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Not a Mycologist—Just Candida

Sobel, Jack M.D.

Infectious Diseases in Clinical Practice: August 2001 - Volume 10 - Issue 6 - p 299-306
THE PFIZER/IDCP DISCOVERY SERIES: TURNING POINTS IN INFECTIOUS DISEASES
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Dr. Sobel, a graduate of the University of the Witwatersrand in Johannesburg, South Africa, is a world-renowned authority on vaginal candidiasis; his other areas of expertise include opportunistic candida infections, various forms of non-candida vaginitis, and urinary tract infection. From 1971 to 1976, he served as a hospitalist at the Rambam University Hospital in Israel. He then completed his clinical training in Infectious Diseases at the National Institutes of Health (NIH) and at the Medical College of Pennsylvania (MCP) between 1976 and 1978. From 1979 to 1981, he served as an infectious disease specialist in Israel. In 1981, he returned to the Division of Infectious Diseases at MCP. In 1985, he was named Chief of Infectious Diseases at Wayne State University (WSU) School of Medicine and Detroit Medical Center in Detroit, Michigan. During the course of his career, Dr. Sobel has studied the pathogenesis, clinical aspects, epidemiology, and treatment of candida vaginitis and has established novel and illuminating concepts with regard to this disease entity. As a member of the Mycoses Study Group (MSG) and the HIV Epidemiology Research Study (HERS) Group, he has published numerous articles that have enhanced the understanding of the complexities associated with recurrent candida vaginitis in both immunocompetent and immunosuppressed individuals. Dr. Sobel is also a member of the American College of Physicians (ACP), the Infectious Diseases Society of America (IDSA), and the American Society of Microbiology (ASM). He has received clinical teaching awards at MCP and a distinguished faculty award at WSU. In addition, he is associate editor for Infectious Diseases in Obstetrics and Gynecology and serves on the editorial boards of Mycology Review and Sexually Transmitted Infections.

Address correspondence to: Jack Sobel, M.D., Harper Hospital, 4 Brush Center, Room 4811, 3990 John R Street, Detroit, MI 48201 (Fax: 313-993-0302; Email: jsobel@intmed.wayne.edu)

I grew up in a small gold-mining town some 20 miles outside of Johannesburg, South Africa. Wanting to be a physician is one of my earliest memories. There were never any questions, hesitations, or doubts as to a lifetime career as a physician. Although it came at great cost to others, the South Africa of the 1950s, 1960s, and 1970s for white individuals was an incredible chapter of both privilege and opportunity. I had a wonderful high school education in an outstanding public school system, which was the product of thousands of exceptional Scottish teachers who had emigrated all over the British commonwealth. Medical school education in South Africa was a reflection of the very best of American and British medical education systems, particularly with regard to clinical training. Socratic education in the hands of outstanding clinical teachers and exposure to the broad spectrum of clinical material seen at the various university hospitals produced superb clinical graduates. Yet, despite the superior quality of our medical education, our qualities were barely recognized by the rest of the world. After a year of conscription service in the South African army as a physician, I was so taken with medicine that I could not decide what area to pursue. I did 2 years of a pediatric residency, but I then fell in love with internal medicine. After acquiring my boards in internal medicine, I struggled to choose a subspecialty, ending up doing a 1-year fellowship in nephrology and a 1-year fellowship in cardiology. I remained unfulfilled, and it took several years before I discovered infectious diseases.

In South Africa, I was exposed to many both clinical and research giants, who had an impact on my life and my career choices. In particular, Dr. Arthur Rubenstein gave me my first taste of bench research as he investigated the role of insulin in diabetes mellitus. In addition, I was especially influenced by Dr. Moses Suzman, the husband of the famous Helen Suzman, who was a remarkable clinician and who was many years ahead of his time. The many other clinicians who influenced me are too numerous to list. However, all of them, collectively, sit on my shoulder, and I sense them every time I examine a patient.

