A. Clinton White

A review of the global burden, novel diagnostics, therapeutics, and vaccine targets for cryptosporidium

Cryptosporidium spp are well recognised as causes of diarrhoeal disease during waterborne epidemics and in immunocompromised hosts. Studies have also drawn attention to an underestimated global burden and suggest major gaps in optimum diagnosis, treatment, and immunisation. Cryptosporidiosis is increasingly identified as an important cause of morbidity and mortality worldwide. Studies in low-resource settings and high-income countries have confirmed the importance of cryptosporidium as a cause of diarrhoea and childhood malnutrition. Diagnostic tests for cryptosporidium infection are suboptimum, necessitating specialised tests that are often insensitive. Antigen-detection and PCR improve sensitivity, and multiplexed antigen detection and molecular assays are underused. Therapy has some effect in healthy hosts and no proven efficacy in patients with AIDS. Use of cryptosporidium genomes has helped to identify promising therapeutic targets, and drugs are in development, but methods to assess the efficacy in vitro and in animals are not well standardised. Partial immunity after exposure suggests the potential for successful vaccines, and several are in development; however, surrogates of protection are not well defined. Improved methods for propagation and genetic manipulation of the organism would be significant advances.

Treatment of cryptosporidiosis: do we know what we think we know?

Purpose of review The management of cryptosporidiosis is fraught with controversies. New research on diagnostics and medications has reached the field in recent years. Therefore, familiarity with key features of current management tools is important. We discuss diagnostic and therapeutic aspects of cryptosporidiosis focusing on evidence behind the medications available to date. Recent findings Molecular methods provide a clearer understanding of cryptosporidiosis epidemiology. The major determinants of severity still are host immune status and parasite species. Children and immunosuppressed individuals, especially with HIV/AIDS, are disproportionately affected. Nitazoxanide is an important advance in treatment of HIV negative patients. However, recent research confirms the limited effectiveness of antiparasitic drugs to treat cryptosporidiosis in AIDS. Questions remain about using partially active drugs paromomycin and nitazoxanide for treatment. Potent antiretroviral combinations modify disease epidemiology and are key components of therapy in AIDS. However, it is unclear whether this is due solely to immune reconstitution or due in part to antiparasitic effects of HIV protease inhibitors. Newer candidate drugs are in development. Summary There is better understanding of the epidemiology of cryptosporidiosis and promising new diagnostic methods. There are significant challenges in terms of control and treatment of cryptosporidiosis among the groups at risk.

Neurocysticercosis: Neglected but Not Forgotten

Neurocysticercosis (NCC) is an infection of the central nervous system caused by the larval form of the tapeworm Taenia solium. Infections occur following the accidental ingestion of tapeworm ova found in human feces. NCC is a major cause of epilepsy and disability in many of the worlds poorer countries where families raise free-roaming pigs that are able to ingest human feces. It is frequently diagnosed in immigrant populations in the United States and Canada, reflecting the high endemicity of the infection in their countries of origin [1]. Although parenchymal cysts are the most common location in the brain and cause seizures, cysts may also be present in the ventricles, meninges, spinal cord, eye, and subarachnoid spaces. Involvement in these other sites may result in aberrant growth (racemose cysts) and complicated disease that is difficult to treat and may cause increased morbidity and mortality.

Neurocysticercosis in Houston, Texas: an update.

Neurocysticercosis, one of the most common parasitic infections of the human nervous system, has emerged as an important infection in the United States. Neurocysticercosis causes significant morbidity associated with acute seizures, chronic epilepsy, and hydrocephalus. We retrospectively identified patients with definitive or probable neurocysticercosis seen at Ben Taub General Hospital, the largest public teaching hospital in Houston, Texas, from September 1997 through December 2005. We collected demographic, clinical, therapeutic, and outcome variables. Neurocysticercosis was classified according to the location of cysts in imaging studies. We compared cases with parenchymal and extraparenchymal disease. We included 111 patients (48 had definitive and 63 probable neurocysticercosis). The mean age was 28.6 years (standard deviation, 13.6 yr), and the male to female ratio was 2:1. Most patients (93%) were Hispanic immigrants. Sixty (54%) patients had parenchymal disease, 22 (20%) intraventricular, 13 (12%) subarachnoid disease, and 13 (12%) had calcifications only. Additionally, 2 patients had hydrocephalus only, and 1 had ocular cysticercosis. Thirteen (40%) of 32 patients with parenchymal disease and 3 (30%) of 10 patients with calcifications had relapsed seizures at follow-up. Extraparenchymal disease was associated with longer duration of hospitalization compared with parenchymal disease. No deaths were identified in our series during a median follow-up of 1 year. Neurocysticercosis has emerged as an important parasitic infection in developed countries as a result of increased migration. With current management, mortality is limited, but there continues to be significant morbidity. Further studies of the epidemiology and pathophysiology of the infection are urgently needed to develop better preventive and therapeutic strategies. Abbreviations BTGH = Ben Taub General Hospital, CSF = cerebrospinal fluid, CT = computed tomography, EITB = enzyme-linked immunoelectrotransfer blot, HCHD = Harris County Hospital District, ICD9 = International Classification of Diseases, 9th revision, MRI = magnetic resonance imaging, NCC = neurocysticercosis, US = United States, VPS = ventriculoperitoneal shunt.

