Vol. 116, October Printed in U.S.A.

THE JOURNAL OF UROLOGY

Copyright © 1976 by The Williams & Wilkins Co.

Review Article GENITOURINARY FUNGAL INFECTIONS STEPHEN MICHIGAN From the Brady Urological Institute, The Johns Hopkins Hospital, Baltimore, Maryland

ABSTRACT

Although fungal urinary tract infections occur less frequently than bacterial urinary tract infections their incidence has increased during the last several decades and their clinical importance to the urologist should not be underestimated. Herein the pertinent literature on fungal urinary tract infections is reviewed, with emphasis on the predisposing factors, pathogenesis, host defense mechanisms and the clinical spectrum of the disease. An approach to the evaluation of positive cultures and therapy is presented. Although fungal infections of the genitourinary tract are far less common than bacterial infections we have seen a striking increase in their incidence' and in the recognition of their importance during the last 25 years. The increased prevalence of systemic and genitourinary fungal infections is at least in part attributable to the widespread use of antibiotics, corticosteroids, immunosuppressive drugs, antineoplastic agents and the ability of the medical profession to prolong the life of patients with serious underlying diseases. Urology has shared in these advances and it is not surprising that fungal infections are being recognized with increasing frequency in patients with urologic diseases. Renal transplant recipients are particularly susceptible to fungal disease. In the not too distant past serious fungal infections were found primarily in patients with such severe underlying illnesses that they would not have been expected to survive anyway and these infections were often the immediate cause of death. They are now seen in a broader range of patients, many of whom can be expected to do well if their infections are controlled. Fortunately, effective antifungal chemotherapeutic agents have been developed. The literature is replete with case reports of patients who have died because the significance of a blood or urine culture positive for fungi was recognized too late. It is of considerable importance that urologists become acquainted with the variable manifestations of fungal infections and the available means of treatment. Candida albicans is the most prevalent and the most pathogenic of the fungi affecting the genitourinary tract. Practically all of the infections not caused by Candida albicans are either caused by one of the other Candida species or by Torulopsis glabrata. Although these fungi have somewhat different culture characteristics and are easily distinguished from one another in the laboratory 2 • 3 their behavior in clinical settings is quite similar. Therefore, while most of this review refers to Candida albicans infections, the comments are applicable to these other organisms except where so stated. Selected other fungi that have occasionally caused genitourinary disease are discussed briefly in a separate section.

Virchow demonstrated that this was not merely a superficial pathogen but was at least capable of penetrating the submucosa of the esophagus. In 1861 Zenker demonstrated fungal metastases to the brain and stated that they were probably spread hematogenously from thrush lesions.• Autopsy reports of spread to the viscera continued to appear sporadically. In 1895 and 1905 autopsy reports demonstrated renal involvement in thrush infections. 5 In 1910 Raffin reported the first case of renal moniliasis 6 and in the 1920s Monilia was recognized as a cause of urethritis. 5 In 1931 Lundquist reviewed 18 cases of renal infection caused by a variety of fungi. 7 Moulder reported on a case of monilial cystitis in 1946 5 and Albers described 2 cases of what has since been known as primary renal candidiasis in 1953. 8 Since that time large numbers of case reports of fungal infections of different parts of the genitourinary tract in a variety of clinical settings have been noted in the literature. FUNGAL CLASSIFICATION

Candida and Torulopsis are classified as Deuteromyces or imperfect fungi because no sexual phase of reproduction has been observed in them. The genus Candida is subdivided into many species of which Candida albicans is by far the most frequent cause of disease in man. Candida are opportunistic fungi. They are dimorphic, being found in the yeast (Y) and hyphal or (pseudo) mycelial (M) forms in vivo and in vitro. Candida albicans is distinguished from the other Candida species by its ability to form thick-walled spores, called chlamydospores, under suboptimal conditions for cellular growth. Torulopsis glabrata belongs to the family cryptococcaceae, section cryptococcoideae, and is closely related to Cryptococcus and Candida species. Unlike Candida it is not dimorphic occurring only as yeast-like cells, which are smaller than the cells of Candida.

BACKGROUND

In 1846 Berg discovered that thrush was caused by the fungus now known as Candida albicans. Shortly thereafter Accepted for publication February 20, 1976. 390

OCCURRENCE

Candida and Torulopsis are widely distributed in nature. They are saprophytic for many animals, including man, but have the ability to become pathogenic under suitable conditions. In healthy individuals Candida can be cultured from the pharynx in 5 to 20 per cent and from the stomach in up to 50

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per cent of the time. 9 It is present in the feces of 10 to 20 per cent of normal subjects 10 and is quite common in the vaginal flora, especially during pregnancy. It has been cultured from the lungs in 15 per cent of routine autopsies. 6 Torulopsis glabrata is found in the same areas. FACTORS FAVORING PATHOGENICITY

Candida organisms tend to emerge as opportunistic pathogens in the host with a serious underlying disease whose defense mechanisms are further altered by modern medical therapy. 11 Factors that have been identified as predisposing to fungal infections include antibiotic therapy, diabetes mellitus, neoplasia, hematopoietic disorders, the use of corticosteroids and other immunosuppressive agents, indwelling intravenous or urinary catheters and heroin addiction. The increased incidence of candidiasis in the antibiotic era is well documented. Many studies have shown a clear-cut increase in the incidence of Candida in cultures from the nose pharynx, sputum and stool in patients receiving antibiotics'. There are several possible explanations for this. Antibiotic therapy upsets the normal equilibrium among the microbial inhabitants of the small intestine. A decrease in the bacterial population may result in less competition for common environmental growth factors. In addition, much of the normal intestinal flora has been shown to have the ability to suppress the growth of Candida. 12 • 13 Mechanisms for this may include alteration of the local pH, changes in the environmental oxidation-reduction potential and the production of antifungal substances. Candida is able to use the tetracyclines as its sole source of nitrogen for protein synthesis. 14 Chlortetracycline has been shown to inhibit polymorphonuclear phagocytosis, which may be an important body defense mechanism against Candida. 9 The administration of cortisone to experimental animals prior to or shortly after the onset of Candida albicans infection markedly increases the mortality rate and is associated with a striking rise in the renal Candida census. These findings are probably caused by a delayed mobilization of inflammatory cells, 9 although the capacity of the neutrophils to kill Candida has not been effected by corticosteroids in vitro. Cytostatic agents may favor Candida infections by producing leukopenia. Corticosteroids and other immunosuppressive agents may favor the development of candidiasis by suppressing cell-mediated immunity. 15 Glycosuria favors the growth of yeasts and their growth rate increases with the amount of glucose present at levels greater than 150 mg. per ml. Below this level the glucose content of urine has no effect on the growth rate. 16 Although structural and functional genitourinary abnormalities and foreign bodies in the urinary tract, such as calculi or catheters, do not directly predispose to candiduria 1 their presence along with 1 or more of the other predisposing factors seems to favor its development. 17 They also complicate the treatment of candiduria and may even make elimination of the fungus impossible. 18 Obviously, transplant patients are at risk from a number of these factors. Funguria is fairly common in these patients, occurring at some time in the postoperative course in up to 20 per cent of them. 1 Published series from several transplantation centers indicated that the major cause of late deaths following transplantation was associated with infection and in 33 to 74 per cent the causative organism was Candida or Aspergillus. 19 SIGNIFICANCE OF POSITIVE URINE CULTURES

