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

Epidemiology

Oropharyngeal and esophageal candidiasis are common in people with HIV.¹ The vast majority of such infections are caused by Candida albicans, although infections caused by non–C. albicans species have been increasingly reported worldwide, in part due to increased selection pressure from increased use of azoles.^2-9 The occurrence of oropharyngeal or esophageal candidiasis is recognized as an indicator of immune suppression and is most often observed in people with CD4 T lymphocyte (CD4) cell counts <200 cells/mm³, with esophageal disease typically occurring at lower CD4 counts than oropharyngeal disease.^10,11 In contrast, vulvovaginal candidiasis—whether a single episode or recurrent—is common in healthy adults and does not suggest HIV.

Clinical Manifestations

Oropharyngeal candidiasis (oral thrush) is characterized by painless, creamy white, plaque-like lesions that can occur on the buccal surface, hard or soft palate, gums, oropharynx, or tongue surface. In many cases, lesions can be scraped off with a tongue depressor or other instrument. Less commonly, erythematous patches without white plaques can be seen on the anterior or posterior upper palate or diffusely on the tongue. Angular cheilosis also can be caused by Candida. Because a proportion of people with HIV who have oropharyngeal candidiasis also manifest esophageal involvement, clinicians should ascertain whether there are symptoms suggestive of esophageal disease in people with oropharyngeal candidiasis.

Esophageal candidiasis generally presents with retrosternal burning pain or discomfort along with odynophagia; occasionally, esophageal candidiasis can be asymptomatic. Endoscopic examination reveals whitish plaques similar to those observed with oropharyngeal disease. On occasion, the plaques may progress to superficial ulcerations of the esophageal mucosa with central or peripheral whitish exudates.

In contrast to oropharyngeal candidiasis, vulvovaginal candidiasis is less common in people with HIV and when it occurs, it is uncommonly refractory to azole therapy unless caused by non-C. albicans species. In people with HIV, Candida vulvovaginitis usually presents with white adherent vaginal discharge associated with mucosal burning and itching of mild-to-moderate severity and sporadic recurrences. In those with advanced immunosuppression, episodes may be more severe and recur more frequently.

Diagnosis

Oropharyngeal candidiasis is usually diagnosed clinically based on the characteristic appearance of lesions. In contrast to oral hairy leukoplakia, the white plaques of oropharyngeal candidiasis can be scraped off the mucosa. If laboratory confirmation is required, scrapings can be examined microscopically for characteristic yeast or hyphal forms, using a potassium hydroxide preparation. Cultures of clinical exudative material yield the species of Candida present.

Esophageal candidiasis should be suspected in people with low CD4 count with substernal chest pain, dysphagia, and odynophagia, especially if there is oral thrush present (though the absence of oral thrush does not rule out esophageal involvement). The diagnosis of esophageal candidiasis is often made empirically based on symptoms plus response to therapy. The definitive diagnosis of esophageal candidiasis requires direct endoscopic visualization of lesions with histopathologic demonstration of characteristic Candida yeast forms in tissue and confirmation by fungal culture and speciation.

Vulvovaginal candidiasis usually is diagnosed based on clinical presentation coupled with the demonstration of characteristic blastosphere and hyphal yeast forms in vaginal secretions when examined microscopically after potassium hydroxide preparation. Culture confirmation is rarely required but may provide supportive information. Self-diagnosis of vulvovaginitis is unreliable; microscopic and culture confirmation is required to avoid unnecessary exposure to treatment and to assess for other potential pathogens including those that cause sexually transmitted infections (STIs).

Preventing Exposure

Candida organisms are common commensals on mucosal surfaces in healthy individuals. No measures are available to reduce exposure to these fungi.

Preventing Disease

Routine primary prophylaxis is not recommended because mucosal disease is associated with very low attributable morbidity and mortality and, moreover, acute therapy is highly effective.^12,13 Primary antifungal prophylaxis can lead to infections caused by drug-resistant Candida strains and introduce significant drug–drug interactions and QTc (QT corrected for heart rate) prolongation. In addition, long-term oral prophylaxis is expensive. Therefore, routine primary prophylaxis is not recommended (AIII). Administration of antiretroviral therapy (ART) and immune restoration is the most effective means to prevent disease.

