Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents With HIV

Epidemiology

Cystoisosporiasis, also known as Isosporiasis, is a protozoan gastrointestinal infection that occurs worldwide but is more common in tropical and subtropical regions. Immunocompromised people, including those who have HIV, are at increased risk for chronic, debilitating illness.^1-7 Infection results from ingestion of sporulated oocysts, such as from contaminated food or water. After ingestion, the parasite invades enterocytes in the small intestine. Ultimately, immature oocysts are produced and shed in stool.⁸ Although Cystoisospora (Isospora) belli completes its life cycle in humans, oocysts shed in the feces of infected individuals must mature (sporulate) outside the host, in the environment, to become infective when ingested. Available data suggest that the maturation process is completed in approximately 1 to 2 days but might occur more rapidly in some settings.² For complete lifecycle, see the Centers for Disease Control and Prevention Cystoisosporiasis webpage.

C. belli is frequently found in tropical and subtropical regions including the Caribbean, Central and South America, Africa, India, and Southeast Asia.⁹ However, cases of C. belli can also occur in resource-rich countries like the United States due to travel and immigration, especially when individuals are exposed to contaminated food or water sources.¹⁰ This parasitic infection is more commonly observed in people with HIV (especially, but not exclusively in those with low CD4 T lymphocyte [CD4] cell counts), and outbreaks among institutionalized groups have also been reported.^11-13

Clinical Manifestations

The most common manifestation of cystoisosporiasis is watery, non-bloody diarrhea, which may be associated with abdominal pain, cramping, anorexia, nausea, vomiting, and low-grade fever. The diarrhea can be profuse and prolonged, lasting several weeks or more, particularly in people with HIV or other immunocompromising conditions. This kind of diarrhea often results in severe dehydration, electrolyte abnormalities (e.g., hypokalemia), weight loss, and malabsorption.^6,7,14-18 Extraintestinal infection—such as in the biliary tract, lymph nodes, spleen, and liver—has been documented in postmortem examinations of people with HIV.^2,19-21 Acalculous cholecystitis/cholangiopathy^2,22-24 and reactive arthritis²⁵ also have been reported.

Diagnosis

Typically, infection is diagnosed by detecting Cystoisospora (Isospora) oocysts (dimensions, 23–‍36 µm by 12–17 µm) in fecal specimens.² Oocysts may be shed intermittently and at low levels, even by individuals with profuse diarrhea. Diagnosis can be facilitated by repeated stool examinations with sensitive methods, such as modified acid-fast techniques, on which oocysts stain bright red, and ultraviolet fluorescence microscopy, under which there is autofluorescence.^2,26 The microbiology/parasitology laboratory should be notified of the patient’s immunodeficiency status to ensure appropriate testing is done. Infection can also be diagnosed by detecting oocysts in duodenal aspirates or mucus, or by identifying developmental stages of the parasite in intestinal biopsy specimens or using the string test (Entero-Test).^2,16

Polymerase chain reaction (PCR) methods are increasingly used to detect C. belli for diagnosis, as supported by existing literature.¹⁰ These molecular quantitative PCR or qPCR techniques offer such advantages as faster detection and the ability to detect multiple parasites simultaneously, making them more efficient than traditional microscopy.²⁷ PCR methods have demonstrated a sensitivity ranging from 87% to 100% and a specificity ranging from 88% to 100% for detecting C. belli.²⁷ However, it is important to note that the availability of PCR may be limited in certain settings.

A distinguishing feature of C. belli is eosinophilia.²⁸ However, other helminths, certain fungi (e.g., coccidioidomycosis, histoplasmosis, cryptococcosis), and certain protozoan parasites (e.g., Dientamoeba fragilis, Sarcocycstis) should be part of the differential diagnosis as these can also cause eosinophilia in the blood.

Preventing Exposure

C. belli is acquired by ingesting contaminated water or food. Hand washing with soap, avoiding potentially contaminated food (e.g., salads) or water in cystoisosporiasis-endemic areas, and proper food preparation (peeling fruits and cooking vegetables) can help prevent infection.