The reported incidence of funguria in routinely collected clean urine specimens has ranged from O to 4 per cent. The literature of the 1950s and 1960s contained considerable discussion on the question of how much funguria was signifi-

cant. Various authors suggested that colony counts of greater than 1,000 or 10,000 per ml. were indicative of significant infection. It has been demonstrated since in a number of studies that such positive urine cultures were only rarely reproducible when catheterized or suprapubically aspirated specimens in female subjects or clean voided midstream specimens in male patients were obtained. 1 • 20 • 21 Since the appearance of any fungal growth is abnormal on a properly collected specimen funguria should be regarded as pathologic, regardless of the size of the colony count. Transient funguria, presumably from an increased intestinal reservoir, has been noted in some patients. Krause and associates administered 80 gm. Candida albicans, estimated to contain 10 12 organisms, to a healthy volunteer and found that Candida was recovered from the blood and urine within 3 hours. 22 The volunteer experienced an unspecified "transient toxic reaction" but was otherwise unharmed. The rapid time sequence was believed to make penetrative growth of the fungus through the intestinal wall unlikely, implying that the intact and unchanged organisms were capable of passing through the intestinal wall and into the blood stream by a process that has been termed presorption. It seems reasonable to suppose that the antibiotic-induced overgrowth of Candida, which has been shown to give up to 10 9 yeast cells per ml. feces, may result in a transient seeding of the blood and some of these fungi are likely to be excreted in the urine. 23 A urine culture that is positive for fungus always calls for confirmation by a properly collected specimen. The best definition of true funguria is "the growth of fungi on culture of urine sediments cultured on 2 occasions with an interval of 1 or more days using proper collection techniques" . 17 Cultures of the sediment of 10 ml. urine centrifuged at 3,000 revolutions per minute for 3 minutes are much more sensitive than ordinary urine cultures and are preferred for diagnosis and evaluation of therapeutic results. The actual colony counts are of little interest and may even be misleading, since there is no absolute correlation between the degree of funguria and the site of or severity of the infection. 1 Among the truly positive urine cultures Candida albicans has been found in 48 to 59 per cent, Candida species occurred in 8 to 28 per cent and Torulopsis glabrata occurred in 25 to 33 per cent. 20 • 24 PATHOGENESIS

The relationship between the intestinal flora and bacterial urinary tract infections is well known. It appears likely that the gastrointestinal tract is also the source for most fungal genitourinary infections and also can be the source for candidiasis in other sites. 25 Infections limited to the lower urinary tract are believed to ascend by way of the urethra. It has been suggested that upper tract fungal infections also may be established via the ascending route. 2 •- 28 One fact that seems to favor the ascension theory is that disseminated candidiasis occurs with equal frequency in male and female subjects, while primary renal candidiasis has been reported much more frequently in female patients, as has candidiasis of the lower urinary tract. Yet there is no convincing experimental evidence to show that Candida instilled in the bladder will produce retrograde renal infection. However, experimental studies have clearly demonstrated that hematogenous spread has the potential to cause all of the manifestations of renal candidiasis. 29-31 Mice given massive intravenous inocula of Candida albicans developed disseminated candidiasis and died within several days. In these animals abscesses were found regularly in the renal cortex. Mice given smaller inocula survived for longer periods and when these animals were examined, fungal disease was found only in the kidneys. The natural history of the experimenting renal lesion has been studied and, at different

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points in time, it simulates all of the clinical expressions of renal candidiasis. In the earliest stages the picture was that of an acute pyelonephritis with multiple focal abscesses containing the Y and M phases and numerous neutrophils. Hyphae were seen growing into and within tubules adjacent to and distant from the abscesses. After forming long pseudohyph~e within the tubules the fungus often reinvaded the parenchyma, causing an even more marked inflammatory reaction. Of note was the fact that no inflammatory reaction was seen within the tubules. By 48 hours large areas of the kidney were involved. Most of the fungi in the medulla reached that area via the tubules. After 9 to 11 days the cortical areas had healed, leaving some cortical scarring but little overt evidence of mycotic infection. At that point mycelia were present in the renal pelvis, the collecting tubules were filled with proliferating fungi and there was necrotizing papillitis. As fungus collected in the renal pelvis it formed obstructing bezoars and the pelvis dilated. In the final stages no fungi were seen within the parenchyma, which was severely damaged owing to hydronephrosis. The kidneys were usually unequally affected and in some cases the disease was unilateral. This work suggested that primary renal candidiasis may be the end result of a mild candidemia in amounts insufficient to cause widely disseminated disease. The bladders in these animals remained normal. Other observations included the facts that the inflammatory response in the kidneys was delayed relative to that of the other viscera and that phagocytized organisms frequently had the ability to grow out through the cell membranes of the neutrophils that had ingested them. These results suggested that the susceptibility of the kidney to involvement with candidiasis may have several bases, including 1) the delayed mobilization of the phagocytic cells increasing the opportunity for the fungus to establish a renal infection, 2) the ability of the more virulent strains to grow out of the cells that had phagocytized them and 3) the ability of the fungus to gain access to the protected environment of the renal tubular lumen in which it may proliferate without interference and then re-invade the parenchyma. In mice treated with cortisone there was an even greater tendency for the fungi to rupture into the tubular lumina, although there was no apparent difference in the mobilization of leukocytes or in their ability to phagocytize. 32 There is also experimental evidence that Candida may generate toxins that may be injurious. 33 • 34 The relative importance of the Y and M forms is not known with certainty. The mycelial form has been considered by many to be the important form for tissue invasion but there also have been arguments for the pathogenicity of the yeast form. The factors that influence the in vivo morphology are complex and incompletely understood. It has been proposed that the host tissue may produce some substance active at an acid pH that instigates the conversion from the Y to the M form. In cases in which significant infection of the urinary tract has occurred the M form always was found in the urinary sediment. The presence of the M form in the urine does not necessarily imply that manifest infection is present and it has been known to disappear spontaneously. 25 While the presence of the M form may be a necessary condition for tissue invasion it would seem unwise to ignore candiduria, even in its apparent absence from the urine sediment, since in vivo transformation may take place. Also, cases have been reported in which aggregates of yeast cells seemed to be obstructing the collecting tubules and filling the renal papillae with only an occasional suggestion of pseudomycelium formation, so the Y form, pathogenic or not, can cause mechanical obstruction leading to anuria and death. 10 Two other forms of Candida, chlamydospores and protoplasts, have been reported in cases of human candidiasis but have not been seen in the genitourinary tract.