Treating Disease

Oropharyngeal Candidiasis

Oral fluconazole is as effective as or superior to topical therapy for oropharyngeal candidiasis.¹⁴ In addition, oral therapy is more convenient than topical therapy and usually better tolerated. Oral therapy has the additional benefit over topical regimens of being efficacious in treating esophageal candidiasis. Oral fluconazole at 100 to 200 mg once a day is considered the drug of choice to treat oropharyngeal candidiasis except during pregnancy (AI).¹⁴ One to 2 weeks of therapy until resolution of infection is recommended for oropharyngeal candidiasis.¹⁴

Using topical agents to treat oropharyngeal candidiasis includes several advantages: it reduces systemic drug exposure, diminishes the risk of drug–drug interactions and systemic adverse events, and may reduce the likelihood that antifungal resistance develops. As an alternative to oral fluconazole, once-daily miconazole in 50-mg mucoadhesive buccal tablets (BI) or five-times-per-day clotrimazole troches can be used to treat oropharyngeal candidiasis (BI); these regimens were shown to be equivalent in a multicenter, randomized study. Nystatin suspension four times daily remains an additional alternative (BII).¹⁵ Unfavorable taste and multiple daily dosing, such as in the cases of clotrimazole and nystatin, may lead to decreased tolerability of and adherence to these topical therapies. If esophageal involvement is suspected, topical therapy alone is not recommended (AI).

Itraconazole is formulated as an oral solution or capsules, which differ in dosing and efficacy. Oral itraconazole for 7 to 14 days is as effective as oral fluconazole for oropharyngeal candidiasis but less well tolerated.¹⁶ Posaconazole oral suspension¹⁷ is also as effective as fluconazole and generally better tolerated than itraconazole solution, but it is more expensive. Although both posaconazole and itraconazole have more drug–drug interactions than fluconazole, there are a few situations, such as in vitro resistance or poor clinical response, that would suggest these drugs be used in preference to fluconazole solely to treat mucosal candidiasis (BI). In a multicenter, randomized study, posaconazole was found to be more effective than fluconazole in sustaining clinical success after antifungal therapy was discontinued.¹⁷ A oral delayed-release tablet formulation of posaconazole, which exhibits less variable absorption than the oral suspension, has been available.¹⁸ Whether it offers any advantage for the treatment of oropharyngeal candidiasis has not been formally tested; however, it has been shown that switching from the oral suspension to the tablet formulation of posaconazole results in greater serum concentrations.¹⁹ Itraconazole capsules are less effective than fluconazole because of their more variable absorption, and they are associated with more drug–drug interactions than fluconazole.

Esophageal Candidiasis

Systemic antifungals are required for effective treatment of esophageal candidiasis (AI). A 14-day to 21-day course of either fluconazole (oral or intravenous [IV]) or oral itraconazole solution is highly effective and therefore recommended (AI). As with oropharyngeal candidiasis, however, itraconazole capsules for esophageal candidiasis may be less effective than fluconazole because of variable absorption Therefore, oral or IV fluconazole remains the preferred therapy for esophageal candidiasis (AI). People with severe symptoms initially may have difficulty swallowing oral drugs; oral fluconazole suspension is available and should be considered in such patients. A 2-week course of isavuconazole, given orally at an initial loading dose of 400 mg followed by 100 mg once daily (BI) or 400 mg once weekly, is as effective as fluconazole for uncomplicated esophageal candidiasis and is recommended as an alternative regimen (BI); however, a higher rate of gastrointestinal adverse effects was seen with the 100-mg, once-daily isavuconazole regimen than with fluconazole and the other isavuconazole regimens.²⁰ Posaconazole, voriconazole, amphotericin B (lipid formulations), and the echinocandins caspofungin, micafungin, and anidulafungin all effectively treat esophageal candidiasis and also can be administered as alternatives (BI); however, esophageal candidiasis appears to have a higher relapse rate after treatment with the echinocandins.^21,22 Cost and insurance coverage also might be issues for the newer therapies.

Although infection with other pathogens that can cause esophagitis (e.g., cytomegalovirus, herpes simplex virus) can result in symptoms that mimic those of esophageal candidiasis, a diagnostic and therapeutic trial of antifungal therapy is usually warranted before endoscopy. In those who do not respond to antifungal therapy within 7 days, endoscopy is recommended to identify other potential causes of esophagitis or drug-resistant Candida (AII).

