Key words: Cryptosporidium parvum * Giardia lamblia * Nitazoxanide * Persistent diarrhea
ABSTRACT
Despite advances in the management of diarrheal disorders, diarrhea is the second most frequent illness in the world. Persistent diarrhea, common in community pediatrics, is often caused by organisms such as Giardia lamblia, Cryptosporidium parvum and, less frequently, Cyclospora, Isospora belli, and Clostridium difficile. Identifying the causative organism is often challenging, and diagnostic tests may be inaccurate and expensive and, thus, of limited benefit. Consequently, carefully chosen empiric therapy guided by a physician’s clinical impressions may be a useful and cost-effective option in children with persistent diarrhea, particularly those whose signs and symptoms suggest a protozoal etiology. This article discusses the empiric use of anti-infective nitazoxanide, a thiazolide compound, in three case reports of children with persistent diarrhea, and presents an overview of the diagnostic and therapeutic issues associated with this disorder and the pharmacodynamics and pharmacokinetics of the drug.
Introduction
Diarrhea is the second leading cause of death among children worldwide and is responsible for approximately 2 million deaths annually’. In the United States, diarrhea is a frequent presenting complaint among children, accounting for 10% of office visits for children younger than 3 years of age2. In a substantial number of patients of all ages, acute diarrhea (≤ 14 days duration) develops into persistent diarrhea (> 14 days duration) without associated findings, such as abdominal pain or weight loss, and poses a significant challenge in terms of effective treatment. Diarrhea that lasts > 30 days is classified as chronic3. Although diarrhea is known to be caused by viruses, bacteria, and parasites, identifying the causative organism is often problematic; laboratory studies may be more costly than clinical impressions, physical examinations, and the outcome of empiric therapy, and may yield false-negative results. A thorough history and physical examination provide the basis for determining whether the child needs further diagnostic tests or consultation with a gastroenterologist. However, if the child with persistent diarrhea is otherwise healthy, empiric therapy may be a reasonable consideration. Fortunately, medications for the treatment of persistent diarrhea are available, effective and inexpensive.
Antiprotozoal agents used in the management of persistent diarrhea include metronidazole (Flagyl*) and, more recently, nitazoxanide (Alinia[dagger]). The following case studies illustrate how the early use of nitazoxanide can effectively manage persistent diarrhea before costly and time-consuming tests are performed to identify the cause.
Case reports
The efficacy of empiric nitazoxanide in children with chronic or persistent diarrhea is undergoing evaluation at the Children’s Center for Digestive Health Care in Atlanta, Georgia, and will be the subject of future publications. Nitazoxanide has been approved by the US Food and Drug Administration as a suspension for the management of diarrhea caused by Giardia lamblia and Cryptosporidium parvum in children aged 1 to 11 years and as a tablet for the management of diarrhea caused by G. lamblia in children and adults aged 12 years and older3. The following case reports derive from patients clinically evaluated and treated by the author as outpatients in this subspecialty practice.
Case 1
A 14-month-old (10.5kg) male previously treated with amoxicillin for bilateral otitis media presented with a 1-month history of diarrhea that persisted despite the implementation of a lactose- free diet. The patient’s history was negative for risk factors for persistent diarrhea (Table 1), and the results of physical examination were unremarkable. Bowel movements were loose, mucoid, and occurred three to eight times daily. Stools were negative for blood, white blood cells, bacterial pathogens, Clostridium difficile toxins, yeast, and ova and parasites. The patient was treated with nitazoxanide suspension 100mg bid (9.52mg/kg bid) for 3 days. Symptoms resolved with therapy, and treatment was well tolerated with only mild bloating.
Case 2
A 12-month-old, 9.5kg male with a history of eczema and gastroesophageal reflux presented with a 3- to 4-week history of diarrhea and vomiting. The mother reported that the infant had three to five large, loose stools daily. The patient’s hypoallergenic formula was lactose-free, and the only medication he was taking was a proton pump inhibitor. The child was afebrile and showed no abnormalities on physical examination. Results of a complete blood cell count and tissue transglutaminase values were within normal limits. Stool culture and examination were negative for ova and parasites and fungi or other pathogens; the stool was also negative for blood and leukocytes. The infant was treated with nitazoxanide suspension 100mg bid (10.5mg/kg bid) for 3 days. Over the next 4 days, symptoms resolved, stool consistency improved, and the number of bowel movements decreased. The treatment was well tolerated with no adverse reactions. The patient remained well.
