903
AIDS COMMENTARY
Cryptosporidiosis in Patients Infected with the Human Immunodeficiency Virus Carolyn Petersen
From the Parasitology Laboratory and the Department ofMedicine, San Francisco General Hospital and the University of California, San Francisco, California
-Merle A. Sande
Recognition ofcryptosporidiosis as a common infection of the gastrointestinal tract in humans accompanied the unfolding of the AIDS epidemic, as the majority ofindividuals with serious, persistent cryptosporidiosis are infected with the human immunodeficiency virus (HIV). In 1982 the Centers for Disease Control (Atlanta) described outbreaks of cryptosporidial diarrhea in 21 patients with AIDS [I] and, in a separate report, in 12 immunocompetent hosts who had acquired their disease from infected calves [2]. Disease in all hosts was characterized by watery diarrhea; immunocompetent hosts cleared their infection in < I month, but immunocompromised hosts went on to develop unrelenting diarrhea. Immunocompetent hosts were found to be at risk if they were exposed to contaminated water or infected animals and humans. Outbreaks were reported among veterinary personnel, travelers, health care workers, and day care center staff and children. High rates of recovery ofCryptosporidium from patients with diarrhea worldwide, coupled with seroprevalence rates of 25%-35% in the United States and 64% in South America, suggest that cryptosporidium infections are very common among healthy persons [3]. In 1983 chronic cryptosporidiosis was designated as one of the AIDS-defining opportunistic infections in HI V-infected persons [4]. Over subsequent years it has been estimated that 10%-15% of patients with AIDS in the United States and as many as 30%-
Received 25 August 1992. Reprints or correspondence: Dr. Carolyn Petersen, Campus Box 1204, Laurel Heights 150. University ofCalifornia. San Francisco. Third and Parnassus Avenues. San Francisco. California 94143.
Clinical Infectious Diseases 1992;15:903-9 © 1992 by The University of Chicago. All rights reserved.
1058-4838/92/1506-000 I$02.00
50% in the developing world have developed chronic cryptosporidiosis [5, 6]. Considerable variability in the clinical course of cryptosporidiosis in HIV -infected hosts has been described. Some patients develop cryptosporidium infection that resolves spontaneously [7], others experience improvement with the initiation of zidovudine therapy [8, 9], and still others go on to have severe and unremitting diarrhea [10]. A recent retrospective review by Flanigan and colleagues [II] of the charts of 47 HIV-seropositive patients with cryptosporidiosis indicated that all patients with CD4 cell counts of> 180 cells/ mrrr' (n = 8) cleared the infection spontaneously within 7 days to I month of its diagnosis without receiving antiretroviral therapy. In addition, five patients (13%) with lower CD4 cell counts, including one with a CD4 cell count of 14/mm 3 , also cleared cryptosporidium infection. Four of the five patients with low CD4 cell counts and self-limited disease began receiving zidovudine at the time of diagnosis of cryptosporidiosis; however, their CD4 cell counts did not rise significantly, a circumstance suggesting that a factor or factors other than the number of CD4 cells may have been responsible for their recovery.
Clinical Disease Infection of healthy hosts with Cryptosporidium occurs when the environmentally resistant oocyst is ingested and excysts in the small bowel; four motile, elongated sporozoites are released that invade the epithelial cells of the small bowel. They develop into eight merozoites that are sequestered in a parasitophorous vacuole in the apex of the cell in a position that has been described as intracellular but extracytoplasmic. Merozoites rupture the cell and rein vade adjacent
Downloaded from http://cid.oxfordjournals.org/ at Michigan State University on February 25, 2015
Infection caused by Cryptosporidium species has proved to be one of the most taxing and frustrating conditions faced by clinicians caring for patients with AIDS. Unfortunately, this unique organism, which was identified as a human pathogen only shortly before the AIDS epidemic began to manifest itself, has received only minimal attention during the past decade. Dr. Carolyn Petersen, an assistant professor of medicine at the University of California, San Francisco, and a member of the Division of Infectious Diseases at San Francisco General Hospital, is a molecular parasitologist whose investigative career is focused on elucidating the biology of Cryptosporidium species. In this AIDS Commentary Dr. Petersen provides an update on recent developments in this field.