Nevertheless, I chose to leave South Africa. Although most forms of voluntary emigration are actually very painful and often difficult, this was not the case for us. My wife and I had decided that the apartheid system was incompatible with our values. We felt powerless and intimidated by a regime that appeared infinite in its strength, and we could no longer live in an immoral society. We left South Africa when virtually no one else was leaving the country; thus, it was easy to obtain a green card since the line waiting to emigrate to the United States was very short. However, the 1967 Six-Day War in Israel convinced me to deviate from my original plan. Consequently, instead of coming to the United States to do a nephrology fellowship, we decided to emigrate to Israel. En route to Israel, I obtained my membership at the Royal College of Physicians in London and Edinburgh. On arrival in Israel, I spent 6 months in an absorption center in Carmiel, a development town of 5000 people. I was soon recruited to spend my afternoons as the only physician in town, while I learned Hebrew in the mornings. The next 6 months were quite blissful, as we explored a new society and were exposed to emigrants from all over the world and as I served the indigenous Arab and Druse communities of the Galilee.

In January of 1971, I joined the Rambam University Hospital in Haifa, Israel. Although I worked throughout this period, it took a year or two to effectively function in the Hebrew language. This was a very difficult period in that there was little local acceptance and recognition of immigrant physicians, especially with so many arriving at that time. One had to prove one’s quality to the local Israeli physicians as well as to the nursing staff. I spent the next 3 or 4 years serving as a hospitalist. Many hospitalists in the United States today see their subspecialty as a new entity; in fact, the concept is very old and has been around in modern western medicine for 30 or 40 years and continues to be a major specialty in western Europe. I thoroughly enjoyed the role of hospitalist but recognized that I had to choose a subspecialty for academic advance.

Having already rejected cardiology and nephrology, I had the unique chance of meeting Dr. Harry Feldman, who was visiting Rambam University in 1975. He opened my eyes to the opportunity of subspecializing in infectious diseases. I was able obtain a Foggarty fellowship at the National Institutes of Health (NIH) with Shelly Wolff and was privileged to work in the laboratory of John Gallin. The focus of the NIH was biased toward understanding the role of the host in the pathogenesis of disease, as opposed to the more conventional emphasis on microbial pathogens. I spent a year working shoulder to shoulder with Mark Klempner and Dan Wright. This was major change of direction in my life, since I had never done any laboratory or basic science research. However, there can be no better place in the world than the NIH to learn the fundamentals of good laboratory research. A highlight of that period for me was the twice-weekly migrations across Wisconsin Avenue to the Naval Hospital to participate in Infectious Disease clinical rounds with Drs. Jack Bennett, Tony Fauci, and Ray Dolin. Under the Dr. Gallin’s guidance, I studied leukocyte chemotaxis and was fortunate in being able to complete a project and have it published in the Journal of Clinical Investigation within a year of my arrival [1].

Because it had been my intent to return to Israel, I wanted to learn conventional blood-and-thunder infectious diseases, which was not available at the clinical center at the NIH. Accordingly, I looked for a second-year fellowship and was fortunate to find one at the Medical College of Pennsylvania (MCP), working under the guidance of Donald Kaye and Matthew Levinson. My stay over the next 2 years at MCP in an extended fellowship afforded me the opportunity of developing under two outstanding clinicians, whose knowledge of the fundamentals of infectious diseases was legendary in the city of Philadelphia. In particular, their strengths in infective endocarditis (IE) and urinary tract infection (UTI) have had a lasting influence on my life. Dr. Kaye mentored me in my writing and proved to be an outstanding role model, and Dr. Levinson provided me with my first exposure to clinical research.