HOST DEFENSE MECHANISMS

The inhibitory effect of the normal bacterial flora has been alluded to previously. Prostatic fluid has been shown to have anticandidal properties, 35 which in part may be responsible, along with the difference in urethral length, for the relative infrequency of lower tract Candida infections in male as opposed to female subjects. The fungi are aerobic organisms and, as such, have a high metabolic requirement for iron. Normal serum is highly fungistatic because of the presence' of siderophilin. 36 Siderophilin renders serum nutritionally deficient for aerobic organisms by chelating any available iron. The inhibitory effect of serum on Candida is, therefore, non-specific. If the siderophilin is experimentally saturated with iron Candida albicans will grow vigorously in serum. This mechanism may not be of great importance in the defense against urinary tract candidiasis. Substantial clinical and experimental evidence indicates that the polymorphonuclear leukocytes play a major role in the host response to Candida infections. 37 In experimental infections the disappearance of Candida from tissue lesions parallels the appearance of the inflammatory response. Leukopenia is a common predisposing factor in disseminated candidiasis in man. Eosinophils, basophils, monocytes and macrophages also participate to a lesser degree in this type of defense. Heat labile factors present in human serum accelerate the rate of phagocytosis of Candida albicans by neutrophils. A similar effect of heat labile opsonins on the phagocytosis of pneumococci by leu·kocytes has been reported. Myeloperoxidase, a lysozymal enzyme, may be an important participant in the candidacidal process of neutrophils. 37 Cell-mediated immunity also is believed to play an important part in the defenses against Candida. Alymphocytic patients often have Candida infections. SPECTRUM OF GENITOURINARY CANDIDIASIS

Candida albicans may be present in the urinary tract in a variety of clinical conditions, including renal involvement as a part of systemic candidiasis, primary renal candidiasis, Candida infection superimposed on chronic pyelonephritis or cystitis with parenchymal and urothelial involvement, symptomatic Candida cystitis, Candida urethritis and asymptomatic candiduria. Systemic or disseminated candidiasis is of interest to the urologist for 2 reasons: 1) it will be seen occasionally in urologic patients with the previously mentioned predisposing factors and 2) the kidney is the target organ most frequently involved. In fact, it may be difficult at times to be certain whether a patient has renal seeding secondary to Candida septicemia or Candida septicemia owing to a primary renal infection. Renal involvement occurs in up to 90 per cent of patients with Candida septicemia. In experimental systemic candidiasis the kidneys are involved approximately twice as often as any of the other viscera. The onset of systemic candidiasis may be sudden or insidious, or it may appear as a sudden worsening in the condition of an already sick patient. Male and female patients are affected equally. Patients are usually febrile, although they may have only a single evening or double daily temperature elevation. Many are hypotensive. Other common findings include shaking chills, splenomegaly, lethargy, tachycardia and petechiae, or other embolic phenomena. Endocarditis and meningitis may occur. Common laboratory findings include leukocytosis, anemia, candiduria, azotemia and pyuria. Renal involvement takes the form of an acute pyelonephritis with multiple abscess formations, primarily in the cortex. Disseminated candidiasis is invariably fatal if not treated. Primary renal candidiasis is defined as renal infection