Water filtration using certified filters is effective (absolute one micron or less, National Sanitation Foundation/American National Standards Institute [ANSI] Standard 53 or Standard 58 for cyst removal or cyst reduction by an ANSI-accredited certification organization).²⁹ Filters that may not be designed to safely remove C. belli and other protozoans include those with a nominal pore size of one micron or smaller, filters labeled as “Effective against Giardia” or “Effective against parasites,” carbon filters, active carbon filters, chlorinated filters, ultraviolet light filters, water purifiers, and filters labeled as “U.S. Environmental Protection Agency (EPA) approved” or “EPA registered” (note: the EPA does not test, certify, or register filters based on their ability to remove Cystoisospora and other protozoans).

Preventing Disease

Several studies have found that chemoprophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) is associated with a lower incidence or prevalence of cystoisosporiasis.^1,3,4,30 In a randomized, placebo-controlled trial, daily TMP-SMX (160/800 mg) was protective against cystoisosporiasis in people with early-stage HIV infection (World Health Organization clinical stage 2 or 3 at enrollment).¹ In an observational study,³ the incidence of cystoisosporiasis decreased after widespread introduction of antiretroviral therapy (ART), except in individuals with CD4 counts <50 cells/mm³. In that study, multivariable analysis found the relative hazard for C. belli infection was 6.2 in individuals with CD4 counts between 50 and 199 cells/mm³ and 15.9 for individuals with CD4 counts <‍50 cells/mm³. After adjustment for the CD4 count, the risk of cystoisosporiasis was substantially lower in those receiving prophylaxis with TMP-SMX, sulfadiazine, or pyrimethamine (unspecified regimens). In analyses of data from a Los Angeles County AIDS surveillance registry during the pre-ART era, the prevalence of cystoisosporiasis was lower in people with a history of Pneumocystis pneumonia (PCP) compared to those without PCP; indirect evidence of a protective effect from the use of TMP-SMX for PCP treatment and secondary prevention.⁴ Given the substantially increased risk of infection in individuals with low CD4 counts, we recommend ensuring that individuals with CD4 counts <200 cells/mm³ are started and maintained on TMP-SMX if they are living in or traveling to regions endemic for C. belli (CII). Primary prophylaxis can be discontinued for people with a sustained increase in CD4 count to ≥200 cells/mm³ for >6 months in response to ART (BIII). Data on alternative medications for primary prophylaxis for people with sulfa intolerance are limited. The primary approach to prevention of cystoisosporiasis is to reduce the risk of acquisition by avoiding potentially contaminated food or water in cystoisosporiasis-endemic areas via regular hand washing, proper food preparation (peeling fruits, cooking vegetables), and use of certified water filters of 1 micron or less.

Treating Disease

Clinical management includes fluid and electrolyte support for people with dehydration (AIII) and nutritional supplementation for people who are malnourished (AIII). TMP-SMX is the antimicrobial agent of choice for treatment of cystoisosporiasis (AII). It is the only agent whose use is supported by substantial published data and clinical experience. Therefore, potential alternative therapies should be reserved for people with documented sulfa intolerance (AIII) or in whom treatment fails (BIII).

Three studies in people with HIV in Haiti have demonstrated the effectiveness of various TMP-SMX treatment regimens.^6,7,31 Participants in these studies were not receiving ART, and laboratory indicators of immunodeficiency (such as CD4 cell counts) were not reported. Based on the initial studies,^6,7 the traditional treatment regimen has been a 10-day course of TMP-SMX (160/800 mg) administered orally four times daily (AII).^7, In another study, TMP-SMX (160/800 mg) administered twice daily for seven days was also effective (BI).³¹ Although published experience using twice-daily TMP-SMX (160/800 mg) is limited, one approach would be to start with this regimen but increase the daily dose and/or the duration of therapy (up to 3 to 4 weeks)^6,16 if symptoms worsen or persist (BIII). Intravenous administration of TMP-SMX should be considered for patients with potential or documented malabsorption or for those who cannot tolerate oral medications.

Some data suggest that therapy with pyrimethamine–sulfadiazine and pyrimethamine–sulfadoxine may be effective.^{2,15,16,33,34} However, the combination of pyrimethamine plus sulfadoxine is not typically recommended (CIII), due to associations with an increased risk of severe cutaneous reactions, including Stevens-Johnson syndrome,³⁵ and slow clearance from the body after therapy is discontinued. In addition, sulfadoxine is not commercially available in the United States.