Because it was not then possible to pursue my research in leukocyte chemotaxis, Dr. Levinson suggested that I look into bacterial adherence, and he recommended that I study gonococcal attachment to epithelial cells. One of the subjects that had fascinated me during my sojourn at the NIH was opportunistic infections in cancer patients. Little was known at the time about fungal superinfections in these compromised hosts, and I was left with a lingering desire to study candida opportunistic infections. Working at MCP 1 to 2 years later, I had the opportunity to study adherence of Candida albicans to epithelial cells in lieu of gonococcal adherence. This was first done with exfoliated buccal epithelial cells initially employing crude assays, which became more sophisticated over time. One of the disadvantages of working with buccal epithelial cells is that they are invariably colonized with gram-positive cocci. Therefore, I chose to work with vaginal epithelial cells simply because it was easier to wash off the lactobacilli. By the end of 2 years in Philadelphia, I had published several papers on Candida adherence to vaginal epithelial cells. The most important contribution I made at the time was identifying that fucose residues were important components of the epithelial cell membrane receptor system, an observation that was confirmed by others several years later [2].

In 1979, as planned, my family and I returned to Israel with the intent of establishing the first infectious disease unit in the north of Israel. At the time, there were three other qualified infectious disease specialists in the country. Convincing general internists that an infectious disease specialist had something to offer was an initial challenge. However, over the course of a few months, my number of consults went from zero to 75 to 100 per month in a busy regional 700-bed hospital. I ended up working 12 to 16 hours a day as the sole infectious disease specialist in the north of Israel, being consulted on virtually all serious infections in both the civilian and military populations. This was a very satisfying and fulfilling experience, but it did not afford opportunity for any bench or clinical research. The clinical load was enormous, and any progress required that I obtain the infectious disease unit, which the ministry of health had promised. When this was not forthcoming, I returned to the United States in 1981 and rejoined the infectious diseases unit at MCP. While a position was being prepared, I had the opportunity of working as a clinician in the sexually transmitted diseases (STD) clinic at the city health department of Philadelphia. This opened my eyes to the opportunities in studying genital tract infections and applying my earlier research experience with Candida to clinical disease.

Thus, in 1981, a 20-year career in the study of candida vaginitis began. Once on the faculty at MCP, I soon recommenced my research and established different models for studying Candida adherence. I was fortunate in creating the first multilayer vaginal epithelial cell tissue culture system for studying Candida adherence [3]. I spent the next 2 to 3 years performing progressively more sophisticated research using radiolabeled techniques to study in vitro attachment in a tissue culture system. The vaginal tissue cultures were created from biopsies of vaginal cuff obtained at the time of hysterectomy; the outgrowth from the explant produced multilayers of epithelial cells, which functioned physiologically in vitro and responded to exogenous estrogen.

The next phase in the Candida story was the availability of ketoconazole, the first oral systemic antifungal agent. I chose to study the effects of ketoconazole on both the morphology and the adherence of C. albicans in different tissue culture systems. We showed that subinhibitory concentrations of ketoconazole interfered with Candida attachment to epithelial cells in vitro and theoretically had the potential to interfere with long-term colonization in vivo; this was the first application for the use of an azole drug as long-term primary and secondary prophylaxis. Of course, further clinical study would necessitate working with women. Initially, I turned to gynecologists to provide me with vaginal epithelial cells as well as patients to study the effects of ketoconazole. However, this approach was unsuccessful, and I decided to establish my own clinic focused purely on candida vaginitis. Given the lack of support from the gynecology community, I resorted to advertising in the press, looking for women with recurrent candida vaginitis who were interested in participating in therapeutic studies. Over the next 3 to 4 years, I saw hundreds of women with candida vaginitis and focused my attention more and more on this entity rather than Candida as an opportunistic pathogen, i.e., invasive candida infection or systemic candidiasis.

One of our early findings was that 9 of 10 women referred to me with a diagnosis of recurrent candida vaginitis did not in fact have candida infection; they either had infection due to one of many other pathogens or no infection at all. Thus, I found myself on a steep learning curve, and I was helped by my earlier solid clinical training in South Africa. I soon found myself seeing patients with recurrent bacterial vaginosis, atrophic vaginitis, and a whole host of entities that were poorly defined at the time in the gynecologic literature. Consequently, I became interested in the various non-Candida causes of vaginitis, something that was thrust upon me not by choice but by the reality of women with non-Candida diagnoses. My candida vaginitis clinic became a general vaginitis clinic for women with refractory vaginal symptomatology. This was also my first exposure to the syndrome of idiopathic vestibulitis, an entity that continues to be a focus of my interest to this day.