GENITOURINARY FUNGAL INFECTIONS

without the presence of candidemia or other systemic organ involvement. It occurs uncommonly and most of the reported cases have been in female patients, many of whom had diabetes mellitus. The possibility of its being caused by a subclinical candidemia has been discussed previously. There is usually diffuse fungal infiltration of the tips of the papillae or infiltration and obstruction of the collecting tubules without fungi in other parts of the kidney. Bezoar formation with secondary obstructive uropathy may occur. A temporary diuresis in the course of an otherwise progressive oliguria is said to be a diagnostic sign. 38 Renal or ureteral colic may occur with the passage of fungus balls. Other symptoms may be indistinguishable from those of bacterial pyelonephritis. Progressive uremia may occur. Pyuria is usually but not invariably present. Candida usually can be demonstrated in the urine. Radiographic features of primary renal candidiasis on excretory urography (IVP) include hydronephrosis, caliceal erosion, radiolucent filling defects in the pelves or ureters, and unilateral or bilateral non-visualization. Diffuse intramural scalloping of the ureters may be seen and probably represents intraluminal projections produced submucosal edema, similar to the cobblestone esophagus seen with esophageal thrush. 39 Candida infection of the urinary tract may coexist with bacterial infections. Although there is experimental evidence showing that Klebsiella, Bacteroides and Escherichia coli can inhibit the growth of Candida it is not unusual to find a Candida infection coexisting with an infection caused by one of these organisms. Candida is not seen in the presence of Proteus urinary tract infections and candiduria has been observed to disappear, coinciding with the onset of a Proteus urinary infection. Candida infections of the lower urinary tract occur 4 times as commonly in women as in men. Candida cystitis usually occurs in the setting of diabetes mellitus, prostatic enlargement or pregnancy, often occurring after a bacterial bladder infection has been cleared. Symptoms include nocturia, constant pain and discomfort, and an unusual degree of frequency. The urine is often turbid or bloody. The bladder capacity may be severely contracted. Pneumaturia may occur. The symptoms tend to be chronic with occasional acute exacerbations, some of which follow treatment with antibiotics. 4 ° Cystoscopy reveals typical thrush-like pearly white and slightly elevated patches, which resemble deposits of coagulated milk. The mucosa bleeds briskly when they are removed. The ureteral orifices may be red and gapping and the entire picture may resemble tuberculous cystitis. 5 Scrapings of the affected areas reveal hyphae and yeast cells. Bezoar formation may occur in the bladder and may be limited in size only by the bladder capacity. 41 Candida urethritis is rare. If it is suspected a suprapubic aspiration should be done to rule out fungal infection of the more proximal urinary tract. The symptoms are similar to those of the non-fungal urethridities. Asymptomatic candiduria implies a colonization of the lower urinary tract without tissue invasion. 17 It usually occurs in a setting in which 1 or more of the predisposing factors, particularly antibiotics, diabetes mellitus and urinary catheters, has been present. It will usually disappear when the predisposing factors are removed, although the disappearance may take several months. The genitourinary tract appears to have a considerable ability to rid itself of fungi in the absence of deep seated infection. Funguria may be present for a long time without causing any apparent harm to the patient and it can disappear after having been present for a long time. Patients with asymptomatic candiduria have undergone major operations and have been treated with broad-spectrum antibiotics without manifest fungal infection developing. However, there have been cases in vvhich asymptomatic candiduria has rise to a fatal in some instances ~Nith bezoar formation and u:rsteral obstruction, This

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followed a serious deterioration in the patient's condition from other causes. Funguria occurs regularly after an operation in which a segment of bowel is incorporated into the urinary tract. It is owing to the large number of fungi in the isolated intestinal segment. These patients often have received antibiotics preoperatively. Funguria of this type behaves in the same way as asymptomatic candiduria.

EVALUATION OF POSITIVE CULTURES

A blood or urine culture that yields fungus must be evaluated in the context of the clinical setting. As has been mentioned previously candidemia and candiduria may occur as transient phenomena. In the case of urine cultures the possibility of contamination in an improperly collected specimen should be kept in mind. It seems only prudent to seek confirmation with repeat cultures before treatment unless the patient is gravely ill. When the patient with candidemia is clinically stable there is no urgency to administering specific antifungal chemotherapy. Evidence of tissue infection should be sought and possible predisposing factors should be removed if possible. Intravenous and urinary catheters should be replaced if they cannot be discontinued. Unnecessary antibiotics and corticosteroids should be discontinued. ff the candidemia persists 2 to 3 days after these measures are taken it is suggestive of disseminated candidiasis. If the patient is in a high risk group or is deteriorating at the time of the initial culture report then immediate specific therapy should be considered, in addition to these non-specific measures, while awaiting confirmation of the initial culture. When candiduria is confirmed it must be regarded as a pathologic finding. Renal function should be evaluated with serum urea nitrogen (SUN) and creatinine determinations, and an IVP is appropriate to assess the condition of the upper tracts. Cystoscopy may help differentiate between cystitis and non-invasive colonization of the lower urinary tract. It should be remembered that while the sudden appearance of large numbers of yeast in the urine occasionally may be the first sign of disseminated candidiasis, 11 quantitation of the urine culture should never be relied on as a guide to the severity of fungal urinary tract infections. Occasionally, it may be difficult to demonstrate funguria in a patient with a significant infection. The sensitivity of sediment cultures should, therefore, be re-emphasized. A sediment culture may yield large numbers of fungi from a urine that has yielded only 1 or 2 colonies on a routine culture. 1 Since the significance of cultures revealing a Candida infection may be difficult to determine, serodiagnostic reactions have been evaluated as a possible adjunct to the diagnosis of deep-seated infections. Agglutinin titers have been of little value because of their inability to distinguish between superficial and deep infections and their frequent cross reaction with other fungi. There are several encouraging reports on the use of Candida precipitin titers. 42 - 44 Titers greater than 1 to 1 are believed to signify deep infections. The reported incidence of falsely positive reactions in these series was 7 .7 and 13 per cent. Most patients with falsely positive reactions had mucocutaneous candidiasis associated with autoimmune hypoparathyroidism and hypoadrenalism. The incidence of falsely negative reactions was only 2 per cent and these were believed to be caused either terminal anergy or the possibility that there is a lag phase between the onset of the infection and the development of precipitin antibodies. The latter has been demonstrated in rabbits. When a patient has been treated ror a seated Candida infection the titers have returned to norrnal,