Prophylaxis with Weekly Versus Daily Fluconazole for Fungal Infections in Patients with AIDS

We compared the efficacy of a 400-mg once-weekly dosage versus a 200-mg daily dosage of fluconazole for the prevention of deep fungal infections in a multicenter, randomized, double-blind trial of 636 human immunodeficiency virus-infected patients to determine if a less intensive fluconazole regimen could prevent these serious but relatively infrequent complications of AIDS. In the intent-to-treat analysis, a deep fungal infection developed in 17 subjects (5.5%) randomly assigned to daily fluconazole treatment and in 24 (7.7%) given weekly fluconazole during 74 weeks of follow-up (risk difference, 2.2%; 95% confidence interval [CI], -1.7% to 6.1%). Thrush occurred twice as frequently in the weekly versus daily fluconazole recipients (hazard ratio, 0.59; 95% CI, 0.40-0.89), and in a subset of patients evaluated, fluconazole resistance was infrequent. Fluconazole administered once weekly is effective in reducing deep fungal infections in patients with AIDS, but this dosage is less effective than the 200-mg-daily dosage in preventing thrush.

Outcomes of treatment for hematogenous Staphylococcus aureus vertebral osteomyelitis in the MRSA ERA

OBJECTIVES Hematogenous vertebral osteomyelitis is caused predominantly by Staphylococcus aureus. The rise in incidence of methicillin-resistant S. aureus (MRSA) has complicated the treatment of this infection. Our objective was to evaluate therapeutic outcomes for S. aureus vertebral osteomyelitis in a setting of high MRSA prevalence. METHODS We conducted a retrospective chart review of all patients who presented with S. aureus vertebral osteomyelitis over a 7-year period at 2 tertiary care hospitals in Houston, TX, USA. RESULTS Thirty-five patients were identified who received > or =2-week course of parenteral antibiotics and had a follow-up period of at least 12 months post-therapy. MRSA was responsible for 20 (57%) cases. Mean duration of total antibiotic therapy was 61.4 days. The overall relapse rate was 14%. At 12 months post-therapy, 86% patients were cured. The one factor significantly associated with relapse was presence of undrained abscesses (p=0.04). CONCLUSIONS When the mean duration of effective antibiotic therapy was 60 days, cure rates for S. aureus vertebral osteomyelitis exceeded 80%. Drainage of all associated abscesses correlated with a significantly higher rate of cure.

Cestode Infestations : Hydatid Disease and Cysticercosis

Although humans can be definitive hosts for cestodes (tapeworms), major pathologic conditions occur during cestode larval stages when humans serve as the intermediate host for these parasites. The most relevant forms of human disease caused by cestode larvae are echinococcosis, caused by Echinococcus granulosus (cystic echinococcosis) and Echinococcus multilocularis (alveolar echinococcosis), and cysticercosis, caused by Taenia solium. These infections occur worldwide, but their relevance is particularly high in developing countries, where poor hygiene conditions facilitate the transmission of the parasites. The therapeutic approach is often complex, requiring surgery and/or chemotherapy or, in the case of cystic echinococcosis, percutaneous treatments.

A novel Calcium Dependent Protein Kinase Inhibitor as a lead compound for treating Cryptosporidiosis

Cryptosporidium parasites infect intestinal cells, causing cryptosporidiosis. Despite its high morbidity and association with stunting in the developing world, current therapies for cryptosporidiosis have limited efficacy. Calcium-dependent protein kinases (CDPKs) are essential enzymes in the biology of protozoan parasites. CDPK1 was cloned from the genome of Cryptosporidium parvum, and potent and specific inhibitors have been developed based on structural studies. In this study, we evaluated the anti-Cryptosporidium activity of a novel CDPK1 inhibitor, 1294, and demonstrated that 1294 significantly reduces parasite infection in vitro, with a half maximal effective concentration of 100 nM. Pharmacokinetic studies revealed that 1294 is well absorbed, with a half-life supporting daily administration. Oral therapy with 1294 eliminated Cryptosporidium parasites from 6 of 7 infected severe combined immunodeficiency-beige mice, and the parasites did not recur in these immunosuppressed mice. Mice treated with 1294 had less epithelial damage, corresponding to less apoptosis. Thus, 1294 is an important lead for the development of drugs for treatment of cryptosporidiosis.

Severe Rift Valley fever may present with a characteristic clinical syndrome.

Rift Valley fever (RVF) virus is an emerging pathogen that is transmitted in many regions of sub-Saharan Africa, parts of Egypt, and the Arabian peninsula. Outbreaks of RVF, like other diseases caused by hemorrhagic fever viruses, typically present in locations with very limited health resources, where initial diagnosis must be based only on history and physical examination. Although general signs and symptoms of human RVF have been documented, a specific clinical syndrome has not been described. In 2007, a Kenyan outbreak of RVF provided opportunity to assess acutely ill RVF patients and better delineate its presentation and clinical course. Our data reveal an identifiable clinical syndrome suggestive of severe RVF, characterized by fever, large-joint arthralgia, and gastrointestinal complaints and later followed by jaundice, right upper-quadrant pain, and delirium, often coinciding with hemorrhagic manifestations. Further characterization of a distinct RVF clinical syndrome will aid earlier detection of RVF outbreaks and should allow more rapid implementation of control.

Advances in the diagnosis and management of neurocysticercosis.

Neurocysticercosis is the most common cause of late-onset epilepsy in developing countries. The larval stage of Taenia solium is the causative agent of the disease. Recent advances in neuroimaging and serologic diagnostic techniques have led to increased recognition of its importance, but its pathogenesis is just beginning to be clarified. Experts now agree that the clinical manifestations, pathogenic mechanisms and optimal treatment vary with the number of parasites, their location and the degree of host inflammation. Symptomatic therapy (i.e., antiepileptic medications and, when indicated, surgery) is critically important but there are also important roles for antiparasitic and anti-inflammatory drugs. Neurocysticercosis is a potentially eradicable disease but this is probably unlikely to be achieved in the short term.