The in vitro, animal, and clinical studies of the azole–Candida interaction were rewarded with an article published in 1986 in the New England Journal of Medicine [4]. In a randomized, placebocontrolled study, low-dose ketoconazole maintenance prophylaxis prevented recurrent disease as long as the drug was taken; in addition, a significant number of women were cured even after the drug was stopped. In another study, I evaluated the effect of treatment of the partners of women with recurrent vaginal candidiasis and showed that male partner treatment with systemic ketoconazole failed to decrease to the attack rate in women prone to recurrent vaginal candidiasis. I spent a great deal of time investigating the pathogenesis of vaginal candida infections because so little was known at that time. There existed sacred cows, such as the need to do an oral glucose tolerance test (OGTT) in any woman with recurrent candida vaginitis and the presumed role of the rectum as the source of reinfection of the vagina in recurrent candida vaginitis. It was possible to slay some sacred cows. For example, we found that the incidence of latent or chemical diabetes, based on the results of OGTT, was no higher in premenopausal women with recurrent vaginal yeast infection than in normal control subjects. In addition, animal studies showed that recurrent candida vaginitis was not due to reinfection from the gastrointestinal tract, but due to failure to eradicate the organism from the vagina. Thus, new concepts of pathogenesis were established.

From the microorganism point of view, one of my last activities at MCP was to develop a biotyping system for typing of Candida organisms. This was probably the first widespread use of Candida typing after serotyping, which was not useful in fingerprinting strains of Candida or reliable as an epidemiologic tool. As a result of the biotyping technique, we were able to establish that women with recurrent candida vaginitis were not being reinfected with new strains but were relapsing with the identical strain [5]. This observation has stood the test of time as we have utilized new typing techniques over the last 20 years culminating in polymerase chain reaction (PCR) and randomly amplified polymorphic DNA; which have confirmed the original biotyping observation, namely vaginal persistence of the same strain in cases of recurrence, with only infrequent cases of recurrent infection due to newly introduced strains. We also showed that vaginal isolates were not uniquely vaginotropic or vaginopathic; virtually any Candida strain was capable of causing disease.

During this time, I also had an important collaboration with the late Helen Buckley from Temple University, who was able to isolate a mutant of C. albicans that could not form germ tubes. I showed that the non–germ tube forming organisms were less able to colonize epithelial cells in vitro [6]. However, more importantly, in the animal model of candida vaginitis, these organisms were avirulent, emphasizing the importance of germ tube formation in establishing vaginal colonization and in serving as a major virulence factor in causing disease. The final research area that I was involved with at MCP was establishing a model for candida vaginitis. A model had been originally described for studying antifungal drugs by researchers at Squibb in the 1960s for studying nystatin, and it became the standard for studying new topical antifungal drugs. We reproduced the model using mice, rats, and guinea pigs, but we were able to modify the model to study pathogenesis and microbial virulence. We confirmed the role of estrogen dependence in candida vaginitis and documented the cellular host response.

During those early years in studying candida vaginitis, I found myself isolated. On the one hand, no self-respecting mycologist or even candidologist had any interest in studying vaginitis. On the other, the gynecologists saw me as an intruder into the clinical world of gynecologic infections. In general, I was migrating from my mainstream interests in infective endocarditis and urinary tract infections to a much more marginalized area, candida vaginitis. In order to maintain my respectability, I had continued throughout this time to study the adherence of bacterial pathogens to uroepithelial cells. At that stage, type 1 and p fimbriae E. coli and were discovered, and a burgeoning field was developing. As always, I found myself riding several horses at the same time. One of my interests then was in Tamm–Horsfall protein. In one of the last studies I did with Dr. Kaye, we looked at the role of uromucoid and Tamm–Horsfall protein as natural protective mechanisms that prevented uropathogens from attaching to bladder epithelial cells. In other studies, we evaluated the protective role of the mucopolysaccharide lining of the bladder in preventing bacterial colonization of the bladder after retrograde introduction of bacteria into bladder urine. Using the animal models, we published several morphologic and qualitative studies showing that enhanced attachment of bacteria to naked uroepithelial cells occurred after removal of the mucopolysaccharide lining of the bladder [7].