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MICHIGAN TREATMENT

Presently, there are only 2 drugs available for the treatment of significant non-mucocutaneous fungal infections, amphotericin Band 5-fluorocytosine (5-FC). Amphotericin B, a polyene antibiotic produced by the soil actinomycete Streptomycetes nodosus, was isolated in 1955. Polyene antibiotics bind to sterol-containing cell membranes, permitting the egress of potassium and other intracellular components and the entrance of water into the cell leading to lysis. Amphotericin B is fungicidal and fungistatic and is effective against most of the fungi, which are pathogenic to man with the exception of the Actinomyces (which are not true fungi) and Nocardia. Although resistant strains of some fungi, including Candida albicans, have been subcultured experimentally there is no present evidence that resistance develops in vivo. Amphotericin B is poorly absorbed from the gastrointestinal tract. It is administered intravenously as a colloidal suspension. Since it is deactivated by light the solution bottle and the intravenous tubing should be covered with aluminum foil or tape. Amphotericin B also is useful as an irrigant in the urinary tract as will be discussed. Several dose schedules have been advocated. 45 In general, they call for a low initial dose that is gradually increased until a daily dose of 1.0 to 1.5 mg. per kg. is reached. The latter dose should never be exceeded. Serum concentrations at therapeutic doses peak between 0.5 and 4.0 µg. per ml. Peak plasma levels are maintained for 6 to 8 hours and the serum half-life is 24 hours. Amphotericin B is poorly excreted by the kidney, only 2 to 4 per cent of a given dose being excreted in its biologically active form in the urine, and the exact pathway of its metabolism is unknown. Diminished renal function has no discernible effect on serum concentration or excretion. Amphotericin B is poorly dialyzable. 46 The major drawback of amphotericin B is its considerable toxicity. There are frequent immediate side effects, including fever (up to 40C), chills, nausea, vomiting, anorexia, headache, vertigo and phlebitis. These may be at least partially controlled by premedication with sedatives and antihistamines and by decreasing the concentration or rate of the infusion. The febrile reactions may be controlled by adding hydrocortisone to the infusion. Steroids usually can be gradually withdrawn from the regimen. 47 Hypersensitivity reactions also may occur and include anaphylaxis, thrombocytopenia, generalized pain, convulsions and flushing. Chronic toxicities include azotemia, anemia secondary to reversible bone marrow depression and electrolyte abnormalities, including mild renal tubular acidosis, symptomatic hypokalemia, hypomagnesemia and increased urinary excretion of sodium and potassium. Hepatocellular dysfunction and acute hepatic failure also have been reported. Diminished renal function occurs in more than 80 per cent of patients receiving amphotericin B and may persist long after the cessation of therapy. The extent of permanent renal damage is related to the total dose received and is generally not of lasting clinical significance if the total dose is less than 4 gm. administered during a period of at least 6 weeks. Dehydration exacerbates the azotemia. The nephrotoxic effects are believed to be related, at least in part, to renal vasoconstriction, with diminished renal blood flow and glomerular filtration rate. There also may be a direct toxic effect on the tubules. Histologically, there is nephrocalcinosis and vacuolation of the renal tubular epithelium. Disruption of the normal glomerular architecture also may be seen at higher doses. Experimental work in dogs has shown that if mannitol is given simultaneously with amphotericin B the marked azotemia and vacuolation of the tubular epithelium can be prevented. 48 Alkali therapy during prolonged treatment with amphotericin B also may help prevent renal damage.4 9 A hemogram, SUN, creatinine and liver function testing should be done at least biweekly during treatment with intravenous amphotericin B. If renal

insufficiency develops therapy should be temporarily discontinued and may be reinstituted when renal function normalizes. In 1957, 5-FC was first synthesized in the hope that it would have cytostatic properties, which it did not. In 1963 it was found to have antifungal activity. The mechanism of action involves its deamination by susceptible fungi to 5-fluorouracil, which is then used in the synthesis of nucleic acids to produce a non-functional ribonucleic acid. Resistance to 5-FC can occur from mutationally induced or naturally occurring loss of function of any of a number of enzymes that are not essential to the organism's survival. Mammalian tissues lack cytosine deaminase and, therefore, do not metabolize 5-FC. 5-FC is effective against Candida, Cryptococcus, Torulopsis and Chromomycosis infections and has limited activity against Aspergillus species. Greater than 90 per cent of an oral dose of 5-FC is absorbed and peak serum levels are achieved in 1 to 2 hours. No parenteral preparations are available. Most of the drug (80 to 90 per cent) is excreted in the urine and also is easily eliminated by hemodialysis. The serum half-life in patients with normal renal function ranges from 2.5 to 6 hours and averages 85 hours (but may also be as high as 250 hours) in anuric patients. A linear correlation exists between the elimination rate constant and the creatinine clearance. Although 5-FC is eliminated almost entirely by the kidneys it has no nephrotoxicity and, unlike amphotericin B, it is not contraindicated in the presence of renal failure if the dosage is adjusted appropriately. In individuals with normal renal function the usual dose is 150 mg. per kg. per day divided into 4 doses. Dose schedules have been worked out for patients with renal insufficiency 50 and for those on dialysis. 46 Serum levels should be followed in these patients and an attempt is made to maintain them between 25 and 120 µg. per ml. Urine levels are 10 to 100 times greater than serum levels in normal individuals and even patients with creatinine clearances as low as 10 ml. per minute usually have urine levels greater than 100 µg. per ml. 50 Minimal fungistatic and fungicidal concentrations for Candida are 0.2 to 3.9 µg. per ml. and 2.0 to 50.0 µg. per ml., respectively. 51 • 52 Toxicity occurs most frequently in but is not limited to azotemic patients and is reversible. Side effects include bone marrow depression, hepatocellular dysfunction, which is usually asymptomatic, nausea, diarrhea, skin rash, eosinophilia of up to 13 per cent and, less frequently, confusion, hallucinations, headache, sedation and vertigo. Hepatic insufficiency is not a contraindication to therapy with 5-FC. Teratogenesis has been observed at high doses in laboratory animals but 5-FC has been used in several pregnant women without discernible injury to the fetus. 53 • 54 The major problem with 5-FC is the occurrence of resistant strains of fungi. In one series resistance to high concentrations of 5-FC was found in 7.5 per cent of strains of Candida albicans, 33 per cent of Candida species and 6 per cent of Torulopsis glabrata isolated from untreated patients. 24 Resistant strains also were noted to emerge during treatment with 5-FC. This appeared most likely to occur in the presence oflow concentrations of the drug. At concentrations greater than 25 µg. per ml., that is those achieved with the recommended doses, the rate of emergence of resistant strains remained constant and could not be decreased by increasing the dose. Cryptococcus neoformans rarely has primary resistance to 5-FC but not uncommonly develops secondary resistance during treatment. In general, only 1 strain of fungus is isolated from a patient but occasionally a patient may harbor sensitive and resistant strains. Sensitivity testing should be done before therapy is begun and periodically during the course of treatment. There is experimental evidence that low doses of 5-FC in combination with low doses of amphotericin B may work

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synergistically. 53 · 55 · 59 This may, hopefully, prove to be a means of circumventing the emergence of resistance to the former and the toxicity of the latter. There is also evidence indicating that rifampicin potentiates the antifungal activity of amphotericin