Table 1. Risk factors for diarrhea in children
Case 3
An 8 -year-old, 30.7kg male presented with a 2-week history of intermittent diarrhea, abdominal discomfort, malodorous stools, anorexia and weight loss. Prior to the onset of the diarrhea, the patient had received amoxicillin/clavulanic acid for culture- confirmed group A streptococcal pharyngitis. Although the family had a septic system, their water was supplied by the city. The patient’s medical history was unremarkable except for surgery to correct transposition of the great vessels at 8 days of age. Guaiac testing revealed trace amounts of blood in the stool; C. difficile toxins were not detected by immunoassay. The stool was negative for bacterial pathogens, ova and parasites, and fungi. The patient was prescribed nitazoxanide suspension 200 mg bid (6.5mg/ kg bid) for 3 days. The treatment was well tolerated with no adverse reactions. His symptoms improved within 2 days, and he remained well thereafter.
Discussion
In case 1, the patient was evaluated after the primary care physician had failed to find a pathogen through standard diagnostic tests. Although the patient’s treatment with an earlier antibiotic suggested the possibility of an opportunistic infection, stools were negative for C. difficile toxin and smear for yeast. Alteration of this patient’s diet indicated that lactose intolerance, a common cause of diarrhea in the United States4, was not responsible for this patient’s diarrhea. The choice was to continue performing potentially diagnostic studies and possibly delay treatment or initiate a 3-day presumptive course of nitazoxanide, which would be more costefficient, with the knowledge that if the patient did not respond we could quickly proceed with the additional diagnostic tests. Initiating therapy with nitazoxanide resolved diarrheal symptoms and obviated the need for additional laboratory testing. Thus, this therapeutic intervention saved the patient and his family from a comprehensive workup for other causes of prolonged diarrhea that would have been unrevealing.
Case 2 demonstrates the efficacy and safety of nitazoxanide, administered as recommended by the manufacturer, for a child who met the criteria of the Infectious Diseases Society of America for persistent diarrhea. The probability of common noninfectious causes for the patient’s symptoms was decreased by a careful history, physical examination, and limited laboratory studies. However, the duration of symptoms and their prompt resolution after treatment suggest that the diarrhea had an infectious etiology or that nitazoxanide is effective for persistent diarrhea for which no cause could be identified at this time.
As in case 1, the history of the patient in case 3 certainly suggests the possibility of infection with C. difficile. The patient had received broad-spectrum antibiotic therapy within the previous month, but the immunoassay of the stool for C. difficile toxins A and B was negative. Although the immunoassay for the toxin is not as sensitive as cytotoxicity in a cell culture system, the patient was not believed to have antibioticassociated diarrhea or colitis. In addition, information from the manufacturer indicates that C. difficile is sensitive to nitazoxanide3. As in the previous cases, empiric nitazoxanide therapy was effective. Further testing still may have failed to demonstrate the etiology of the patient’s gastrointestinal manifestations while adding cost and time.
As demonstrated by these cases, the evaluation and effective management of diarrhea characterized by a duration of 14 days or longer is clinically challenging. Although the differential diagnosis is broad, a clinical history is invaluable in guiding physicians toward the appropriate evaluation of each patient with diarrhea. When treating patients with persistent diarrhea, it is important to rule out common noninflammatory disorders56. Patients with diarrhea of 2 to 3 days duration rarely necessitate a workup unless they present with fever, bloody diarrhea, or severe abdominal pain. However, there are a substantial yet ill-defined number of patients whose diarrhea becomes persistent witho\ut associated findings, such as abdominal pain and weight loss. As demonstrated in all three cases, a complete history, including a dietary and medication history as well as a detailed description of the patient’s diarrhea, describing the color, consistency, and frequency of elimination of the stools, is important in evaluating patients with persistent diarrhea. Patients with persistent diarrhea may be infected with parasites such as Giardia and Cryptosporidium, or less common parasites such as Entamoeba histolytica, Cyclospora, and Isospora belli. C. difficile is a potential, common causative pathogen for diarrhea that persists beyond 3 days in hospitalized patients and patients who have recently taken broad-spectrum antibiotics, such as the patient in case 3(7).
Identifying the causative organism
The causes of persistent diarrhea typically differ from those of acute or chronic diarrhea. The probability that persistent diarrhea is caused by a non-dysenteric organism increases significantly after excluding the following from the diagnosis: postinfectious or primary lactose intolerance, chronic nonspecific diarrhea, and the prodromal manifestations of other chronic diarrheal states (i.e., celiac syndrome, inflammatory bowel disease).