In July 1985, I moved to Detroit, Michigan to assume the role of division chief of Infectious Diseases at Wayne State University (WSU). I left Philadelphia reluctantly, having had a wonderful experience at MCP, where I enjoyed great mentorship under Drs. Kaye and Levinson and where I had the opportunity to work with colleagues including Jerome Santoro, Hymie Carrizosa, Oksana Korzenowski, and Eli Abrutyn.

Upon arriving at the Detroit Medical Center (DMC) and WSU, I was provided with several new opportunities. In particular, the DMC housed a large cancer center funded by the National Cancer Institute. Finally, after 10 years, I had returned to a large population at risk for developing opportunistic infections. The DMC also had a very active bone marrow transplant (BMT) unit. Accordingly, I decided to return to studying opportunistic infections, particularly candida infections. I encouraged a fellow, Shahe Komshian, to review our experience with fungemias caused by various Candida species. We published this analysis of fungemia cases seen over 5 years in Review of Infectious Diseases, and it represented the first of many articles dealing with the epidemiology of candida infections [8]. For better or for worse, I again found myself riding multiple horses simultaneously. Roger Cook, a microbiologist who had expertise in vaginal flora, joined my laboratory, and we explored the pathophysiology of recurrent bacterial vaginosis (BV). As a result of these studies, we confirmed the high recurrence rate of BV after conventional therapy with metronidazole. Moreover, we acquired new insight into why some women were prone to recur, in that recurrence was associated with failure of lactobacilli to re-establish their dominance among vaginal flora. In addition, Roger and I looked at vaginal lactobacillus numbers in women with recurrent candida vaginitis. In contrast to everyone’s expectations, several of our studies showed that lactobacillus numbers and species were no different in women with recurrent candida vaginitis and normal female control subjects [9]. Thus, women who develop recurrent candida vaginitis do not lack lactobacilli, and the whole emphasis on re-establishing lactobacillus-dominant flora by exogenous means such as yogurt as treatment for recurrent vaginal candidiasis was unfounded.

Over the past 16 years since arriving in Detroit, my pursuit of Candida has been directed at multiple targets. I have been involved in clinical, therapeutic, diagnostic, and epidemiologic studies of candiduria, oropharyngeal candidiasis, disseminated candidiasis, and candidemia. Although I have a strong interest in Candida and both its superficial and deep infections, I do not consider myself a mycologist. Nevertheless, a breakthrough for me was being accepted into the Mycoses Study Group (MSG) in 1992. Before that time, the MSG had been interested primarily in studying treatment of endemic mycoses. The introduction of both Candida and Aspergillus studies transformed the MSG and opened up its ranks to many new centers. For me, personally, it was a major advance, as I have benefited enormously by participating in this Group through conference calls, annual meetings, and clinical studies. The MSG is an incredibly successful and highly effective group of individuals whose collaborative teamwork has been extremely productive in numerous clinical studies. The MSG has been skillfully guided by Bill Dismukes, who has shown tremendous vision in developing new clinical areas for study. In particular, the Candida subgroup was led by Jack Edwards, who proved to be both a personal friend and a wise and competent leader, as candidemia was transformed from an ignored infection, not worthy of routine therapy, to the status that it now enjoys. Over this period, we progressed from a one-drug solution (amphotericin B) to the availability of several parenteral and oral azoles plus combination therapy; we now find ourselves in the world of lipid formulations of amphotericin B as well as the new echinocandins. Accordingly, with the introduction of each new antifungal agent, new questions arise and new levels of sophistication are applied to both diagnosis and therapy.

