床调查与耐药现状研究[J].中华医院感染学杂志,2002：12(7)：485-487.
[25]HS Mirsky.Fungal infection in acute leukemia[J].Cancer,2006;30(2):348-352.
[26]Patton LL. Sensitivity, specificity, and positive predictive value of oral opportunistic infections in adults with HIV/AIDS as markers of immune suppression and viral burden[J]. Oral Surg Oral Med Oral Pathol Oral Radiol Endod.2000,90:182-188.
[27]GAO Ning,FAN Zhen,XiAO Xiao-tong,et al.Quantitative changes of microflora on stress-bearing areas relating to bases of removable partial dentures [J]. West China J Stomatology,2002;20(5):349-352.
[28]Wilkieson C,Samaranayake LP,MacFarlane TW,et al.Oral candidosis in the elderly in long term hospital care[J].J Oral Pathol Med.1991;2O(1):13-16.
[29]Van den Bossche H, Willemsen G, Cools W, et al. Hypothesis on the molecular basis of the antifungal activity of N-substituted imidazoles and trizaoles[J]. Biochem Soc Trans 1983;(11):665-667.
[30]Morschhauser J.The genetic basis of fluconamle resistance development in Candida albicans [J].Biochim Biophys Acta,2002;1587(2-3):240-248.
[31]Anna Selmecki,Maryam Gerami-Nejad,Carsten Paulson,et al.An isochromosome confers drug resistance in vivo by amplification of two genes, ERG11 and TAC1[J]. Molecular Microbio logy,2008;68(3):624-641.
[32]Henry KW,CruzMC,KatiyarSK,et al. Antagonism of azole activity against Candida albicans following induction of multidrug resistance genes by selected antimicrobial agents[J].Antimicrob Agents Chemother,1999;43(8):1968-1974.
[33]Riccardo Torelli, Brunella Posteraro,Selene Ferrari,et al.The ATP-binding cassette transporter-encoding gene CgSNQ2 is contributing to the CgPDR1-dependent azole resistance of Candida glabrata[J].Molecular Microbiology,2008;68(1):186-201
[34]Hubert Wolfger,Yasmine M Mamnun,Karl Kuchler.Fungal ABC proteins:pleiotropic drug resistance, stress response and cellular detox ification[J]. Research in Microbiology, 2001;(15):375-389.
[35]Georgiev VS.Membrane transporters and antifungal drug resistance[J].Curr Drug Target,2000; 1(3):261-284.
[36]Chia-Geun Chen, Yun-Liang Yang, Kuo-Yun Tseng.et al.Replp negatively regulating MDR1 efflux pump involved in drug resistance in Candida albicans[J].Fungal Genetics and Biology,2009;46(9):714-720.
[37]Chandra J,Kuhn DM,Muukherjee PK,el al.Biofilrn formation by the fungal pathogen Candida albicans:development,architecture,and drug resistance[J].J Bacteriol, 2001;183(18):5385-5394.
[38]Kumamoto CA.Candida biofilms[J] Curr Opin Microbiol,2002,5(6):608-611.
[2]Joel B.Epstein, DMD,MSD,et al.Oral Fungal Infections[M]. Essentials of Oral Medicine, 2002:170-179.
[3]Odds FC.Candida and candidosis:Areview and bibliography[J].London:Bailliere Tindall, 1998.10:124-135.
[4]Denning DW.Munozp Advances in invasive fungal infectionand antifungal therapy: Introduction [J].Clin Microbiol Infect,2001;7(suppl 2):6.
[5]Fatema Nomanbhoy, Chad Steele, Junko Yano,et al.Vaginal and Oral Epithelial Cell Anti-Candida Activity[J].Infect Immun. 2002 December; 70(12):7081-7088.
[6]F.Sabatelli,R.Patel,P.A.Mann,et al.In vitro activities of posaconazole,fluconazole, itraconazole, voriconazole,and amphotericin B against a large collection of clinically important molds and yeasts[J].AntimicrobialAL agents and chemotherapy,2006; 50(6): 2009-2015.
[7]National Committee for Clinical Laboratory Standards.Reference method for broth dilution antifungal susceptibility testing of yeasts. Approved standard-Second Edition[S].National Committee for Clinical Laboratory Standards,2002;22(15):1-30.
[8]Arkel S.Shinnick A Update on oral candidosis[J]. Nurs Times.2003;99:52-53.
[9]吴安华,任南,文细毛,等.全国医院感染监控网1998-1999年监测资料分析[J].中华医院感染学杂志,2000：10(6)：401-403.
[10]尹有宽,张继明,黄玉仙,等.医院内深部真菌感染的前瞻性调查[J].中华医院感染学杂志,2004：14(11)：1308-1310.