B. 53,

56

Guide lines for treating the various forms of genitourinary fungal infections are based on an appreciation of their natural history and of the limitations of therapy cited. Asymptomatic funguria may persist for long periods without harming the patient and may disappear spontaneously after having been present for a long time. Most patients with asymptomatic funguria should not be treated with antimycotic agents. Their urine should be alkalized since yield best at moderately acid and are inhibited an alkaline environment. Predisposing factors should be eliminated whenever Patients who are ueu1J1ccncu have grave illnesses or whose deteriorates treated vvith ""''°u'cn, are at risk to a of choice for these is 5-FC unless the fungi are resistant. cystitis may be treated with 5-FC or with B. Alkalization of the urine is a useful adjunct to either of these modalities. Amphotericin B irrigations have been successful with intermittent• and continuous 59 irrigations. Up to 50 mg. per day have been used without local irritation or discornfort. Blood levels of amphotericin B have not exceeded 0.4 /J.g. per ml. and no changes were noted on serial SUN determinations or hemograms. Clinical improvement may be noted as early as the second or third day. Treatment is continued until 2 negative urine sediment cultures are obtained with a 1-week interval between them. Nephrectomy was the only hope for curing renal candidiasis 20 years ago. Today, nephrectomy is only indicated if medical therapy fails but other surgical procedures, such as relieving ureteral obstruction, may be valuable adjunctive measures. Amphotericin B irrigations of the renal pelvis, through netubes and through u.reteral catheters, have been used in the treatment of primary renal candidiasis. Therapy with 5-FC and alkali.zation of the urine is preferred when the fungi are sensitive to 5-FC. Treatment should be continued for at least 4 weeks and longer if cultures have not reverted to negative by that time. In the absence of significant tissue invasion intravenous amphotericin B, which is poorly excreted in the urine, is unlikely to be as effective as 5-FC or amphotericin B irrigations. Systemic candidiasis requires at least 4 to 6 weeks of treatment and frequently a much longer course of therapy is required. Optimal therapy includes amphotericin Band 5-FC, provided the renal function is adequate for the former and that the infecting organism is sensitive to the latter. The patient should be monitored for the emergence of organisms resistant to 5-FC. In one clinical study 10 of 11 patients were treated successfully for disseminated candidiasis with 5-FC alone. 60 In view of the grave prognosis associated with disseminated candidiasis, this cannot be recommended as adequate therapy without more extensive clinical trials.

disseminated coccidioidomycosis, making the kidney the sixth most commonly involved organ. 62 Involvement of the prostate and the epididymis has been reported, although it occurs much less commonly. 63 Amphotericin Bis the drug of choice and the epididymal lesion may require excision. Renal involvement with a variable degree of renal damage occurs in 12 per cent of patients with aspergillosis. 64 There are several reported cases of Aspergillus infection limited to the kidney, 58 • 64 · 65 with presenting signs and symptoms related to obstruction of the collecting system. Some species of Aspergillus are sensitive to 5-FC and the organism is generally sensitive to amphotericin B. 66 Penicillium 67 and ¼:r,nv•nT~, have been reported involving various parts of the urinary tract. These are not sensitive to 5-FC and appropriate should inciude , - , ~ h n r n ¥ , B, either or as an depending upon the type of infection present. REFERENCES

1. Schone beck, J, and Ansehn, S.: The occurrence of yeast-like fungi

2.

3. 4.

5. 6. 7. 8. 9. 10. 11. 12.

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17.

OTHER FUNGI

Sporadic reports have been made on other fungi invading the urinary tract. Fifty-one per cent of patients with disseminated cryptococcosis have renal involvement. Prostatic lesions appear to be less common but may be extensive and occasionally ~ay be the presenting feature of a disseminated cryptococcal infection. 61 Cryptococcus neoformans is usually sensitive to

5-FC. Genitourinary involvement is also common in patients with disseminated I:n one autopsy series it ?iho died of

18. 19. 20. 21

in the urine under normal conditions and in various types of urinary tract pathology. Scand. J. Urol. Nephrol., 6: 123, 1972. Seneca, H., Longo, F. and Peer, P.: Candida pyelonephritis and candiduria: the clinical significance of Candida albicans in urine cultures. J. Urol., HlO: 266, 1968. Newman, D. M. and Hoog, J.M.: Torulopsis glabrata pyelonephritis. J. Urol., 102: 547, 1969. Hurley, R.: Acute disseminated (septicaemic) moniliasis in adults and children, Postgrad. Med. J ., 40: 644, 1964. Moulder, M. K.: Thrush of the urinary bladder: case report. J. Urol., 56: 420, 1946. Goldman, H. J., Littman, M. L., Oppenheimer, G. D. and Glickman, S. I.: Monilial cystitis-effective treatment with instillations of amphotericin B. J.A.Ivl.A., 174: 359, 1960. Guze, L. B. and Haley, L. D.: Fungus infections of the urinary tract. Yale J. Biol. Med., 30: 292, 1958. Albers, D. D.: Monilial infection of the kidney: case reports. J. Urol., 69: 32, 1953. Louria, D. B., Stiff, D. P. and Bennett, B.: Disseminated moniliasis in the adult. Medicine, ,n: 307, 1962. Schonebeck, J., Winb!ad, B. and Ansehn, S.: Renal candidosis complicating caeco-cystoplasty. Case report with scanning electron microscopic studies. Scand. J. Urol. Nephrol., 6: 129, 1972. Ellis, C. A. and Spivack, M. L.: The significance of candidemia. Ann. Intern. Med., 67: 511, 1967. Isenberg, H. D., Pisano, M.A., Carito, S. L. and Berkman, J. I.: Factors leading to overt monilial disease. I. Preliminary studies of the ecological relationship between Candida albicans and intestinal bacteria. Antibiot. Chemother., lO: 353, 1960. Paine, T. F., Jr.: The inhibitory actions of bacteria on Candida growth. Antibiot. Chemother., 8: 273, 1958. Schonebeck, J. and Winblad, B.: Primary renal Candida infection. Scand. J, UroL Nephrol., 5: 281, 1971. Folb, P. I. and Trounce, J. R.: Immunological aspects of Candida infection complicating steroid and immunosuppressive drug therapy. Lancet, 2: 1112, 1970. Johnson, S. A. M.: Candida (monilia) albicans; effect of amino acids, glucose, pH, chlortetracycline (aureomycin), dibasic sodium and calcium phosphates, and anaerobic and aerobic conditions on its growth. Arch. Dermat. Syph., 70: 49, 1954. Schonebeck, J.: Asymptomatic candiduria. Prognosis, complications and some other clinical considerations. Scand. J. Urol. Nephrol., S: 136, 1972. Hodgin, U, G., Jr.: Cystitis due to Candida pseudotropicalis. A persistent case secondary to bladder calculus. Rocky Mt. Med. J., 66: 30, 1969. Lindquist, J. A., Rabinovich, S. and Smith, I. M.: 5-Fluorocytosine in the treatment of experimental candidiasis in immunosuppressed mice. Antimicrob. Agents Chemother., 4: 58, 1973. Haley, L. D.: Yeast infections of the lower urinary tract. I. In vitro studies of the tissue phase of Candida albicans. Sabouraudia, 4: 98, 1965. lvt · Candida infection of the urinary ttact. Case a revie~.v of the !_iteratu:re and a stud:v frequency