Other individuals who have been leaders in the field of candidiasis have been John Rex and Tom Walsh. John Rex has provided invaluable expertise to the study of new antifungals and insightful statistical knowledge in developing models for clinical studies. Tom Walsh has demonstrated superb knowledge in the development of animal models for the purposes of studying pharmacokinetics and new diagnostic tests. I was fortunate to collaborate with him in one major national study that evaluated enolase as a new diagnostic test for invasive candidiasis [10]. Needless to say, the relevant diagnostic test still eludes us, but we have made great strides in this field. I have benefited enormously from my collaboration with Drs. Edwards, Rex, Walsh, and others, culminating in the development of practice guidelines for the treatment of candidiasis [11].

In Detroit, we have conducted some of the first studies of the epidemiology of candida infections, which have been provided useful clinical information. A decade ago, I was fortunate to mentor an infectious disease fellow, Jose Vasquez, and convinced him to turn his attention to candidiasis. He was a whiz in the laboratory and used the contour-clamped homogenous electrical field technique to type Candida. We used this new typing technique to investigate the epidemiology of Candida in the hospital setting [12,13]. He was the first to show the nosocomial acquisition of Candida species, especially in intensive care units and BMT units, and that these Candida isolates spread rapidly among patients, often on the hands of nursing and medical personnel. Over the years, Jose has played a critical role in various epidemiologic studies, and his collaboration in developing more sophisticated typing techniques, culminating in PCR-based RAPD and DNA probes, has contributed substantially to our understanding of the epidemiology of both vaginal and invasive candidiasis. As a member of the MSG, I was afforded an opportunity of collaborating with Carol Kaufmann in an epidemiologic study on candiduria. At this time, the MSG also initiated a study on the treatment of candiduria. This was the first prospective, randomized study comparing the effects of fluconazole versus placebo in the treatment of candiduria. We were able to confirm what we already suspected, that fluconazole rapidly eradicated candiduria, but we also showed that relapse rates were high in high-risk populations. More importantly, we confirmed the lack of benefit of eradication of candiduria in asymptomatic patients. Needless to say, we continue to monitor the epidemiology of nosocomial candidiasis because there is much to learn and the facts are constantly changing.

While continuing to study invasive and disseminated candidiasis, I turned my attention to studying the immune response within the lower genital tract, specifically the vagina, in candida vaginitis. Early on, we showed that women with recurrent candida vaginitis had adequate immunoglobulins in vaginal and cervical secretions and that lack of immunoglobulins was not a factor in the susceptibility to recurrent infection. I was fortunate to work with a young postdoctoral fellow, Paul Fidel, and convinced him that Candida was more interesting than Cryptococcus. Together, we were able to use the experimental animal model of candida vaginitis in mice and rats to study the role of cell-mediated immunity (CMI) in the pathogenesis of candida infections. Among the first experiments that Paul did was to show that experimental candida vaginitis induced in Candida-naïve mice could induce a systemic immune response to Candida antigens, which could be measured in the foot pad and in peripheral lymphocytes in vitro. From the opposite direction, it was widely assumed that systemic immunity, as a function of CMI, would impact directly on the vagina and provide some level of protection. We were the first to show a distinct separation between mucosal immunity and systemic immunity. By altering systemic immunity through either enhancement or inhibition of CMI, we showed that systemic CMI had no impact on vaginal candidiasis in the experimental model. This led to the concept of compartmentalization of CMI and the possibility that vaginal immunity to Candida and vaginal protective immune mechanisms existed and functioned independently of systemic CMI.

