Disseminated candidosis

IIDNI Volume 4, Number 11, ~o~,d~er t1985 _, ,ARY

Editor

Bos oI',.,

Paul D. Hoeprich, ~ o

i 8 ~',,!OV 1985

Division of Infectious and Immunologic Diseases University of California, Davis Medical Center

Associate Editors R u t h M. Lawrence, MD

Larry K. Pickering, MD

Charles W. Stratton, MD

Di,Asion of Infectious Diseases Texas Tech University Health Sciences Center

Program in Infectious Diseases and Clinical Microbiology The University of Texas Medical School at Houston

Department of Pathology Vanderbilt University Medical Center

Disseminated Candidosis J o h n E. E d w a r d s , Jr., MD Disseminated Candidosis John E. Edwards, Jr.

Department of Medicine, ttarbor-UCLA Medical Center, Torrance, California

81

Polysaccharide Vaccines against Haemophilus

influenzae, Neisseria meningitidis, and Streptococcus pneumoniae

84

Larry K. Picketing and E. Stephen Buescher COMMENTS ON CURRENT PUBLICATIONS Paul D. H o e p r i c h

Elsevier 0278-2316/85/$0.00 + 2.20

87

Severe candidal infections, previously rare, have become common problems in medical practices associated with advanced technology for life support. Candidal infections localized to specific organs have increased in both frequency and severity, paralleling an increase in hematogenously disseminated candidosis. Patients are more susceptible to invasive candidal infections if they have malignancies; have protracted postoperative courses; receive immunosuppressive therapy following organ transplantation; are neonates with low birth weight; have sustained extensive bums; are addicted to heroin; or have AIDS, AIDS-related complex, or lymphadenopathy syndrome. Several measures frequently used in caring for these patients are conducive to invasive candidosis: plastic catheters for intravenous access, cytotoxic chemotherapeutic agents, multiple broad-spectrum antimicrobics, plas-

tic prosthetic materials, glucosteroids in pharmacologic doses, and hyperalimentation fluids. The combination of factors operative in the development of severe local and widespread disseminated disease is generalized immunosuppression of both phagocytic and lymphocytic cells in parallel with overgrowth of Candida spp. in anatomical sites where the normal bacterial flora competes with the fungal organisms. It must be emphasized that disseminated candidosis is not a disease unique to patients undergoing treatment for malignancy; approximately half the patients are in other categories, such as postoperative patients or low-birth-weight neonates. Candidal infections are not reportable to the Centers for Disease Control. However, the change in the magnitude of problems related to candidal infections is exemplified by the increase in the number of articles on the subject in htdex Medicus,

ISSN 0278-2316

IDINDN 4(11)81-88, 1985

82 Infectious Diseases Newsletter 4(11) November 1985 from fewer than 20 in 1942 to the current listing of over 400 articles per year. In disseminated candidosis, the route through which the organism enters the bloodstream is not completely defined; it is most likely either along plastic catheters that penetrate into the intravascular compartment, or through mucosal sites (usually gastrointestinal mucosa), where a heavy burden of organisms develops under appropriate conditions. Once within the intravascular compartment, the organism may seed virtually any organ and establish foci of infection, most commonly as multiple microabscesses or small macroabscesses. The organs most frequently involved (not in order) are the kidney, brain, heart, eye, bone, skin, liver, spleen, lungs, and skeletal muscle. Once these organs are infected, the following evidence of their involvement may be found: kidney--renal failure, candiduria (not related to catheterization); brain--cerebral dysfunction, neurological signs of a mass lesion, meningitis; eye--loss of vision, pain, lesions typical for hematogenous candidal endophthalmi° tis (HCE); heart--cardiac failure due to diffuse myocarditis, arrhythmias due to conduction bundle abscesses; bone--severe pain, vertebral destruction with neurologic sequelae, arthritis; skin-classic macronodular skin lesions of disseminated candidosis, ecthyma gangrenosum (rare); liver--abdominal pain, biliary duct obstruction; spleen--abscess formation; lungs-severe diffuse pneumonia (usually diagnosed at autopsy); skeletal muscle--severe pain. Diagnosis of Disseminated Candidosis Unfortunately, the majority of patients with hematogenously disseminated candidosis are not diagnosed until autopsy. Two important fac-