Vulvovaginal Candidiasis

In most people with HIV, vulvovaginal candidiasis is uncomplicated and responds readily to short-course oral or topical treatment with any of several therapies, including the following:

• Oral fluconazole (AII)
• Topical azoles (i.e., clotrimazole, butoconazole, miconazole, tioconazole, or terconazole) (AII)
• Oral ibrexafungerp (BI)

Severe or recurrent episodes of vaginitis should be treated with oral fluconazole or topical antifungal therapy for ≥7 days (AII).

There are now additional options for recurrent vulvovaginal candidiasis that include treatment for the acute episode plus treatment to reduce incidence of recurrent episodes. One option for people who are not of reproductive potential is oteseconazole, a new tetrazole antifungal that was U.S. Food and Drug Administration (FDA)–approved in 2022. It exhibited efficacy when administered as 600 mg on Day 1 and 450 mg on Day 2, followed by once-weekly 150 mg dosing starting at Day 14 for 11 weeks or when it was administered after three fluconazole 150-mg doses administered at Days 1, 4, and 7, followed by oteseconazole 150 mg daily dosing at Days 14 through 20, followed by oteseconazole 150 mg once weekly starting at Day 28 for 11 weeks (Weeks 4 through 14) (AI).^23,24

Ibrexafungerp is an oral b-glucan synthase inhibitor that belongs in the class of triterpenoids. It was effective in Phase 2 and Phase 3 clinical trials of uncomplicated vulvovaginal candidiasis and was approved by the FDA in 2021.^25,26 In December 2022, ibrexafungerp was approved by the FDA for women with recurrent vulvovaginal candidiasis. Specifically, administration of fluconazole 150 mg every 72 hours for three doses, followed by ibrexafungerp 300 mg twice daily 1 day per month for 6 months was associated with absence of recurrent infection through week 24 in 65.4% of women compared to 53.1% of women who received placebo. These findings have been reported only in a press release,²⁷ with results available at ClinicalTrials.gov and on the FDA label,²⁸ and are thereby less compelling than peer-reviewed publication. Therefore, ibrexafungerp can be administered for recurrent vulvovaginal candidiasis (BI). Given the potential teratogenic effects of ibrexafungerp, treatment of women with recurrent vulvovaginal candidiasis who may become pregnant requires institution and documentation of effective contraception during treatment and for 4 days after the last dose.²⁹ For additional advice on managing Vulvovaginal Candidiasis, see the section in the STI Treatment Guidelines from the Centers for Disease Control and Prevention.

Special Considerations with Regard to Starting ART

There are no special considerations regarding initiation of ART in people with mucocutaneous candidiasis. Specifically, there is currently no evidence that treatment with ART needs to be delayed until treatment for candidiasis has been completed. For information about drug–drug interactions between azoles and ARV agents, see the Drug–Drug Interactions section in the Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. For information about drug–drug interactions between azoles and other drugs used for the treatment of opportunistic infections, see Table 4: Significant Pharmacokinetic Interactions Between Drugs Used to Treat or Prevent Opportunistic Infections.

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

For most people with mucocutaneous candidiasis, response to antifungal therapy is rapid; signs and symptoms improve within 48 to 72 hours. Short courses of topical therapy rarely result in adverse effects, although people may experience cutaneous hypersensitivity reactions characterized by rash and pruritus. Oral azole therapy can be associated with nausea, vomiting, diarrhea, abdominal pain, or transaminase elevations. Liver function and the QTc interval should be monitored if azole therapy is anticipated for >21 days, especially in people with other hepatic comorbidities or on concomitant hepatotoxic drugs (AII). The echinocandins appear to be associated with very few adverse reactions: histamine-related infusion toxicity, transaminase elevations, and rash have been attributed to these drugs. No dose adjustments are required in renal failure.³⁰

Immune reconstitution inflammatory syndrome (IRIS) with ART has rarely been reported for mucocutaneous candidiasis in people with HIV. Indeed, ART is associated with a markedly reduced incidence of candidiasis.^31,32

Managing Treatment Failure

Antifungal treatment failure is typically defined as the persistence of signs or symptoms of oropharyngeal or esophageal candidiasis within 7 days of appropriate antifungal therapy. Refractory disease occurs in approximately 4% to 5% of people with HIV who have oral or esophageal candidiasis, typically those with CD4 counts <50 cells/mm³ who have received multiple courses of azole antifungals.⁴ Confirmatory culture with drug susceptibilities and, in the case of esophageal candidiasis, endoscopy, are necessary to assess for treatment failure due to azole resistance or other causes of esophagitis, especially if these procedures were not initially performed.