904
Petersen
has been modified acid-fast staining offeces (either fresh samples or samples fixed with formaldehyde or sodium acetateacetic acid-formalin). Acid-fast-stained oocysts stain red, and fecal debris and yeasts stain blue or green, depending on the counterstain. In most clinical laboratories routine examination for ova and parasites is not designed to detect Cryptosporidium; thus, examination for this organism must be separately requested. A monoclonal antibody to the oocyst wall (Merifluor, Meridian Diagnostics, Cincinnati) and an ELISA with a soluble Cryptosporidium-specific antigen (ProSpecT, Cryptosporidium microtiter assay~ Alexon, Sunnyvale, CA) have become commercially available but have not been used extensively for diagnosis. The differential diagnosis of cryptosporidiosis for HIV-infected persons includes infection due to other gastrointestinal pathogens such as CMV, Mycobacterium avium complex (MAC), Microsporidium, Isospora, Shigella, Salmonella, Campylobacter, Clostridium difficile, Giardia, and Entamoeba. Although infections due to most of these pathogens can be diagnosed with suitable cultures, stool examinations, or assays, several are still difficult to diagnose. Infection with CMV or MAC may be suggested by the presence of abdominal pain and fever, but endoscopy and biopsy may be necessary to establish the diagnosis. Diagnosis of microsporidium infection usually requires biopsy and visualization with use of electron microscopy, although several centers have reported the development of improved light microscopic techniques for examination of stools [18].
What Methods of Treatment Have Been Tried? Nonspecific treatment of established cryptosporidiosis is empiric and depends on the judicious use of antidiarrheal agents (opiates, diphenoxylate, and loperamide), nutritional management, and administration offluids. Central or peripheral parenteral nutrition is most effective when initiated before the patient has lost a large amount of weight. Specific chemotherapy has thus far not been shown to be efficacious, although a large number of drugs-more than 90-have been tried. Perhaps the most promising treatment modality under investigation is the passive oral transfer of protective antibody in hyperimmune bovine colostrum (HBC), which has led to marked abatement of symptoms in some cases ofsevere cryptosporidiosis in immunocompromised patients [19-21] and in animals. The Cryptosporidium antigens that are the targets of protective antibody in HBC have not been identified. A three-center, double-blind crossover study ofthe efficacyofa concentrated immunoglobulin preparation prepared with HBC for treatment of AIDS patients with protracted cryptosporidiosis has been approved by the U.S. Food and Drug Administration. A wide variety of drugs, including antiparasitic drugs like quinine, chloroquine, difluoromethylornithine, pyrimetha-
Downloaded from http://cid.oxfordjournals.org/ at Michigan State University on February 25, 2015
cells to repeat the cycle. A sexual cycle culminating with the development of sporulated oocysts that can excyst and release invasive sporozoites or be shed into the environment also occurs. In patients with AIDS, infection of the small bowel predominates, but all sites of the gastrointestinal tract (including the esophagus, stomach, colon, and rectum) have been involved. Diarrhea may be watery and often cholera-like; the stool volume of patients with AIDS may reach 17 Lid [1]. However, less fulminant diarrhea is common. Blood or white blood cells are not seen in the stool of patients with cryptosporidiosis, but mucus may be. Crampy abdominal pain is common, as are fatigue, anorexia, nausea, and vomiting. These symptoms may lead to severe malnutrition and dehydration. Fever may be present but is difficult to ascribe to cryptosporidiosis in severely immunocompromised persons, who frequently have other infections. Cryptosporidiosis of the extrahepatic bile ducts may result in acalculous biliary disease, which has been estimated to occur in 10% of AIDS patients with cryptosporidiosis [12]. The true incidence, however, is unknown as patients usually do not undergo the invasive procedures needed for confirmation of the diagnosis. Results of ultrasonography and computed tomography are notable for demonstration of biliary duct dilatation and thickening of the wall as well as abnormalities of the gall bladder. Cholangiograms often show features suggestive of sclerosing cholangitis, intrahepatic strictures with irregular, beaded dilatation of ducts, and dilatation of the common bile duct with or without papillary stenosis [13]. The alkaline phosphatase level is usually elevated. Diagnosis requires examination of tissue or bile for Cryptosporidium. The value