Single-agent therapy with pyrimethamine has been used, with anecdotal success for treatment and prevention of cystoisosporiasis.^3,36,37 Pyrimethamine (50–75 mg/day) plus leucovorin (10–‍25 mg/day) for 4 weeks may be an effective treatment alternative option for sulfa-intolerant patients (BIII). The leucovorin is given to prevent myelosuppression from pyrimethamine.

Ciprofloxacin is a second-line agent that can be used for individuals with sulfa allergy and an inability to obtain pyrimethamine (CI). In a randomized, controlled trial in Haiti, ciprofloxacin 500 mg orally (PO) twice daily for 7 days was less effective than PO TMP-SMX but may have modest activity against C. belli.³¹

Special Considerations With Regard to Starting ART

There are limited data on the effectiveness of ART for C. belli infection in the setting of HIV coinfection.^3,23,30 Immune reconstitution with ART may result in fewer relapses of cystoisosporiasis, and immune reconstitution inflammatory syndrome (IRIS) has not been reported. Therefore, for people with HIV and cystoisosporiasis, TMP-SMX therapy and ART should both be started as soon as possible, and ART initiation should not be deferred (AIII).

Monitoring of Response to Therapy and Adverse Events (Including IRIS)

People treated for cystoisosporiasis should be monitored for clinical response and adverse events. In people with HIV, TMP-SMX therapy is commonly associated with side effects, such as rash, fever, leukopenia, thrombocytopenia, elevated transaminase levels, and hyperkalemia. For ciprofloxacin, side effects beyond gastrointestinal issues include prolong QT intervals and tendonitis and tendon rupture. For pyrimethamine, side effects include bone marrow suppression. As noted earlier, IRIS has not been described in this population.

Managing Treatment Failure

If symptoms worsen or persist despite approximately 5 to 7 days of TMP-SMX therapy, the possibilities of nonadherence, malabsorption, and concurrent other gastrointestinal infections or enteropathies should be considered and the TMP-SMX regimen (daily dose, duration, and mode of administration) should be reevaluated (AIII).³⁸ For people with documented sulfa intolerance or in whom treatment fails, use of a potential alternative agent (typically pyrimethamine) should be considered (BIII).

The effectiveness of albendazole,^37,39,40 nitazoxanide,^41,42 doxycycline,⁴³ and the macrolides roxithromycin and spiramycin,^33,44,45 have not been substantiated. Metronidazole, quinacrine, iodoquinol, paromomycin, and furazolidone appear to be ineffective.^{14,33,34,36,44}

Preventing Recurrence

People with HIV with CD4 counts <200 cells/mm³ should receive secondary prophylaxis (chronic maintenance therapy) with TMP-SMX (AI), which is also protective against Pneumocystis jirovecii and Toxoplasma gondii infections. Based on observational studies in Haiti, approximately 50% of patients who did not receive secondary prophylaxis had symptomatic recurrences approximately 2 months after completing a course of TMP-SMX therapy. These relapses rapidly responded to retreatment and secondary prophylaxis decreased the risk of another relapse.^6,7,31 In a randomized, placebo-controlled trial in Haiti, no symptomatic recurrences were noted in people who received maintenance therapy with thrice-weekly TMP-SMX (160/800 mg) (AI).⁷ Daily TMP-SMX (160/800 mg) (AIII) and thrice-weekly TMP-SMX (320/1600 mg) have been effective (BIII)^5,16; however, clinical and parasitological relapses despite maintenance TMP-SMX therapy and ART have been reported.²³ Many of these studies were conducted in the pre-ART era. It is unclear if recurrent Cystoisospora infections are due to relapse or reinfection.

In sulfa-intolerant patients, pyrimethamine (25 mg/day) with leucovorin (5–10 mg/day) has been used (BIII).³⁶ Based on limited data, ciprofloxacin (500 mg thrice weekly) is considered a second-line alternative, although some data question whether it is efficacious at all (CI).³¹

When To Stop Secondary Prophylaxis

The issue of discontinuing prophylaxis has not been evaluated in a clinical trial. Chemoprophylaxis probably can be safely discontinued in individuals without evidence of active C. belli infection who have a sustained increase in the CD4 count to levels ≥200 cells/mm³ for >6 months after initiation of ART (BIII).