tors are partially responsible for the diagnostic difficulty: blood cultures are an insensitive method for diagnosing disseminated disease (about half the patients who die with disseminated candidosis have had positive blood cultures), and there is no readily available serodiagnostic method that has an acceptably small number of false negatives. An additional factor, less of a problem in recent years, is the interpretation of positive blood cultures for candida as due to either skin contaminants or simple, catheter-associated, spontaneously resolving candidemia. Because of the absence of reliable laboratory methods, successful diagnosis is dependent upon skillful clinical assessment of predisposed patients. Implicit in the concept of "skillful clinical assessment" is the recognition of the combination of iatrogenic and demographic factors that results in predisposition. Whereas it has been known for years that patients with hematological malignancies and burns are at risk, the recognition that postoperative patients (without malignancy), transplant recipients, and very-lowweight neonates are important risk groups was pivotal in broadening the patient base for surveillance. Once the diagnosis of disseminated candidosis is considered, successful diagnosis in time to initiate appropriate treatment depends predominantly upon the clinical skills of the primary physician in examining the patient repetitively for evidence of hematogenous involvement of target organs. Finding a macronodular skin lesion and obtaining biopsy and cultural proof of a candidal etiology establishes the diagnosis of disseminated candidosis. Similarly, the presence of an ocular lesion consistent with hematogenous candidal endophthalmitis, in the proper setting, allows a diagnosis of disseminated disease because the incidence © 1985 Elsevier Science Publishing Co., Inc. 0278-2316/85/$0.00+ 2.20

of other organ involvement is so high. Repeated examinations for bone pain with appropriate radiographic examinations and bone or joint aspiration may disclose underlying hematogenous osteomyelitis a n d / o r arthritis. Periodic evaluation of the urine for candiduria (in the noncatheterized patient) and monitoring of renal function may assist in diagnosing hematogenous renal disease. Biopsy of painful muscle groups, especially in neutropenic patients, may disclose candidal microabscesses and again facilitate establishing the diagnosis of hematogenously disseminated disease. In patients with right-upper-quadrant tenderness, a CT scan may disclose abscesses that can be aspirated percutaneously and cultured for Candida spp. Additionally, detection and appropriate evaluation of cerebral or myocardial dysfunction may disclose underlying candidal infection. Laboratory Diagnosis In patients predisposed to disseminated candidosis, any elevation in temperature requires evaluation with blood cultures. The minimal volume for culture is 10 ml. The use of vented bottles to increase the oxygen tension improves the probability of recovering Candidu spp. Recently, interest has focused on a lysiscentrifugation technique of culturing blood for both bacteria and fungi. The cellular elements of the blood are lysed, and the precipitate collected by centrifugation is plated on solid media. Presently, it is the method by which fungal organisms are recovered most rapidly. Two significant problems exist with blood cultures. First, there is only a 50% rate of recovery in patients with disseminated candidosis. This figure, extracted from retrospective studies, would likely be somewhat higher in prospective studies wherein patients at risk were

83 Infectious Diseases Newsletter4(11) November 1985 cultured frequently on a serial basis. Second, when a positive blood culture is obtained in a patient with an indwelling intravascular plastic line, usually the line is removed. Removal of the line is frequently followed by resolution of the candidemia. However, resolution of the candidemia is not a guarantee of the absence of disseminated candidosis. This situation reflects again the high rate of false-negative blood cultures in disseminated candidosis. When positive blood cultures for Candida albicans are obtained, whether or not they are associated with indwelling lines, they should be considered indicative of disseminated candidosis until proven otherwise. Repeated blood cultures and serial examination for the manifestations of disseminated candidosis (see above) should be undertaken with frequent and methodical reevaluation. All patients with documented C. albicans candidemia who are neutropenic should be started on antifungal therapy while undergoing evaluation for disseminated disease. Other patients in whom the diagnosis of disseminated disease is even remotely possible should also be started on antifungal chemotherapy. It is exceptionally dangerous to conclude that a positive blood culture for Candida spp. represents either skin or laboratory contamination, or is related to an indwelling line and will clear without sequelae. Therefore, the majority of patients with Candida spp. in blood cultures should receive antifungal treatment, and only a small percentage should be selected for observation without chemotherapy. Of additional concern regarding the withholding of chemotherapy from patients with candidemia has been a group of patients with no evidence of disseminated disease at the time of positive blood cultures, who return weeks to months later with an active focus of infection, usually in the eye