of papillotomy is controversial [13, 14] except when an obstruction due to papillary stenosis is noted. Although involvement of the respiratory epithelium ofpatients with AIDS who have cryptosporidiosis has been reported, the clinical significance ofthis finding is unclear [15]. Cough, shortness of breath, and wheezing have been noted in such patients, who usually have concomitant respiratory infections due to Pneumocystis carinii or cytomegalovirus (CMV). The diagnosis ofcryptosporidiosis has been made by the finding of oocysts in sputum, tracheal aspirates, bronchoalveolar lavage fluid, or lung tissue. One report indicates that four HIV-seropositive persons had no other pulmonary pathogens but Cryptosporidium [16]. Of this small group, all patients were alive 9 months after diagnosis. Although the condition has not been reported in patients with AIDS, recurrent sinusitis due to Cryptosporidium has been noted in a hypogammaglobulinemic patient who had prolonged intestinal cryptosporidiosis [17]. Dissemination of cryptosporidiosis outside the villous epithelium of the gastrointestinal tract and the contiguous respiratory epithelium does not appear to occur. The mainstay of diagnosis of cryptosporidium infection
CID 1992; 15 (December)
ClD 1992; 15 (December)
HIV Infection and Cryptosporidiosis
with AIDS, but the results ofa prospective, multicenter clinical trial showed that it was not [27]. Recently, lytic proteins that form ionic channels in the membranes of cells have been found in the guts of pigs and mice. It has been postulated that the function of lytic peptides in the gut might be to defend the intestinal tract against microbes. Lytic peptides have been shown to be anticryptosporidial in vitro, but studies to determine whether they are toxic in animals have not been concluded [28].
What Other Measures Need To Be Addressed with Regard to Patients? Cryptosporidiosis in HIV-infected persons has not been studied in a prospective manner; thus, many epidemiological parameters have not been defined. The source of infection and mode of spread among persons with AIDS as well as factors that protect individuals from or predispose them to infection are not known. However, our current information allows us to make some recommendations. Cryptosporidium appears not to have species specificity among mammals and appears to preferentially infect the young of all species. Domestic pets might constitute a reservoir from which immunocompromised hosts are likely to become infected [29]. It is also possible that Cryptosporidium is acquired from contaminated water or from other persons. In any case, two attributes of Cryptosporidium render it especially infectious. First, oocysts are very resistant in the environment and are shed fully sporulated and infectious. Disinfectants that are usually employed to clean household or hospital surfaces are not effective in neutralizing oocysts. Chlorination and ozonation procedures used to eradicate waterborne organisms do not kill Cryptosporidium [30]. Second, the ID 90 for Cryptosporidium appears to be very low; although there are no figures for adult humans, studies of cryptosporidiosis in immunocompetent infant macaques suggest that the ID 90 for these animals is between 10 and 100 oocysts [31]. It appears that the highly infectious nature of Cryptosporidium and the ubiquity of its reservoirs account for primary disease in patients with AIDS; however, we do not know if there is a latent state from which patients relapse, as is the case for infection due to Pneumocystis and Toxoplasma [32].
The risk of transmission of cryptosporidiosis to other persons in the hospital, especially in wards dedicated to the care of patients with AIDS, has not been determined. Outbreaks of cryptosporidiosis among immunocompetent health care workers [33] exposed to patients with cryptosporidium infection suggest that this risk may be substantial. Body-substance handling precautions, with particular emphasis on enteric precautions, should be observed for all institutionalized patients with cryptosporidiosis. As DNA and antibody probes become available, it will be possible to define the epidemiol-
Downloaded from http://cid.oxfordjournals.org/ at Michigan State University on February 25, 2015