Special Considerations During Pregnancy

TMP-SMX is the agent of choice for treatment as well as primary and secondary prophylaxis during pregnancy. Although first-trimester exposure to TMP has been associated with a small increase in the risk of birth defects,^46-49 TMP-SMX therapy should be provided in the setting of maternal symptomatic C. belli infection. Due to concerns about possible teratogenicity associated with first-trimester drug exposure, clinicians may withhold secondary prophylaxis during the first trimester and treat only symptomatic infection, unless TMP-SMX is needed for PCP prophylaxis (CIII). Most members of the Panel on Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents With HIV recommend that clinicians give supplemental folic acid 4 mg/day to women who are on TMP-SMX if they are capable of becoming pregnant, or as soon as possible in their first trimester (BIII).^48-50 Additional details regarding the use of TMP-SMX during pregnancy are provided at Pneumocystis Pneumonia. Although pyrimethamine has been associated with birth defects in animals, limited human data have not suggested an increased risk of defects.⁵¹ Long-term therapy with pyrimethamine should be used only if the potential benefit outweighs the potential risk. Human data about the use of ciprofloxacin during several hundred pregnancies have not suggested an increased risk of birth defects or cartilage abnormalities, but efficacy against C. belli has been questioned.⁵² Both TMP-SMX and ciprofloxacin are category C for pregnancy.