Of the parasites associated with persistent diarrhea, Giardia is the most frequently diagnosed in public health laboratories in the United States8. Illness caused by infection with C. parvum has been linked to water from swimming pools, fountains, public water supplies, and institutions such as hospitals9. Blastocystis hominis is a protozoan parasite commonly identified in stool specimens. There is ongoing debate about the pathogenicity of this organism10. Some studies suggest that it is an etiologic agent of persistent diarrhea, whereas others are unable to demonstrate an association between symptoms and the presence of the organism in the stool11- 13.
Diagnostic testing
For patients with persistent diarrhea, attempts to identify the responsible organism, guide treatment, and help contain healthcare costs can be problematic. Common tests include stool examination for ova and parasites; immunofluorescence and enzyme immunoassay for Giardia and Cryptosporidium; acid-fast stains for Cryptosporidium, Cyclospora, and lsospora; polymerase chain reaction for Cryptosporidium; acid-fast stains or culture for Mycobacterium avium complex; and chromotrope or other stains for Microsporidia7. The most common laboratory test for diagnosing C. difficile mediated disease is an enzyme immunoassay that detects toxins A and B. This test provides results within 2 to 6 hours with a specificity of 93% to 100% and a sensitivity of 63% to 99%’4. The majority of combination enzyme immunoassays have a sensitivity of 85% to 95%15.
While it is not within the scope of this paper to discuss diagnostic testing at length, many diagnostic laboratories are unable to identify the organisms associated with persistent diarrhea. According to studies, the detection rate for Giardia is 67% in a single specimen submitted for microscopic ova and parasite examination, and 85% when three specimens are submitted on 3 separate days16,17. Thus, even under the best circumstances, this pathogen is not detected in approximately one of every six patients. Importantly, the performance of most of these tests relies on skill sets not available in all laboratories, and the accuracy of the results depends on other factors such as proper collection and delivery. If stools are not placed in preservatives or examined immediately, the sensitivity can fall. Moreover, the turnaround time and reporting of test results may delay therapy.
Empiric therapy as a diagnostic tool
Although the acceptance of empiric therapy is not universal among physicians, it is counterproductive to delay treatment in a patient who is ill (and unable to work or attend school) while waiting for the results of diagnostic testing; this often leads to diagnostic evaluations with poor positive predictive values. Separating pediatrie patients whose diarrhea is self-limiting from patients infected with Giardia or Cryptosporidium also may support the role for empiric therapy. Although the Infectious Diseases Society of America guidelines recommend empiric therapy in patients who have traveler’s diarrhea and febrile diarrhea, the role of empiric therapy in patients with other types of diarrhea is still unclear7. However, as demonstrated in all three of the cases described here, particularly case 1, the use of empiric therapy enables physicians to initiate treatment based on clinical impressions – a comprehensive history and clinical examination – of the patient, thus obviating the need for invasive testing that may increase the cost of care.
Common antiprotozoal agents
The most common antiprotozoal agents used in persistent diarrhea are metronidazole and nitazoxanide, both of which are effective in the management of giardiasis in children aged 2 to 11 years. Both treatments have been well tolerated18. While therapeutic equivalence between these two drugs is important, other distinguishing features may make nitazoxanide the better choice. For example, it may be advantageous to use a drug such as nitazoxanide, which is approved for both children and adults and covers both Cryptosporidium and Giardia. There are no data supporting the use of metronidazole in the management of Cryptosporidium. Also, metronidazole is associated with a potential risk of genotoxicity7,19,20. Other factors to consider are that nitazoxanide can be dosed twice daily whereas metronidazole requires three-times-daily dosing, and nitazoxanide is available in a strawberryflavored oral suspension, which may impact compliance in pediatrie patients. Also, because the length of therapy for nitazoxanide is shorter than for metronidazole (3 vs. 5 days), there may be cost benefits to using the former. Recommended nitazoxanide dosage and administration are shown in Table 2(21).
Table 2. Nitazoxanide dosage and administration21
Nitazoxanide
Mechanism of action
The antiprotozoal activity of nitazoxanide appears to result from interference with the pyruvate-ferredoxin oxidoreductase (PFOR) enzyme-dependent electron transfer reaction, which is essential to anaerobic energy metabolism (Figure I)22. Studies have shown that the PFOR enzyme from G. lamblia directly reduces nitazoxanide by a transfer of electrons in the absence of ferredoxin. The DNA-derived PFOR protein sequence of C. parvum appears to be similar to that of G. lamblia, accounting for the activity of nitazoxanide against both pathogens23’24. Because of its selectivity, nitazoxanide does not appear to be mutagenic22.