Another theory that had existed for many years was that women with recurrent candida vaginitis were thought to be more susceptible to such infection as a result of a Candida antigen–specific T-cell abnormality, since they showed cutaneous anergy to Candida antigens. However, we were able to show in longitudinal studies in women that the so-called cutaneous anergy was very transient and self-limited and that anergy was present during the acute vaginitis only and an appropriate response to Candida antigens in vitro and in vivo occurred several weeks after antifungal treatment had eliminated infection. Cutaneous anergy to Candida antigens and decreased CMI response to Candida were not the cause but rather the result of these infections. The concept that emerged was that the Candida polysaccharide capsule had an important role in down-regulating both local and systemic immune responses. This was a whole new way of looking at Candida and consequent vaginitis. It brought us to the understanding that the lower genital tract, which is in general, an immune downregulated area, could be further down-regulated by Candida to facilitate long-term yeast colonization. Once introduced, Candida became part of the normal flora. We were able to show in human studies that long-term colonization with Candida could continue virtually forever. Low numbers of Candida can coexist long-term with normal bacterial flora and normal lactobacillus species without causing disease. Teleologically, it is never in Candida’ s interest for vaginal symptoms and disease to develop. Symptomatic disease occurred either when the host reacted to secondary changes in Candida or when changes in the host immune reactivity developed. These concepts represented a new view of candida infections. Studies conducted by Paul also showed that there was a level of protective immunity in vivo that could be induced experimentally in animals by infecting them with Candida. However, the immunity could be overcome by either host or microbial factors. This led us to the belief, especially under natural circumstances, that the likelihood of a Candida vaccine producing critical protection was low but not impossible. After 5 years of remarkable productivity, Paul went on to pursue a highly successful career at Louisiana State University. We continue to collaborate in investigating vaginal immune mechanisms, including innate immunity, such as the role of vaginal epithelial cells in providing some level of resistance to Candida proliferation [14–16].

Over the same period, I continued seeing patients with candida vaginitis in my clinic. Virtually no topical or oral azole currently available for the treatment of candida vaginitis has not been studied in our laboratory and clinic. We have acquired a magnificent library of Candida vaginal isolates, available to any interested investigator. I believe an important contribution made was the classification of clinical candida vaginitis into complicated and uncomplicated disease [17]. This was a new classification system that aids physicians in selecting both an antifungal drug and duration of therapy. Most women with uncomplicated disease can be treated with short-course oral or systemic therapy. In contrast, women with complicated candida vaginitis need long-term therapy and, frequently, alternatives to azole therapy. It is only in the past 3 to 4 years, however, that one has been able to validate the criteria that went into this new classification. Nevertheless, this classification makes it infinitely easier for residents and clinicians to select appropriate therapy for candida vaginitis. I have continued to see many women with recurrent candida vaginitis and continue to be challenged by understanding its pathogenesis. I have learned to appreciate that recurrent candida vaginitis is anything but an entity that fits into a single unifying concept. Recurrent candida vaginitis can occur for a variety of host and organism factors. Significant progress has been made in identifying some of the exogenous causes of recurrent candida vaginitis but especially in controlling recurrent disease.

In 1992, WSU was selected by the Centers for Disease Control and Prevention (CDC) to become part of a four-center cohort study evaluating human immunodeficiency virus (HIV) infection in women. The study was prompted by the absence of data on the natural history of HIV infection in women, at a time when numerous studies were pouring forth data on HIV infection in men. Over the past 8 years, the HIV Epidemiology Research Study (HERS) Group has allowed Paula Schuman and myself to study oral and vaginal candidiasis in HIV-infected women. Several publications have emerged, as well as the acquisition of a remarkable library of oral and vaginal isolates of Candida from almost 1400 women who were followed for 7 years and seen twice yearly. Several thousand clinical Candida isolates have been speciated, typed, and tested for antifungal susceptibility. The primary goal was to understand the pathogenesis of oropharyngeal and vaginal candidiasis in HIV-infected women, primarily its natural and treated history, with particular focus on the pathogenesis of resistant mucosal candidiasis. Most of the published analyses so far deal with the first 2 to 3 years of the 7-year study. The initial observations have shown high colonization rates in both the oropharynx and the vagina, together with a gradual shift in Candida species over time with the progressive acquisition of non-albicans Candida species in both sites. This study has also shown the enormous differences between oropharyngeal and vaginal candidiasis, with regard to colonization and attack rates, species involved, drug susceptibility, and epidemiologic risk factors [18]. Although both sites represent superficial candidiasis, it has been always inappropriate for physicians to equate oropharyngeal and vaginal candidiasis and to consider these manifestations as being expressions of the same pathogenic process. We anticipate that continued study and evaluation of collected isolates, paired with the epidemiologic data, will provide additional insights into the pathogenesis of reduced azole susceptibility and in vivo resistance.