mine, and trimethoprim-sulfamethoxazole, have been tried unsuccessfully for treatment of cryptosporidiosis. It is unclear whether the refractoriness ofcryptosporidium infection to a given chemotherapeutic agent useful for treatment of other parasitic diseases is due to a block in delivery of the drug to the intracellular, extracytoplasmic form of the parasite, to structural variation of the drug's molecular target, or to unusual metabolic pathways that circumvent the drug's effect. The first drug believed to be effective for treatment of cryptosporidiosis was spiramycin, a macrolide antibiotic used to treat toxoplasmosis in pregnant women in Europe. In spite of early promising reports, neither oral spiramycin nor intravenous spiramycin, tested in a later trial, has proven efficacious (unpublished data, R. Soave). Recently, three other macrolide antibiotics (azithromycin, clarithromycin, and roxithromycin) have become available. Azithromycin has been reported to be effective as suppressive therapy for cryptosporidiosis in steroid-immunosuppressed rodents [22, 23]. A double-blind, placebo-controlled trial of azithromycin in outpatients with AIDS is under way at four centers (in New York, San Francisco, San Diego, and Memphis). Preliminary information suggests that this drug may be effective in some patients (unpublished observation, R. Soave). The drug is available from the manufacturer for use with approval from the Institutional Review Board. Initial, encouraging results of studies of an investigational antimalarial drug, 566C80, used in animals with cryptosporidiosis have not been reproducible [24]. Diclazuril, a static drug for treatment of infection with Eimeria (an apicocomplexan parasite that invades the gut epithelial cells of animals) was shown to be ineffective in human cryptosporidiosis in a small controlled trial, possibly because of inadequate levels of the agent in blood. Letrazuril, a congener ofdiclazuril with four times greater bioavailability than the latter agent, is currently undergoing ACTGsponsored clinical trials in multiple centers (personal communication, R. Soave). Paromomycin, a nonabsorbable aminoglycoside, is an effective luminal agent for Entamoeba histolytica infection. Several abstracts suggest that paromomycin may be effective against cryptosporidiosis in vivo and in vitro. The ACTG is about to open a multicenter, doubleblind, placebo-controlled trial of paromomycin. However, results of uncontrolled studies with patients at San Francisco General Hospital do not indicate that paromomycin is effective against cryptosporidiosis in vivo and in vitro [25, 26]. In the presence ofintestinal damage, a large amount ofparomomycin may be absorbed, leading to nephrotoxicity. Octreotide, a synthetic cyclic octapeptide analog of somatostatin, has been reported to be effective in the treatment of secretory diarrhea ofendocrine origin and in the control of the secretory diarrhea of some patients with AIDS. Initial studies suggested that octreotide might be useful in treating the diarrhea associated with cryptosporidiosis in patients
905
906
Petersen
ogy of this disease both in the community and in the hospital. It appears prudent to advise persons with
AIDS COMMENTARY
Cryptosporidiosis in Patients Infected with the Human Immunodeficiency Virus Carolyn Petersen
From the Parasitology Laboratory and the Department ofMedicine, San Francisco General Hospital and the University of California, San Francisco, California
-Merle A. Sande
Recognition ofcryptosporidiosis as a common infection of the gastrointestinal tract in humans accompanied the unfolding of the AIDS epidemic, as the majority ofindividuals with serious, persistent cryptosporidiosis are infected with the human immunodeficiency virus (HIV). In 1982 the Centers for Disease Control (Atlanta) described outbreaks of cryptosporidial diarrhea in 21 patients with AIDS [I] and, in a separate report, in 12 immunocompetent hosts who had acquired their disease from infected calves [2]. Disease in all hosts was characterized by watery diarrhea; immunocompetent hosts cleared their infection in < I month, but immunocompromised hosts went on to develop unrelenting diarrhea. Immunocompetent hosts were found to be at risk if they were exposed to contaminated water or infected animals and humans. Outbreaks were reported among veterinary personnel, travelers, health care workers, and day care center staff and children. High rates of recovery ofCryptosporidium from patients with diarrhea worldwide, coupled with seroprevalence rates of 25%-35% in the United States and 64% in South America, suggest that cryptosporidium infections are very common among healthy persons [3]. In 1983 chronic cryptosporidiosis was designated as one of the AIDS-defining opportunistic infections in HI V-infected persons [4]. Over subsequent years it has been estimated that 10%-15% of patients with AIDS in the United States and as many as 30%-
Received 25 August 1992. Reprints or correspondence: Dr. Carolyn Petersen, Campus Box 1204, Laurel Heights 150. University ofCalifornia. San Francisco. Third and Parnassus Avenues. San Francisco. California 94143.
Clinical Infectious Diseases 1992;15:903-9 © 1992 by The University of Chicago. All rights reserved.