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of yeast isolations from the urine of children with bacterial urinary infections. Brit. J. Urol., 40: 293, 1968. Krause, W., Matheis, H. and Wulf, K.: Fungaemia and funguria after oral administration of Candida albicans. Lancet, 1: 598, 1969. Schonebeck, J., Andersson, L., Lingi!.rdh, G. and Winblad, B.: Ureteric obstruction caused by yeast-like fungi. Scand. J. Urol. Nephrol., 4: 171, 1970. Schonebeck, J. and Ansehn, S.: 5-Fluorocytosine resistance in Candida spp. and Torulopsis glabrata. Sabouraudia, 11: 10, 1973. Schone beck, J .: Studies on Candida infection of the urinary tract and on the antimycotic drug 5-fluorocytosine. Scand. J. Urol. Nephrol., suppl. vol. 11, p. 1, 1972. Tennant, F. S., Jr., Remmers, A. R., Jr. and Perry, J.E.: Primary renal candidiasis. Associated perinephric abscess and passage of fungus balls in the urine. Arch. Intern. Med., 122: 435, 1968. Lehner, T.: Systemic candidiasis and renal involvement. Lancet, l: 1414, 1964. Miraglia, G. J. and Renz, K. J.: Experimental urinary tract infections in rats caused by Candida albicans. Antimicrob. Agents Chemother., 3: 474, 1973. Adriano, S. M. and Schwarz, J.: Experimental moniliasis in mice. Amer. J. Path., 31: 859, 1955. Louria, D. B., Brayton, R. G. and Finkel, G.: Studies on the pathogenesis of experimental Candida albicans infections in mice. Sabouraudia, 2: 271, 1963. Hurley, R. and Winner, H. I.: Experimental renal moniliasis in a mouse. J. Path. Bact., 86: 75, 1963. Louria, D. B., Fallon, N. and Browne, H. G.: The influence of cortisone on experimental fungus infections in mice. J. Clin. Invest., 39: 1435, 1960. Dobias, B.: Moniliasis in pediatrics. Amer. J. Dis. Child., 94: 234, 1957. Salvin, S. B.: Endotoxin in pathogenic fungi. J. Immunol., 69: 89, 1952. Gip, L. and Molin, L.: On the inhibitory activity of human prostatic fluid on Candida albicans. Mykosen, 13: 61, 1970. Caroline, L., Taschdjian, C. L., Kozinn, P. J. and Schade, A. L.: Reversal of serum fungistasis by addition of iron. J. Invest. Dermatol., 42: 415, 1964. Lehrer, R. I. and Cline, M. J .: Interaction of Candida albicans with human leukocytes and serum. J. Bacteriol., 98: 996, 1969. Taylor, H. and Rundle, J. A.: Acute moniliasis of the urinary tract. Lancet, 1: 1236, 1952. Cohen, G. H.: Obstructive uropathy caused by ureteral candidiasis. J. Urol., 110: 285, 1973. O'Connell, C. J. and Hardner, G. J.: Thrush of urinary bladder due to Candida guilliermondii. N. Y. State J. Med., 73: 1685, 1973. Chisholm, E. R. and Hutch, J. A.: Fungus ball (Candida albicans) formation in the bladder. J. Urol., 86: 559, 1961. Gaines, J. D. and Remington, J. S.: Diagnosis of deep infection with Candida. A study of Candida precipitins. Arch. Intern. Med., 132: 699, 1973. Wise, G. J., Ray, B. and Kozinn, P. J.: The serodiagnosis of significant genitourinary candidiasis. J. Urol., 107: 1043, 1972. Taschdjian, C. L., Kozinn, P. J., Okas, A., Caroline, L. and Halle, M.A.: Serodiagnosis of systemic candidiasis. J. Infect. Dis., 117: 180, 1967. Goodman, L. S. and Gilman, A.: The Pharmacological Basis of Therapeutics, 5th ed. New York: Macmillan Publishing Co., Inc., p. 1237, 1975. Block, E. R., Bennett, J. E., Livoti, L. G., Klein, W. J., Jr., MacGregor, R.R. and Henderson, L.: Flucytosine and amphotericin B: hemodialysis effects on the plasma concentration and clearance. Studies in man. Ann. Intern. Med., 80: 613, 1974. Bennett, J.E.: Chemotherapy of systemic mycoses. New Engl. J. Med., 290: 30, 1974. Hellebusch, A. A., Salama, F. and Eadie, E.: The use of mannitol to reduce the nephrotoxicity of amphotericin B. Surg., Gynec. & Obst., 134: 241, 1972. McCurdy, D. K., Frederic, M. and Elkinton, J. R.: Renal tubular acidosis due to amphotericin B. New Engl. J. Med., 278: 124, 1968. Schonebeck, J., Polak, A., Fernex, M. and Scholer, H. J.: Pharmacokinetic studies on the oral antimycotic agent 5-fluorocytosine in individuals with normal and impaired kidney