References

1. Anglaret X, Chene G, Attia A, et al. Early chemoprophylaxis with trimethoprim-sulphamethoxazole for HIV-1-infected adults in Abidjan, Cote d’Ivoire: a randomised trial. Cotrimo-CI Study Group. Lancet. 1999;353(9163):1463-1468. Available at: https://pubmed.ncbi.nlm.nih.gov/10232311.
2. Lindsay DS, Dubey JP, Blagburn BL. Biology of Isospora spp. from humans, nonhuman primates, and domestic animals. Clin Microbiol Rev. 1997;10(1):19-34. Available at: https://pubmed.ncbi.nlm.nih.gov/8993857.
3. Guiguet M, Furco A, Tattevin P, Costagliola D, Molina JM, French Hospital Database on HIVCEG. HIV-associated Isospora belli infection: incidence and risk factors in the French Hospital Database on HIV. HIV Med. 2007;8(2):124-130. Available at: https://pubmed.ncbi.nlm.nih.gov/17352769.
4. Sorvillo FJ, Lieb LE, Seidel J, Kerndt P, Turner J, Ash LR. Epidemiology of isosporiasis among persons with acquired immunodeficiency syndrome in Los Angeles County. Am J Trop Med Hyg. 1995;53(6):656-659. Available at: https://pubmed.ncbi.nlm.nih.gov/8561272.
5. Certad G, Arenas-Pinto A, Pocaterra L, et al. Isosporiasis in Venezuelan adults infected with human immunodeficiency virus: clinical characterization. Am J Trop Med Hyg. 2003;69(2):217-222. Available at: https://pubmed.ncbi.nlm.nih.gov/13677379.
6. DeHovitz JA, Pape JW, Boncy M, Johnson WD, Jr. Clinical manifestations and therapy of Isospora belli infection in patients with the acquired immunodeficiency syndrome. N Engl J Med. 1986;315(2):87-90. Available at: https://pubmed.ncbi.nlm.nih.gov/3487730.
7. Pape JW, Verdier RI, Johnson WD, Jr. Treatment and prophylaxis of Isospora belli infection in patients with the acquired immunodeficiency syndrome. N Engl J Med. 1989;320(16):1044-1047. Available at: https://pubmed.ncbi.nlm.nih.gov/2927483.
8. Centers for Disease Control and Prevention. Cystoisosporiasis. 2024. Available at: https://www.cdc.gov/dpdx/cystoisosporiasis/index.html.
9. Hechenbleikner EM, McQuade JA. Parasitic colitis. Clin Colon Rectal Surg. 2015;28(2):79-86. Available at: https://pubmed.ncbi.nlm.nih.gov/26034403.
10. Legua P, Seas C. Cystoisospora and cyclospora. Curr Opin Infect Dis. 2013;26(5):479-483. Available at: https://pubmed.ncbi.nlm.nih.gov/23982239.
11. Johnstone SL, Erasmus L, Thomas J, et al. Epidemiology and aetiology of moderate to severe diarrhoea in hospitalised patients >/=5 years old living with HIV in South Africa, 2018–2021: a case-control analysis. PLOS Glob Public Health. 2023;3(9):e0001718. Available at: https://pubmed.ncbi.nlm.nih.gov/37682831.
12. Nsagha DS, Njunda AL, Assob NJC, et al. Intestinal parasitic infections in relation to CD4(+) T cell counts and diarrhea in HIV/AIDS patients with or without antiretroviral therapy in Cameroon. BMC Infect Dis. 2016;16:9. Available at: https://pubmed.ncbi.nlm.nih.gov/26754404.
13. Assefa S, Erko B, Medhin G, Assefa Z, Shimelis T. Intestinal parasitic infections in relation to HIV/AIDS status, diarrhea and CD4 T-cell count. BMC Infect Dis. 2009;9:155. Available at: https://pubmed.ncbi.nlm.nih.gov/19765310.
14. Forthal DN, Guest SS. Isospora belli enteritis in three homosexual men. Am J Trop Med Hyg. 1984;33(6):1060-1064. Available at: https://pubmed.ncbi.nlm.nih.gov/6507724.
15. Modigliani R, Bories C, Le Charpentier Y, et al. Diarrhoea and malabsorption in acquired immune deficiency syndrome: a study of four cases with special emphasis on opportunistic protozoan infestations. Gut. 1985;26(2):179-187. Available at: https://pubmed.ncbi.nlm.nih.gov/4038492.
16. Whiteside ME, Barkin JS, May RG, Weiss SD, Fischl MA, MacLeod CL. Enteric coccidiosis among patients with the acquired immunodeficiency syndrome. Am J Trop Med Hyg. 1984;33(6):1065-1072. Available at: https://pubmed.ncbi.nlm.nih.gov/6334448.
17. Bialek R, Overkamp D, Rettig I, Knobloch J. Case report: nitazoxanide treatment failure in chronic isosporiasis. Am J Trop Med Hyg. 2001;65(2):94-95. Available at: https://pubmed.ncbi.nlm.nih.gov/11508398.
18. Williams DT, Smith RS, Mallon WK. Severe hypokalemia, paralysis, and AIDS-associated isospora belli diarrhea. J Emerg Med. 2011;41(6):e129-132. Available at: https://pubmed.ncbi.nlm.nih.gov/18993015.