1058-4838/92/1506-000 I$02.00
50% in the developing world have developed chronic cryptosporidiosis [5, 6]. Considerable variability in the clinical course of cryptosporidiosis in HIV -infected hosts has been described. Some patients develop cryptosporidium infection that resolves spontaneously [7], others experience improvement with the initiation of zidovudine therapy [8, 9], and still others go on to have severe and unremitting diarrhea [10]. A recent retrospective review by Flanigan and colleagues [II] of the charts of 47 HIV-seropositive patients with cryptosporidiosis indicated that all patients with CD4 cell counts of> 180 cells/ mrrr' (n = 8) cleared the infection spontaneously within 7 days to I month of its diagnosis without receiving antiretroviral therapy. In addition, five patients (13%) with lower CD4 cell counts, including one with a CD4 cell count of 14/mm 3 , also cleared cryptosporidium infection. Four of the five patients with low CD4 cell counts and self-limited disease began receiving zidovudine at the time of diagnosis of cryptosporidiosis; however, their CD4 cell counts did not rise significantly, a circumstance suggesting that a factor or factors other than the number of CD4 cells may have been responsible for their recovery.
Clinical Disease Infection of healthy hosts with Cryptosporidium occurs when the environmentally resistant oocyst is ingested and excysts in the small bowel; four motile, elongated sporozoites are released that invade the epithelial cells of the small bowel. They develop into eight merozoites that are sequestered in a parasitophorous vacuole in the apex of the cell in a position that has been described as intracellular but extracytoplasmic. Merozoites rupture the cell and rein vade adjacent
Downloaded from http://cid.oxfordjournals.org/ at Michigan State University on February 25, 2015
Infection caused by Cryptosporidium species has proved to be one of the most taxing and frustrating conditions faced by clinicians caring for patients with AIDS. Unfortunately, this unique organism, which was identified as a human pathogen only shortly before the AIDS epidemic began to manifest itself, has received only minimal attention during the past decade. Dr. Carolyn Petersen, an assistant professor of medicine at the University of California, San Francisco, and a member of the Division of Infectious Diseases at San Francisco General Hospital, is a molecular parasitologist whose investigative career is focused on elucidating the biology of Cryptosporidium species. In this AIDS Commentary Dr. Petersen provides an update on recent developments in this field.
904
Petersen
has been modified acid-fast staining offeces (either fresh samples or samples fixed with formaldehyde or sodium acetateacetic acid-formalin). Acid-fast-stained oocysts stain red, and fecal debris and yeasts stain blue or green, depending on the counterstain. In most clinical laboratories routine examination for ova and parasites is not designed to detect Cryptosporidium; thus, examination for this organism must be separately requested. A monoclonal antibody to the oocyst wall (Merifluor, Meridian Diagnostics, Cincinnati) and an ELISA with a soluble Cryptosporidium-specific antigen (ProSpecT, Cryptosporidium microtiter assay~ Alexon, Sunnyvale, CA) have become commercially available but have not been used extensively for diagnosis. The differential diagnosis of cryptosporidiosis for HIV-infected persons includes infection due to other gastrointestinal pathogens such as CMV, Mycobacterium avium complex (MAC), Microsporidium, Isospora, Shigella, Salmonella, Campylobacter, Clostridium difficile, Giardia, and Entamoeba. Although infections due to most of these pathogens can be diagnosed with suitable cultures, stool examinations, or assays, several are still difficult to diagnose. Infection with CMV or MAC may be suggested by the presence of abdominal pain and fever, but endoscopy and biopsy may be necessary to establish the diagnosis. Diagnosis of microsporidium infection usually requires biopsy and visualization with use of electron microscopy, although several centers have reported the development of improved light microscopic techniques for examination of stools [18].