or kidney and occasionally on the cardiac valves. The precise frequency of this occurrence has not been defined, but its recognition stimulates even further caution in withholding therapy in candidemic patients. Serodiagnostic Techniques Considerable investigation has been directed toward the development of serodiagnostic tests for disseminated candidosis. Two related major problems have persistently detracted from the success of these tests. One has been the inability of the test to discriminate between simple colonization with Candida spp. and true tissue invasion. The other has been a high incidence of false negatives. Most investigators have concentrated on antigen detection systems in recent years. A partial list of antigens for which detection systems have been used includes mannan, a heat-labile antigen, D-mannose, arabinitol, and o-arabinitol. None of the tests for these antigens, with the exception of the latex-particle agglutination test for a heat-labile candidal antigen, are commercially available on a widespread basis; the efficacy of the commercial latex-particle test awaits more extensive evaluations. Since there is no single laboratory test that can be used to diagnose or rule out disseminated candidosis, making the correct diagnosis is dependent upon correct interpretation of the composite of both the clinical and laboratory findings, with the knowledge that there is generally a high incidence of false negatives from both serodiagnostic and blood-culturing methodologies. Treatment of Disseminated Candidosis Removal of as many of the predisposing factors for disseminated candidosis as possible, within the confines of the clinical situation, is © 1985 Elsevier Science Publishing Co., Inc. 0278-2316/85/$0.00+ 2.20

central to successful treatment. Of the anticandidal antimicrobics, amphotericin B remains the first choice. Rapidly advancing the drug to doses of 1 mg/kg body weight per day is necessary to achieve therapeutic levels as quickly as possible. The rapidity of the advancement is tailored to patient tolerance. After several days (approximately a week) of 1 mg/kg daily dose, reduction of the dose to approximately 0.5 m g / k g / d a y will generally diminish renal toxicity. A minimum of 500 mg total should be given, preferably 1-1.5 g. In life-threatening situations where achievement of therapeutic antifungal levels is paramount, 5-fluorocytosine (5-FC) should be added to the amphotericin B at a dose of 150 m g / k g / d a y (adjusted if renal failure is present). The combination of amphotericin B and 5-FC is highly toxic, predominantly to bone marrow, and monitoring for toxicity should be done routinely in conjunction with measuring 5-FC in the blood. If evidence of bone marrow suppression develops, the dose of the 5-FC should be reduced. The role of other agents in the management of disseminated candidosis is incompletely defined because of the lack of substantive data regarding efficacy. Whereas ketoconazole is active against most Candida spp., it is not readily available in an intravenous form. Miconazole can be'given intravenously, but it is a second-line alternative compared with amphotericin B. Generally these agents are considered when renal failure virtually precludes the use of amphotericin B and 5-FC. Other, experimental compounds are undergoing evaluation.

Summary Candidal infections of all forms are increasing impressively in severity and frequency. The diagnosis of disseminated candidosis remains dif-

84 Infectious Diseases Newsletter 4(11) November 1985 ficult and is best made on the basis of combined careful clinical and laboratory evaluation of the patient. The threshold for administering amphotericin B to patients with candidemia is decreasing precipitously. Amphotericin B remains the therapeutic agent of first choice.