While the HERS Group has given me access to a large number of non-albicans Candida isolates, I also continued to see an increased number of HIVnegative women with vaginitis due to non-albicans species. There was nothing in the literature to assist me in the management of these infections, which were difficult to eradicate. I was fortunate to stumble on the use of boric acid and flucytosine for treatment of C. glabrata infections [19]. Treatment of these non-albicans Candida species over the years has emphasized the inadequacy of the azoles as a group in managing non-albicans Candida species. The azoles proved to be miraculous in the control of C. albicans infections and other susceptible species. However, they remain inadequate in the treatment of C. glabrata. The most important lesson has been the recognition that C. glabrata is the Achilles’ heel of the azole drug group. Another important lesson was the recognition that the fungistatic nature of azole drugs and all drugs currently used to treated candida vaginitis inevitably resulted in persistence of the organism in the vagina in low numbers, which allowed the organisms to emerge with time to cause symptomatic relapse. The lack of available fungicidal drugs to treat candida vaginitis remains a major shortcoming of existing therapy.

Over the past 16 years, my vaginitis clinic has seen approximately 1200 women per year, including 300 to 400 new patients, of whom approximately 100 present with recurrent candida vaginitis. I also have been required to see a large number of chronically symptomatic women with a variety of non-candida infections and noninfectious etiologies. I have become intrigued with metronidazole-resistant vaginal trichomoniasis, idiopathic vulvovestibulitis syndrome, erosive lichen planus of the vagina, and resistant bacterial vaginosis [20,21]. I have also been fortunate to see a significant number of women with unexplained purulent vaginitis that is responsive to both clindamycin and high-dose steroids. Unfortunately, vaginitis continues not to be in the mainstream of both the academic infectious diseases and obstetrics–gynecology communities. Nevertheless, these multiple syndromes of unknown etiology afford a great challenge and opportunity to any young investigator interested in understanding the pathogenesis of vaginitis.

Thus, after 23 years of involvement with Candida and its infections, I continue to be a prisoner of the Candida world. I have been fortunate to associate with a strong team of collaborators within the division of infectious diseases at WSU, who provide a critical mass in the pursuit and clinical investigation of invasive fungal infections. They include Jose Vasquez, Pranathar Chandrasekar, and George Alangaden. As such, each of the four of us is able to focus on a different aspect of fungal infection. I find myself spending less time with disseminated and invasive candida infections and more time with candida vaginitis. I recently completed a large multicenter study of more than 700 women with recurrent candida vaginitis, and I look forward to analyzing the data with my co-investigators so as to determine the best way to treat these patients with recurrent chronic candida vaginitis, and to decipher the microbiologic, epidemiologic, and susceptibility data that will be forthcoming. We are also investigating PCR as a new diagnostic test and as a more sensitive fingerprint to trace and track candida vaginitis in women with recurrent disease. As the PCR data becomes available, we are obtaining new insights into long-term persistence of Candida in the vagina at a time that cultures become negative with conventional clinical therapy. I believe that we will have a far better understanding of the epidemiology and pathogenesis as a result of these studies.

This two-decade love affair with Candida and its infections, hopefully, is not over. For the future, I look forward to vaccine studies and to new insights that will be obtained, in both animal and human studies, which allow direct inoculation of Candida organisms into the vagina. More importantly, utilizing the Candida genome studies, we need a breakthrough in treatment, with development of new broad-spectrum anti-Candida fungicidal agents that will achieve a substantial reduction in the existing tendency of women to suffer from these recurring infections.

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REFERENCES

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