[11]曹鸿玮,王瑞,于建斌.50例深部真菌感染病例回顾性分析[J].中外健康文摘,2008；5(1)：48-51.
[12]李春阳,刘方,郭淑兰,等.医院内真菌感染的调查分析临床皮肤科杂志[J].2002；31(2)：121-122.
[13]Benjamin DK Jr,Stoll BJ,Fanaroff AA,et al.Neonatal candid ias is among extremely low birth weight infants:risk factors,mortality rates,and neurodevelopmental outcomes at 18 to 22 months[J].Pediatrics.2006; 117(1):84-92.
[14]Joel B.Epstein,MD, et al.Oral Fungal Infections[M]. Essentials of Oral Medicine. 2002:170-179.
[15]Odds FC.Candida and candidosis:A review and bibliography[J].London:Bailliere Tindall,1998;10:124-135.
[16]F Cox.Adherence of Candida albicans to buccal epithelial cells in children and adults[J].J Lab Clin Med.1983 Dec;102(6):960-972.
[17]Negroni M, Gonzalez MI,Levin B.Candida carriage in the oral mucosa of a student population adhes iveness of the strains and predisposing factors[J].Rev Argent Microbiol,2002;34(1):22.
[18]GAO Ning,FAN Zhen,XiAO Xiao-tong,et al:Quantitative changes of microflora on stress-bearing areas relating to bases of removable partial dentures [J]. West China J Stomatology,2002;20(5):349-352.
[19]Wilkieson C,Samaranayake LP,MacFarlane TW,et al.Oral candidosis in the elderly in long term hospital care[J] J Oral Pathol Med.1991;2O(1):13-16.
[20]inghoff H,Bischoff T,Tal lent SM,et al.Nosocomial bloodstream infections in US hospitals analysis of 24179 cases from a prospective nationwide surveillance Study[J].Clin Infect DiS 2004;39:309-317.
[21]景炳文.危重患者医院真菌感染的原因及对预后的影响[J].中华医院感染学杂志,2002；12(10)：748-749.
[22]ay E.Timsit JF,Tafflet M,et al.Candida Colonization of the respiratory tract and subsequent pseudomonas ventilator-associated pneumonia[J].Chest.2006;129(1):110-117.
[23]Brown RE,Overview of fungal infection in cancer patients[J].Seminoncol,1990; 17(36): 2-5.
[24]李从荣,彭少华,李栋.深部真菌医院感染的临床调查与耐药现状研究[J].中华医院感染学杂志,2002；12(7)：485-487.
[25]李景苏,蔡长春.78例应用抗菌药物继发真菌感染的临床分析[J].中华医院感染学杂志,.2002：12(12)：888-889.
[26]Masakazu Niimi,Norman A,Firthl,Richard D.Cannonl. Antifungal drug resistance of oral fungi[J].Odontology,2010;98(1):15-25.
[27]Samaranayake LP,Keung Leung W,Jin L.Oral mucosal fungal infections[J]. Periodontology 2000,2009;49:39-59.
[28]周正任.医学微生物学(第六版)[M].北京：卫生出版社,2003.
[29]Fekety R.Infections associated with corticosteroids and immunosuppressive therapy. In:Gorbach SL, Bartlett JG,Blacklow NR,eds [J].Infectious Diseases. PhiladeIphia: W BSaunders Company 1992;1050-1051.
[30]周正任.医学微生物学(第六版).[M].北京：卫生出版社,2003.
[31]Joel B. Epstein, DMD, MSD, et al. Essentials of Oral Medicine[M].2002: 170-179.
[32]陈方淳,林梅.口腔假丝酵母菌病患者口内菌株的检出和药敏性观察[J].华西口腔医学杂志,2007：25(1)：37-41.
[33]Muzyka BC,Glick M. Areview of oral fungal infections and appropriate therapy[J].J Am Dent Assoc,1995;126:63-72.
[34]Naglik J,Albrecht A,Bader o, et al.Candida albicans proteinases and host/pathogen interactions[J].Cell Microbiol,2004;6(10):915-926.
[35]Cotter G,Kavanagh KAdherence mechanisms of Candida albicans[J].Br J Biomed Sci,2000;57(3):241-249.
[36]Mathias L,Richard, Armel Plaine. Comprehensive Analysis of Glycosylphosphatidylinositol-Anchored Proteins in Candida albicans[J]. Eukaryotic Cell,February 2007;6(2):119-133.
[37]Louise A, Carol A,Irene de Bruijn,et al.Stimulation of Chitin Synthesis Rescues Candida albicans from Echinocandins [J].PLoS Pathogens,2008;4(4):1-12.
[38]Denning DW.Munozp Advances in invasive fungal infectionand antifungal therapy: Introduction [J]. ClinMicrobiol Infect,2001;7(suppl 2):6.