19. Frenkel JK, Silva MB, Saldanha J, et al. Isospora belli infection: observation of unicellular cysts in mesenteric lymphoid tissues of a Brazilian patient with AIDS and animal inoculation. J Eukaryot Microbiol. 2003;50 Suppl:682-684. Available at: https://pubmed.ncbi.nlm.nih.gov/14736218.
20. Restrepo C, Macher AM, Radany EH. Disseminated extraintestinal isosporiasis in a patient with acquired immune deficiency syndrome. Am J Clin Pathol. 1987;87(4):536-542. Available at: https://pubmed.ncbi.nlm.nih.gov/3826017.
21. Bernard E, Delgiudice P, Carles M, et al. Disseminated isosporiasis in an AIDS patient. Eur J Clin Microbiol Infect Dis. 1997;16(9):699-701. Available at: https://pubmed.ncbi.nlm.nih.gov/9352268.
22. Benator DA, French AL, Beaudet LM, Levy CS, Orenstein JM. Isospora belli infection associated with acalculous cholecystitis in a patient with AIDS. Ann Intern Med. 1994;121(9):663-664. Available at: https://pubmed.ncbi.nlm.nih.gov/7944075.
23. Lagrange-Xelot M, Porcher R, Sarfati C, et al. Isosporiasis in patients with HIV infection in the highly active antiretroviral therapy era in France. HIV Med. 2008;9(2):126-130. Available at: https://pubmed.ncbi.nlm.nih.gov/18257775.
24. Walther Z, Topazian MD. Isospora cholangiopathy: case study with histologic characterization and molecular confirmation. Hum Pathol. 2009;40(9):1342-1346. Available at: https://pubmed.ncbi.nlm.nih.gov/19447468.
25. Gonzalez-Dominguez J, Roldan R, Villanueva JL, Kindelan JM, Jurado R, Torre-Cisneros J. Isospora belli reactive arthritis in a patient with AIDS. Ann Rheum Dis. 1994;53(9):618-619. Available at: https://pubmed.ncbi.nlm.nih.gov/7979603.
26. Bialek R, Binder N, Dietz K, Knobloch J, Zelck UE. Comparison of autofluorescence and iodine staining for detection of Isospora belli in feces. Am J Trop Med Hyg. 2002;67(3):304-305. Available at: https://pubmed.ncbi.nlm.nih.gov/12408672.
27. Taniuchi M, Verweij JJ, Sethabutr O, et al. Multiplex polymerase chain reaction method to detect Cyclospora, Cystoisospora, and Microsporidia in stool samples. Diagn Microbiol Infect Dis. 2011;71(4):386-390. Available at: https://pubmed.ncbi.nlm.nih.gov/21982218.
28. Dubey JP, Almeria S. Cystoisospora belli infections in humans: the past 100 years. Parasitology. 2019;146(12):1490-1527. Available at: https://pubmed.ncbi.nlm.nih.gov/31303182.
29. Centers for Disease Control and Prevention. About choosing home water filters. 2024. Available at: https://www.cdc.gov/drinking-water/prevention/about-choosing-home-water-filters.html.
30. Dillingham RA, Pinkerton R, Leger P, et al. High early mortality in patients with chronic acquired immunodeficiency syndrome diarrhea initiating antiretroviral therapy in Haiti: a case-control study. Am J Trop Med Hyg. 2009;80(6):1060-1064. Available at: https://pubmed.ncbi.nlm.nih.gov/19478276.
31. Verdier RI, Fitzgerald DW, Johnson WD, Jr., Pape JW. Trimethoprim-sulfamethoxazole compared with ciprofloxacin for treatment and prophylaxis of Isospora belli and Cyclospora cayetanensis infection in HIV-infected patients. A randomized, controlled trial. Ann Intern Med. 2000;132(11):885-888. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10836915.
32. Shane AL, Mody RK, Crump JA, et al. 2017 Infectious Diseases Society of America clinical practice guidelines for the diagnosis and management of infectious diarrhea. Clin Infect Dis. 2017;65(12):e45-e80. Available at: https://pubmed.ncbi.nlm.nih.gov/29053792.
33. Ebrahimzadeh A, Bottone EJ. Persistent diarrhea caused by Isospora belli: therapeutic response to pyrimethamine and sulfadiazine. Diagn Microbiol Infect Dis. 1996;26(2):87-89. Available at: https://pubmed.ncbi.nlm.nih.gov/8985661.
34. Trier JS, Moxey PC, Schimmel EM, Robles E. Chronic intestinal coccidiosis in man: intestinal morphology and response to treatment. Gastroenterology. 1974;66(5):923-935. Available at: https://pubmed.ncbi.nlm.nih.gov/4826994.
35. Navin TR, Miller KD, Satriale RF, Lobel HO. Adverse reactions associated with pyrimethamine-sulfadoxine prophylaxis for Pneumocystis carinii infections in AIDS. Lancet. 1985;1(8441):1332. Available at: https://pubmed.ncbi.nlm.nih.gov/2860516.