Posaconazole immediate-release oral suspension (400 mg twice daily for 28 days) is effective in 75% of people with azole-refractory oropharyngeal or esophageal candidiasis and is therefore recommended (AI).³³ Again, although the delayed-release tablet formulation of posaconazole is now available, it is not known whether it offers an advantage over the suspension for treating this particular disease. Alternatively, oral itraconazole solution is effective, at least transiently, in approximately two-thirds of people with fluconazole-refractory mucosal candidiasis and can be used as alternative therapy (BII).¹⁶ If necessary, azole-refractory esophageal candidiasis also can be treated with anidulafungin (BII), caspofungin (BII), micafungin (BII), or voriconazole (BII).^21,22,34,35

IV amphotericin B (BII), amphotericin B deoxycholate (BII), and the lipid preparations of amphotericin B (BII) are usually effective for treating azole-refractory disease and are therefore recommended. Amphotericin B oral suspension (1 mL of the 100-mg/mL suspension four times daily) can be administered to people with refractory oropharyngeal candidiasis who cannot take other oral options (BII), but this product is not commercially available in the United States and requires compounding by pharmacies.³⁶

Patients with refractory vaginal candidiasis may benefit from intravaginal boric acid suppositories, which are commercially available at 600 mg.^37,38

Preventing Recurrence

When to Start Suppressive Therapy 

A randomized clinical trial³⁹ of people with HIV who had CD4 counts <150 cells/mm³ documented significantly fewer episodes of oropharyngeal candidiasis and other invasive fungal infections with continuous fluconazole therapy (three times a week) than with episodic fluconazole treatment for recurrences. This clinical trial also demonstrated no difference in the risk of developing clinically significant fluconazole resistance between the two fluconazole-treated groups among patients who were receiving ART.

However, secondary prophylaxis (chronic suppressive therapy) for recurrent oropharyngeal or vulvovaginal candidiasis is not recommended by most HIV specialists unless people have frequent or severe recurrences (CIII) because therapy for acute disease is effective, mortality associated with mucocutaneous disease is low, potential exists for drug interactions and for the development of antifungal-resistant Candida, and prophylaxis is costly. 

If recurrences are frequent or severe, oral fluconazole can be used as suppressive therapy for oropharyngeal (BI), esophageal (BI), or vulvovaginal (AII) candidiasis.^40-42 Oral posaconazole twice daily is also effective for esophageal candidiasis (BII).⁴³ The potential for development of secondary azole resistance should be considered when contemplating chronic maintenance therapy using azoles in people with HIV who are severely immunocompromised.⁴⁴ Several important factors should be considered when making the decision to use secondary prophylaxis. These factors include the effect of recurrences on the person’s well-being and quality of life, the need for prophylaxis against other fungal infections, cost, adverse events, and, most importantly, drug–drug interactions.⁴⁵ 

Rates of relapse are high in people with azole-refractory oropharyngeal or esophageal candidiasis who have initially responded to echinocandins, voriconazole, or posaconazole therapy. In such people, secondary prophylaxis should be instituted until immune reconstitution is achieved with the use of ART (AIII). 

For information regarding oteseconazole and ibrexafungerp, see the Vulvovaginal Candidiasis Treatment Section above. 

When to Stop Suppressive Therapy 

In situations where secondary prophylaxis has been instituted, no data exist to guide recommendations regarding its discontinuation. Based on experience with other opportunistic infections, it would be reasonable to discontinue secondary prophylaxis when the CD4 count has increased to >200 cells/mm³ following initiation of ART (AIII). 

Special Considerations During Pregnancy 

Pregnancy increases the risk of vaginal colonization with Candida species. Diagnosis of oropharyngeal, esophageal, and vulvovaginal candidiasis is the same in pregnant people as in those who are not pregnant. 