function. Chemotherapy, 18: 321, 1973. 51. Holt, R. J. and Newman, R. L.: The antimycotic activity of 5-fluorocytosine. J. Clin. Path., 26: 167, 1973. 52. Shadomy, S.: In vitro studies with 5-fluorocytosine. Appl. Microbiol., 17: 871, 1969. 53. Bennett, J.E.: Chemotherapy of systemic mycoses. New Engl. J. Med., 290: 320, 1973. 54. Schonebeck, J. and Segerbrand, E.: Candida albicans septicaemia during first half of pregnancy successfully treated with 5-fluorocytosine. Brit. Med. J., 4: 377, 1973. 55. Titsworth, E. and Grunberg, E.: Chemotherapeutic activity of 5-fluorocytosine and amphotericin B against Candida albicans in mice. Antimicrob. Agents Chemother., 4: 306, 1973. 56. Medoff, G., Kobayashi, G. S., Kwan, C. N., Schlessinger, D. and Venkov, P.: Potentiation of rifampicin and 5-fluorocytosine as antifungal antibiotics by amphotericin B. Proc. Nat. Acad. Sci., 69: 196, 1972. 57. Rabinovich, S., Shaw, B. D., Bryant, T. and Donta, S. T.: Effect of 5-fluorocytosine and amphotericin B on Candida albicans infection in mice. J. Infect. Dis., 130: 28, 1974. 58. Melchior, J., Mebust, W. K. and Valk, W. L.: Ureteral colic from a fungus ball: unusual presentation of systemic aspergillosis. J. Urol., 108: 698, 1972. 59. Wise, G. J., Wainstein, S., Goldberg, P. and Kozinn, P. J.: Candida! cystitis. Management by continuous bladder irrigation with amphotericin B. J.A.M.A., 224: 1636, 1973. 60. Eilard, T., Alestig, K. and Wahlen, P.: Treatment of disseminated candidiasis with 5-fluorocytosine. J. Infect. Dis., 130: 155, 1974. 61. Salyer, W. R. and Salyer, D. C.: Involvement of the kidney and prostate in cryptococcosis. J. Urol., 109: 695, 1973. 62. Forbus, W. D. and Bestebreurtje, A. M.: Coccidioidomycosis: a study of 95 cases of the disseminated type with special reference to the pathogenesis of disease. Mil. Surg., 99: 653, 1946. 63. Conner, W. T., Drach, G. W. and Bucher, W. C., Jr.: Genitourinary aspects of disseminated coccidioidomycosis. J. Urol., 113: 82, 1975. 64. Warshawsky, A. B., Keiller, D. and Gittes, R. F.: Bilateral renal aspergillosis. J. Urol., 113: 8, 1975. 65. Comings, D. E., Turbow, B. A., Callahan, D. H. and Waldstein, S. S.: Obstructing Aspergillus cast of the renal pelvis. Report of a case in a patient having diabetes mellitus and Addison's disease. Arch. Intern. Med., 110: 255, 1962. 66. Langston, C., Roberts, D. A., Porter, G. A. and Bennett, W. M.: Renal phycomycosis. J. Urol., 109: 941, 1973. 67. Gilliam, J. S., Jr. and Vest, S. A.: Penicillin infection of the urinary tract. J. Urol., 65: 484, 1951. ADDITIONAL REFERENCES

BLOCK, E. R. and BENNETT, J.E.: The combined effect of 5-fluorocytosine and amphotericin B in the therapy of murine cryptococcosis. Proc. Soc. Exp. Biol. Med., 142: 476, 1973. BLOCK, E. R. and BENNETT, J. E.: Pharmacologic studies with 5-fluorocytosine. Antimicrob. Agents Chemother., 1: 476, 1972. BLUM, J. A.: Acute monilial pyohydronephrosis: report of a case successfully treated with amphotericin B continuous renal pelvis irrigation. J. Urol., 96: 614, 1966. BUTLER, W. T.: Pharmacology, toxicity, and therapeutic usefulness of amphotericin B. J.A.M.A., 195: 371, 1966. DAVIES, R.R. and SAVAGE, M.A.: Observations on 5-fluorocytosine and Candida albicans. Sabouraudia, 12: 302, 1974. GERLE, R. D.: Roentgenographic features of primary renal candidiasis. Fungus ball of the renal pelvis and ureter. Amer. J. Roentgen., 119: 731, 1973. HARBACH, L. B., BURKHOLDER, G. V. and GOODWIN, W. E.: Renal candidiasis. A cause of anuria. Brit. J. Urol., 42: 258, 1970. HoEPRICH, P. D., INGRAHAM, J. L., KLEKER, E. and WINSHIP, M. J.: Development of resistance to 5-fluorocytosine in Candida parapsilosis during therapy. J. Infect. Dis., 130: 112, 1974. KNEPSHIELD, J. H., FELLER, H. A. and LEB, D. E.: Papillary necrosis due to Candida albicans in a renal allograft. Arch. Intern. Med., 122: 441, 1968. MARKS, M. I., LANGSTON, C. and EICKHOFF, T. C.: Torulopsis glabrata-an opportunistic pathogen in man. New Engl. J. Med., 283: 1131, 1970. MEDOFF, G., COMFORT, M. and KOBAYASHI, G. S.: Synergistic action of amphotericin Band 5-fluorocytosine against yeast-like organisms. Proc. Soc. Exp. Biol. Med., 138: 571, 1971.

GENITOURINARY FUNGAL INFECTIONS

NoRMARK, S. and ScHONEBECK, J.: In vitro studies of 5-fluorocytosine resistance in Candida albicans and Torulopsis glabrata. Antimicrob. Agents Chemother., 2: 114, 1972. RIFKIND, D., MARCHIORO, T. L., SCHNECK, S. A. and HILL, R. B.: Systemic fungal infections complicating renal transplantation and immunosuppressive therapy. Clinical, microbiologic, neurologic and pathologic features. Amer. J. Med., 43: 28, 1967. ScHONEBECK, J ., STEEN, L. and TARNVIK, A.: 5-Fluorocytosine treatment of Candida infections of the urinary tract and other sites. Scand. J. Urol. Nephrol., 6: 37, 1972.

397

SPELLER, D. C.: Torulopsis glabrata urinary tract infection treated with 5-fluorocytosine. J. Clin. Path., 27: 50, 1974. WISE, G. J., WAINSTEIN, S., GOLDBERG, P. and KozINN, P. J.: Flucytosine in urinary Candida infections. Urology, 3: 708, 1974. YOUNG, R. C., BENNETT, J. E., GEELHOED, G. W. and LEVINE, A. S.: Fungemia with compromised host resistance. A study of 70 cases. Ann. Intern. Med., 80: 605, 1974. ZINCKE, H., FURLOW, W. L. and FARROW, G. M.: Candida albicans cystitis: report of a case with special emphasis on diagnosis and treatment. J. Urol., 109: 612, 1973.