36. Weiss LM, Perlman DC, Sherman J, Tanowitz H, Wittner M. Isospora belli infection: treatment with pyrimethamine. Ann Intern Med. 1988;109(6):474-475. Available at: https://pubmed.ncbi.nlm.nih.gov/3261956.
37. Jongwutiwes S, Sampatanukul P, Putaporntip C. Recurrent isosporiasis over a decade in an immunocompetent host successfully treated with pyrimethamine. Scand J Infect Dis. 2002;34(11):859-862. Available at: https://pubmed.ncbi.nlm.nih.gov/12578164.
38. Iordanov RB, Leining LM, Wu M, Chan G, DiNardo AR, Mejia R. Case report: molecular diagnosis of Cystoisospora belli in a severely immunocompromised patient with HIV and Kaposi sarcoma. Am J Trop Med Hyg. 2021;106(2):678-680. Available at: https://pubmed.ncbi.nlm.nih.gov/34844211.
39. Dionisio D, Sterrantino G, Meli M, Leoncini F, Orsi A, Nicoletti P. Treatment of isosporiasis with combined albendazole and ornidazole in patients with AIDS. AIDS. 1996;10(11):1301-1302. Available at: https://pubmed.ncbi.nlm.nih.gov/8883600.
40. Zulu I, Veitch A, Sianongo S, et al. Albendazole chemotherapy for AIDS-related diarrhoea in Zambia--clinical, parasitological and mucosal responses. Aliment Pharmacol Ther. 2002; 16(3):595-601. Available at: https://pubmed.ncbi.nlm.nih.gov/11876715.
41. Romero Cabello R, Guerrero LR, Munoz Garcia MR, Geyne Cruz A. Nitazoxanide for the treatment of intestinal protozoan and helminthic infections in Mexico. Trans R Soc Trop Med Hyg. 1997;91(6):701-703. Available at: https://pubmed.ncbi.nlm.nih.gov/9580117.
42. Doumbo O, Rossignol JF, Pichard E, et al. Nitazoxanide in the treatment of cryptosporidial diarrhea and other intestinal parasitic infections associated with acquired immunodeficiency syndrome in tropical Africa. Am J Trop Med Hyg. 1997;56(6):637-639. Available at: https://pubmed.ncbi.nlm.nih.gov/9230795.
43. Meyohas MC, Capella F, Poirot JL, et al. [Treatment with doxycycline and nifuroxazide of Isospora belli infection in AIDS]. Pathol Biol (Paris). 1990;38(5 ( Pt 2)):589-591. Available at: https://pubmed.ncbi.nlm.nih.gov/2385457.
44. Gaska JA, Tietze KJ, Cosgrove EM. Unsuccessful treatment of enteritis due to Isospora belli with spiramycin: a case report. J Infect Dis. 1985;152(6):1336-1338. Available at: https://pubmed.ncbi.nlm.nih.gov/4067332.
45. Musey KL, Chidiac C, Beaucaire G, Houriez S, Fourrier A. Effectiveness of roxithromycin for treating Isospora belli infection. J Infect Dis. 1988;158(3):646. Available at: https://pubmed.ncbi.nlm.nih.gov/3411149.
46. Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA. Neural tube defects in relation to use of folic acid antagonists during pregnancy. Am J Epidemiol. 2001;153(10):961-968. Available at: https://pubmed.ncbi.nlm.nih.gov/11384952.
47. Jungmann EM, Mercey D, DeRuiter A, et al. Is first trimester exposure to the combination of antiretroviral therapy and folate antagonists a risk factor for congenital abnormalities? Sex Transm Infect. 2001;77(6):441-443. Available at: https://pubmed.ncbi.nlm.nih.gov/11714944.
48. Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J. The teratogenic risk of trimethoprim-sulfonamides: a population based case-control study. Reprod Toxicol. 2001;15(6):637-646. Available at: https://pubmed.ncbi.nlm.nih.gov/11738517.
49. Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA. Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med. 2000;343(22):1608-1614. Available at: https://pubmed.ncbi.nlm.nih.gov/11096168.
50. Bortolus R, Filippini F, Cipriani S, et al. Efficacy of 4.0 mg versus 0.4 mg folic acid supplementation on the reproductive outcomes: a randomized controlled trial. Nutrients. 2021;13(12). Available at: https://pubmed.ncbi.nlm.nih.gov/34959975.
51. Deen JL, von Seidlein L, Pinder M, Walraven GE, Greenwood BM. The safety of the combination artesunate and pyrimethamine-sulfadoxine given during pregnancy. Trans R Soc Trop Med Hyg. 2001;95(4):424-428. Available at: https://pubmed.ncbi.nlm.nih.gov/11579889.
52. Nahum GG, Uhl K, Kennedy DL. Antibiotic use in pregnancy and lactation: what is and is not known about teratogenic and toxic risks. Obstet Gynecol. 2006;107(5):1120-1138. Available at: https://pubmed.ncbi.nlm.nih.gov/16648419.