What Methods of Treatment Have Been Tried? Nonspecific treatment of established cryptosporidiosis is empiric and depends on the judicious use of antidiarrheal agents (opiates, diphenoxylate, and loperamide), nutritional management, and administration offluids. Central or peripheral parenteral nutrition is most effective when initiated before the patient has lost a large amount of weight. Specific chemotherapy has thus far not been shown to be efficacious, although a large number of drugs-more than 90-have been tried. Perhaps the most promising treatment modality under investigation is the passive oral transfer of protective antibody in hyperimmune bovine colostrum (HBC), which has led to marked abatement of symptoms in some cases ofsevere cryptosporidiosis in immunocompromised patients [19-21] and in animals. The Cryptosporidium antigens that are the targets of protective antibody in HBC have not been identified. A three-center, double-blind crossover study ofthe efficacyofa concentrated immunoglobulin preparation prepared with HBC for treatment of AIDS patients with protracted cryptosporidiosis has been approved by the U.S. Food and Drug Administration. A wide variety of drugs, including antiparasitic drugs like quinine, chloroquine, difluoromethylornithine, pyrimetha-
Downloaded from http://cid.oxfordjournals.org/ at Michigan State University on February 25, 2015
cells to repeat the cycle. A sexual cycle culminating with the development of sporulated oocysts that can excyst and release invasive sporozoites or be shed into the environment also occurs. In patients with AIDS, infection of the small bowel predominates, but all sites of the gastrointestinal tract (including the esophagus, stomach, colon, and rectum) have been involved. Diarrhea may be watery and often cholera-like; the stool volume of patients with AIDS may reach 17 Lid [1]. However, less fulminant diarrhea is common. Blood or white blood cells are not seen in the stool of patients with cryptosporidiosis, but mucus may be. Crampy abdominal pain is common, as are fatigue, anorexia, nausea, and vomiting. These symptoms may lead to severe malnutrition and dehydration. Fever may be present but is difficult to ascribe to cryptosporidiosis in severely immunocompromised persons, who frequently have other infections. Cryptosporidiosis of the extrahepatic bile ducts may result in acalculous biliary disease, which has been estimated to occur in 10% of AIDS patients with cryptosporidiosis [12]. The true incidence, however, is unknown as patients usually do not undergo the invasive procedures needed for confirmation of the diagnosis. Results of ultrasonography and computed tomography are notable for demonstration of biliary duct dilatation and thickening of the wall as well as abnormalities of the gall bladder. Cholangiograms often show features suggestive of sclerosing cholangitis, intrahepatic strictures with irregular, beaded dilatation of ducts, and dilatation of the common bile duct with or without papillary stenosis [13]. The alkaline phosphatase level is usually elevated. Diagnosis requires examination of tissue or bile for Cryptosporidium. The value of papillotomy is controversial [13, 14] except when an obstruction due to papillary stenosis is noted. Although involvement of the respiratory epithelium ofpatients with AIDS who have cryptosporidiosis has been reported, the clinical significance ofthis finding is unclear [15]. Cough, shortness of breath, and wheezing have been noted in such patients, who usually have concomitant respiratory infections due to Pneumocystis carinii or cytomegalovirus (CMV). The diagnosis ofcryptosporidiosis has been made by the finding of oocysts in sputum, tracheal aspirates, bronchoalveolar lavage fluid, or lung tissue. One report indicates that four HIV-seropositive persons had no other pulmonary pathogens but Cryptosporidium [16]. Of this small group, all patients were alive 9 months after diagnosis. Although the condition has not been reported in patients with AIDS, recurrent sinusitis due to Cryptosporidium has been noted in a hypogammaglobulinemic patient who had prolonged intestinal cryptosporidiosis [17]. Dissemination of cryptosporidiosis outside the villous epithelium of the gastrointestinal tract and the contiguous respiratory epithelium does not appear to occur. The mainstay of diagnosis of cryptosporidium infection
CID 1992; 15 (December)
ClD 1992; 15 (December)
HIV Infection and Cryptosporidiosis
with AIDS, but the results ofa prospective, multicenter clinical trial showed that it was not [27]. Recently, lytic proteins that form ionic channels in the membranes of cells have been found in the guts of pigs and mice. It has been postulated that the function of lytic peptides in the gut might be to defend the intestinal tract against microbes. Lytic peptides have been shown to be anticryptosporidial in vitro, but studies to determine whether they are toxic in animals have not been concluded [28].