Bibliography Bailey JW, Sada E, Brass C, Bennett JE: Diagnosis of systemic candidiasis by latex agglutination for serum antigen. J Clin Microbiol 21:749-752, 1985. Bodey GP: Candidiasis in cancer patients. Am J Med 77:13-19, 1984. de Repentigny L, Reiss E: Current trends in immunodiagnosis of

candidiasis and aspergillosis. Rev Infect Dis 6:301-312, 1984. Edwards JE Jr: Candida species, in Mandel GL, Douglas RG Jr, Bennett JE (eds): Principles and practice of infectious diseases. New York, John Wiley, 1984. Edwards JE Jr: Candida endophthalmitis. In Bodey GP, Fainstein V (eds): Candidiasis. New York, Raven Press, 1985, p. 211. Epstein JB, Truelove EL, Izutau KT: Oral candidiasis: pathogenesis and host defenses. Rev Infect Dis 6:96-106, 1984. Faix RG: Systemic eandida infections in infants in intensive care nurseries: high incidence of central nervous system involvement. J Pediatr 105:616-622, 1984.

Polysaccharide Vaccines against Haemophilus influenzae, Neisseria meningitidis, and

Streptococcus pneumoniae Larry K. Pickering and E. Stephen Buescher

Program in Infectious Diseases and Clinical Immunology, University of Texas Medical School at Houston, Houston, Texas

Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae are common causes of morbidity and mortality in children and adults throughout the world. In the United States, 81% of the cases of bacterial meningitis reported to the Centers for Disease Control from 1978 to 1981 were caused by these microorganisms. Almost all influenzal and pneumococcal meningitis was caused by strains represented in vaccines; however, 50% of the cases of meningococcal meningitis were

caused by group B N. meningitidis, a serogroup that is not in any vaccine. When used appropriately, the polysaccharide vaccines induce humoral immunity, decreasing both morbidity and mortality.

Available Polysaccharide Vaccines Polysaccharide vaccines against H. influenzae type b (b Capsa I), N. meningitidis serogroups A, C, Y, and W-135 ( M e n o m u n e - A / C / Y /

Table 1. Organisms and Serovars Included in Polysaccharide Vaccines Organism Known serovars

Haemophilus it~uenzae Neisseria meningitidis Streptococcus pneumoniae

Nontypable, a, b, c, d, e, f A, B, C, Y, W-135, X, Z, 29-e, L 83 serotypes

Hughes WI: Systemic candidiasis: a study of 109 fatal cases. Pediatr Infect Dis 1:11, 1982. Lipton SA, Hickey WF, Morris JH, Loscalzo J: Candidal infection of the central nervous system. Am J Med 76:101-108, 1984. Odds FC: Candida and candidosis. Baltimore, University Park Press, 1979. Rippon JW: Candidiasis and the pathogenic yeasts, in Rippon JW (ed): Medical mycology. The pathogenic fungi and the pathogenic actinomycetes. Philadelphia: WB Saunders, 1982. Solomkin JS, Flolm AM, Simmons RL: Indications for therapy for fungemia in postoperative patients. Arch Surg 117:1272, 1982.

W-135), and 23 types of S. pneumoniae (Pneumovax 23, Pnu-Immune 23) are licensed for use in the United States (Table 1). The H. influenzae type b vaccine contains 25 /tg of capsular polysaccharide (polyribosyl phosphate) per dose. The meningococcal vaccine consists of 50/~g each of the respective purified capsular polysaccharides per dose, and the pneumococcal vaccine contains 25 /~g of each of the 23 constituent polysaccharide antigens per dose.

Effectiveness of the Vaccines In general, antibody responses to polysaccharide vaccines in humans are age dependent, relatively shortlived, and nonboostable. Development of antibodies to the antigens in all three polysaccharide vaccines correlates with protection against

Serovars included in vaccine

b A, C, Y, W-135 1-5, 8, 9, 12, 14, 17, 19, 20, 22, 23, 26, 34, 43, 51, 54, 56, 57, 68, 70

© 1985 ElsevierSciencePublishingCo., Inc. 0278-2316/85/$0.00 + 2.20