[39]Fatema Nomanbhoy, Chad Steele, Junko Yano, et al.Vaginal and Oral Epithelial Cell Anti-Candida Activity[J].Infect Immun.2002 December; 70(12):7081-7088.
[40]Milens AR,et al.Normal Microbiota on the Teeth of Preschool children[J].Microbial Ecology in Health and Disease,1993;6:213.
[41]Kleinegger CL,Lockhard SR,Vargas l,et al.Frequency, Intensity Speciesand Strains of Oral Candida Vary a8 a Function of Host Age[J].J Clin Micrcbiol,1996;30(9):2246.
[42]Ugun B,Kadir T,Akytiz S.Oral candidal carriage in children with andwithout dental caries[J].Quintessence Int,2007,38(1);45.
[43]Zaremba ML,Daniluk T,Rozkiewicz D,et al.Incidence rate of Candida species in the oral cavity of middle-aged and elderly subjects[J].Adv Med Sci,2006;51(1):233.
[44]Marsh PD,Percival RS,Challacombe SJ.The influence of denturewearing and age on the oral microflora[J].J Dent Res,1992;71:1374.
[45]Edgerton M,Levine MJ.Ch aracterization of acquired denure pellicle from healthy and stomatitis patients[J].J ProsthetDent,1992;68(6):683.
[46]Jennifer K,Chow,Yoav Golan,et al.Factors Associated with Candidemia Caused by Non-albicans Candida Species Versus Candida albicans in the Intensive Care Unit [J].CID,2008;46:1206-1213.
[47]Pfaller MA, Diekema DJ.Epidemiology of invasive candidiasis:a persistent public health problem[J]Clin Microbiol Rev,2007;20:133-63.
[48]C Vaishnavi,S Kaur,S Prakash.Speciation of Fecal Candida Isolates in Antibiotic-Associated Diarrhea in Non-HIV Patients[J].J Infect Dis,2008;61:1-4.
[49]MS Lionakis, DP Kontoy iannis.Glucocorticoids and invasive fungal infections [J].The Lancet,2003;362:1828-1838.
[50]Fridkin SK.The changing face of fungal infections in health care settings [J].Clin Infect Dis,2005;41:1455-1460.
[51]H Schacke, KAsadullah, WD Docke. Side Effects of Topical and Oral Glucocorticoids [M]. Overcoming Steroid Ins ens itivity in Respiratory Disease,2008.
[52]Van den Bossche H, Willemsen G, Cools W, et al. Hypothesis on the molecular basis of the antifungal activity of N-substituted imidazoles and trizaoles[J]. Biochem Soc Trans 1983;(11):665-667.
[53]National Committee for Clinical Laboratory Standards. Reference method for broth, dilution antifungal susceptibility testing of yeasts. Approved standard-Second Edition[S].National Committee for Clinical Laboratory Standards,2002;22(15):1-30.
[54]Morschhauser J.The genetic basis of fluconamle resistance development in Candida albicans[J].Biochim Biophys Acta,2002;1587(2-3):240-248.
[55]Riccardo Torelli, Brunella Posteraro,Selene Ferrari,et al.The ATP-binding cassette transporter-encoding gene CgSNQ2 is contributing to the CgPDR1-dependent azole resistance of Candida glabrata[J].Molecular Microbiology,2008;68(1):186-201.
[56]Kumamoto CACandida biofilms[J] Curr Opin Microbiol,2002,5(6):608-611.
[57]Anna Selmecki,Maryam Gerami-Nejad,Carsten Paulson,et al.An isochromosomeconfers drug resistance in vivo by amplification of two genes, ERG11 and TAC1[J]. Molecular Microbiology,2008;68(3):624-641.
[58]Henry KW,CruzMC,KatiyarSK,et al. Antagonism of azole activity against Candida albicans following induction of multidrug resistance genes by selected antimicrobial agents[J].Antimicrob Agents Chemother,1999;43(8):1968-1974.
[59]Hubert Wolfger,Yasmine M Mamnun,Karl Kuchler.Fungal ABC proteins:pleiotropic drug resistance, stress response and cellular detoxification[J]. Research in Microbiology,2001; (15):375-389.
[60]Georgiev VS.Membrane transporters and antifungal drug resistance[J].Curr Drug Target,2000;1(3):261-284.
[61]Chia-Geun Chen, Yun-Liang Yang, Kuo-Yun Tseng.et al.Replp negatively regulating MDR1 efflux pump involved in drug resistance in Candida albicans[J].Fungal Genetics and Biology,2009;46(9):714-720.
[62]Chandra J,Kuhn DM,Muukherjee PK,el al.Biofilrn formation by the fungal pathogen Candida albicans:development,architecture,and drug resistance[J].J Bacteriol, 2001;183(18):5385-5394.
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