Pharmacokinetics
Following oral administration, nitazoxanide is rapidly hydrolyzed to the active metabolite, tizoxanide (desacetyl-nitazoxanide). Tizoxanide undergoes conjugation, primarily by glucuronidation. Tizoxanide has no significant inhibitory effect on cytochrome P450 enzymes. The parent drug nitazoxanide is not detected in plasma following oral administration. Maximum plasma concentrations of the active metabolites tizoxanide and tizoxanide glucuronide are observed within 2 to 4 hours of administration. In plasma, > 99% of tizoxanide is bound to protein. Pharmacokinetic parameters of tizoxanide and tizoxanide glucuronide are shown in Table 3(21).
Figure 1. Pyruvate-ferredoxin oxidoreductase (PFOR)-dependent metabolic pathway. Adapted from Dunne et al.22 CoASH, reduced coenzyme A; Fd(ox), ferredoxin oxidised; Hyd, hydrogenase; Fd(red), ferredoxin reduced; CoA, coenzyme A; RNO^sub 2^, prodrug metronidazole.
Tizoxanide is excreted in the urine, bile, and feces, and tizoxanide glucuronide is excreted in the urine and bile. Nitazoxanide oral suspension is not bioequivalent to the tablet. The relative bioavailability of the suspension is 70% compared with the tablet23″26.
Clinical studies
Nitazoxanide is safe and generally well tolerated27’28. In the course of 31 clinical studies, 2983 children were exposed to the drug3. In controlled and uncontrolled studies in 613 children treated with nitazoxanide oral suspension, the most commonly reported adverse events were abdominal pain (48/613 patients; 7.8%), diarrhea (13/613 patients; 2.1%), vomiting (7/613 patients; 1.1%), and headache (7/613 patients; 1.1%)3. All events were mild and transitory. The administration of nitazoxanide was not associated with a significant effect on hematologie parameters, clinical chemistry values, or urinalysis test results. In placebo-controlled clinical studies in children treated at the recommended doses, the rates of occurrence of adverse events did not differ significantly between nitazoxanide and placebo3.
Table 3. Pharmacokinetic parameters of tizoxanide and tizoxanide glucuronide21
Table 4. Spectrum of activity of nitazoxanide in preclinical studies
Safety and efficacy
Nitazoxanide has been shown to be both safe and effective in the treatment of children with giardiasis29, cryptosporidiosis4-28, and blastocystosis (personal communications, J.-F. Rossignol, Romark Institute for Medical Research). Studies demonstrate high efficacy rates (> 80%) for nitazoxanide compared with placebo; rates as high as 86% for C. parvum30 and 85% for G. lamblia29 have been reported. Studies by the manufacturer indicate that nitazoxanide is also safe and effective when used against a number of other parasites that may cause persistent diarrhea (Table 4)24’3U33. In fact, the drug has shown activity against some diarrhea-causing bacterial pathogens, including C. difficile31.
Conclusion
In selected situations, following a careful history and physical examination, some patients may be better served by empiric therapy than by extensive diagnostic evaluations. Certainly, in pediatrie patients with persistent diarrhea without serious symptoms such as fecal blood or leukocytes, a therapeutic trial with an appropriate antiprotozoal agent would be wor\thwhile. The broad efficacy of nitazoxanide against organisms responsible for persistent diarrhea and its favorable safety profile provide a foundation for the rational use of empiric therapy in this population. Moreover, as supported by the case studies reported herein, the apparent success of nitazoxanide against diarrhea for which no cause has been identified suggests an infectious etiology for the disorder or a broad spectrum of efficacy for the drug. Because persistent diarrhea continues to be a huge public concern worldwide, the potential of nitazoxanide in the management of lower gastrointestinal tract pathogens warrants further investigation and may lead to the earlier clinical use of this agent or its use as a diagnostic measure.
Acknowledgement
Declaration of interest: The author received a grant in 2005 from Romark Pharmaceuticals (Tampa, FL), the manufacturer of nitazoxanide.
The author is also grateful for the assistance provided by Medesta Publications in the preparation of this manuscript, funded by Romark Pharmaceuticals.
* Flagyl is a trade name of Pharmacia Corporation, Chicago, IL
[dagger] Alinia is a trade name of Remark Laboratories, Tampa, FL
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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com
Paper CMRO-2949_4, Accepted for publication: 29 April 2005
Published Online: 24 May 2005
doi: 10.1185/030079905X50534
Stanley A. Cohen
Children’s Center for Digestive Health Care, Atlanta, GA, USA
Address for correspondence: Dr Stanley A. Cohen, Children’s Center for Digestive Health Care, 993 D Johnson Ferry Road, #440, Atlanta, GA 30342, USA. Tel.: +1-404-257-0799; Fax: +1-404-503- 2280; email: [email protected]
Copyright Librapharm Jul 2005
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