What Other Measures Need To Be Addressed with Regard to Patients? Cryptosporidiosis in HIV-infected persons has not been studied in a prospective manner; thus, many epidemiological parameters have not been defined. The source of infection and mode of spread among persons with AIDS as well as factors that protect individuals from or predispose them to infection are not known. However, our current information allows us to make some recommendations. Cryptosporidium appears not to have species specificity among mammals and appears to preferentially infect the young of all species. Domestic pets might constitute a reservoir from which immunocompromised hosts are likely to become infected [29]. It is also possible that Cryptosporidium is acquired from contaminated water or from other persons. In any case, two attributes of Cryptosporidium render it especially infectious. First, oocysts are very resistant in the environment and are shed fully sporulated and infectious. Disinfectants that are usually employed to clean household or hospital surfaces are not effective in neutralizing oocysts. Chlorination and ozonation procedures used to eradicate waterborne organisms do not kill Cryptosporidium [30]. Second, the ID 90 for Cryptosporidium appears to be very low; although there are no figures for adult humans, studies of cryptosporidiosis in immunocompetent infant macaques suggest that the ID 90 for these animals is between 10 and 100 oocysts [31]. It appears that the highly infectious nature of Cryptosporidium and the ubiquity of its reservoirs account for primary disease in patients with AIDS; however, we do not know if there is a latent state from which patients relapse, as is the case for infection due to Pneumocystis and Toxoplasma [32].
The risk of transmission of cryptosporidiosis to other persons in the hospital, especially in wards dedicated to the care of patients with AIDS, has not been determined. Outbreaks of cryptosporidiosis among immunocompetent health care workers [33] exposed to patients with cryptosporidium infection suggest that this risk may be substantial. Body-substance handling precautions, with particular emphasis on enteric precautions, should be observed for all institutionalized patients with cryptosporidiosis. As DNA and antibody probes become available, it will be possible to define the epidemiol-
Downloaded from http://cid.oxfordjournals.org/ at Michigan State University on February 25, 2015
mine, and trimethoprim-sulfamethoxazole, have been tried unsuccessfully for treatment of cryptosporidiosis. It is unclear whether the refractoriness ofcryptosporidium infection to a given chemotherapeutic agent useful for treatment of other parasitic diseases is due to a block in delivery of the drug to the intracellular, extracytoplasmic form of the parasite, to structural variation of the drug's molecular target, or to unusual metabolic pathways that circumvent the drug's effect. The first drug believed to be effective for treatment of cryptosporidiosis was spiramycin, a macrolide antibiotic used to treat toxoplasmosis in pregnant women in Europe. In spite of early promising reports, neither oral spiramycin nor intravenous spiramycin, tested in a later trial, has proven efficacious (unpublished data, R. Soave). Recently, three other macrolide antibiotics (azithromycin, clarithromycin, and roxithromycin) have become available. Azithromycin has been reported to be effective as suppressive therapy for cryptosporidiosis in steroid-immunosuppressed rodents [22, 23]. A double-blind, placebo-controlled trial of azithromycin in outpatients with AIDS is under way at four centers (in New York, San Francisco, San Diego, and Memphis). Preliminary information suggests that this drug may be effective in some patients (unpublished observation, R. Soave). The drug is available from the manufacturer for use with approval from the Institutional Review Board. Initial, encouraging results of studies of an investigational antimalarial drug, 566C80, used in animals with cryptosporidiosis have not been reproducible [24]. Diclazuril, a static drug for treatment of infection with Eimeria (an apicocomplexan parasite that invades the gut epithelial cells of animals) was shown to be ineffective in human cryptosporidiosis in a small controlled trial, possibly because of inadequate levels of the agent in blood. Letrazuril, a congener ofdiclazuril with four times greater bioavailability than the latter agent, is currently undergoing ACTGsponsored clinical trials in multiple centers (personal communication, R. Soave). Paromomycin, a nonabsorbable aminoglycoside, is an effective luminal agent for Entamoeba histolytica infection. Several abstracts suggest that paromomycin may be effective against cryptosporidiosis in vivo and in vitro. The ACTG is about to open a multicenter, doubleblind, placebo-controlled trial of paromomycin. However, results of uncontrolled studies with patients at San Francisco General Hospital do not indicate that paromomycin is effective against cryptosporidiosis in vivo and in vitro [25, 26]. In the presence ofintestinal damage, a large amount ofparomomycin may be absorbed, leading to nephrotoxicity. Octreotide, a synthetic cyclic octapeptide analog of somatostatin, has been reported to be effective in the treatment of secretory diarrhea ofendocrine origin and in the control of the secretory diarrhea of some patients with AIDS. Initial studies suggested that octreotide might be useful in treating the diarrhea associated with cryptosporidiosis in patients
905
906
Petersen
ogy of this disease both in the community and in the hospital. It appears prudent to advise persons with