Topical therapy is preferable for treatment of oral candidiasis and vulvovaginal candidiasis in pregnancy. Oral fluconazole should be avoided when treating vulvovaginal candidiasis in the first trimester (AIII). Data derived from women with vulvovaginal candidiasis suggest that fluconazole should not be used at any dose (including a single 150-mg dose) in the first trimester due to the risk of spontaneous abortion, while higher exposures (>150 mg dosing) during the first trimester are associated with cardiac septal closure defects.^46-50 A recent analysis of registry data from Sweden and Denmark did not find any increase in stillbirth or neonatal death associated with exposure to fluconazole at any dose during pregnancy.⁵¹ Five cases of a syndrome consisting of craniosynostosis, characteristic facies, digital synostosis, and limb contractures (fluconazole embryopathy) have been reported in women chronically prescribed fluconazole at doses of 400 mg daily or higher in pregnancy.⁴⁸ A report from a national cohort register in Denmark found an increased hazard ratio (HR) of 1.48 for spontaneous pregnancy loss with any exposure to oral fluconazole from 7 to 22 weeks of pregnancy compared to unexposed, matched controls.⁴⁹ An increased HR of 1.47 was also noted with low-dose (150–300-mg cumulative dose) exposure. No increase in stillbirth was seen with fluconazole exposure broadly, but an increase in risk of stillbirth (HR, 4.10) was noted with fluconazole doses >300 mg. 

Based on these data, substitution of amphotericin B for fluconazole in the first trimester is recommended for invasive or refractory esophageal Candida infections (AIII). Neonates born to those receiving chronic amphotericin B at delivery should be evaluated for renal dysfunction and hypokalemia. 

Other azoles are similarly not recommended in pregnancy. Itraconazole at high doses has been shown to be teratogenic in animals,⁵² but the metabolic mechanism accounting for these defects is not present in humans, so the data supporting this finding are of uncertain significance to human pregnancy. Case series in humans do not suggest an increased risk of birth defects with itraconazole,⁵³ but experience is limited. Human data are not available for posaconazole; however, the drug was associated with skeletal abnormalities in rats and was embryotoxic in rabbits when given at doses that produced plasma levels equivalent to those seen in humans.⁵⁴ Evidence is inconclusive or inadequate for determining fetal risk associated with voriconazole use during pregnancy. An association with cleft palate and renal defects has been seen in rats, as well as embryotoxicity seen in rabbits.⁵⁵ Human data on the use of voriconazole are not available, so its use is not recommended. In animals, multiple anomalies have been seen with exposure to micafungin, and ossification defects have been seen with the use of anidulafungin and caspofungin.⁵⁶ Human data are not available for these drugs, thus their use in human pregnancy is not recommended (AIII). 

The recently FDA-approved drugs for the treatment of vulvovaginal candidiasis, ibrexafungerp and oteseconazole, are contraindicated in pregnancy as animal studies have shown fetal malformations including ocular toxicity from oteseconazole.^29,57

Chemoprophylaxis, either chronic maintenance therapy or secondary prophylaxis, against oropharyngeal, esophageal, or vaginal candidiasis using systemically absorbed azoles should not be initiated during pregnancy (AIII). Furthermore, prophylaxis with systemic azoles should be discontinued in people with HIV who become pregnant (AIII).

References

1. Boesecke C, Schellberg S, Schneider J, Schuettfort G, Stocker H. Prevalence, characteristics and challenges of late HIV diagnosis in Germany: an expert narrative review. Infection. 2023;51(5):1223-1239. Available at: https://www.ncbi.nlm.nih.gov/pubmed/37470977.
2. Martins MD, Lozano-Chiu M, Rex JH. Point prevalence of oropharyngeal carriage of fluconazole-resistant Candida in human immunodeficiency virus-infected patients. Clin Infect Dis. 1997;25(4):843-846. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9356799.
3. Maenza JR, Merz WG, Romagnoli MJ, Keruly JC, Moore RD, Gallant JE. Infection due to fluconazole-resistant Candida in patients with AIDS: prevalence and microbiology. Clin Infect Dis. 1997;24(1):28-34. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8994752.
4. Fichtenbaum CJ, Koletar S, Yiannoutsos C, et al. Refractory mucosal candidiasis in advanced human immunodeficiency virus infection. Clin Infect Dis. 2000;30(5):749-756. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10816143.
5. Rex JH, Rinaldi MG, Pfaller MA. Resistance of Candida species to fluconazole. Antimicrob Agents Chemother. 1995;39(1):1-8. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7695288.
6. Patel PK, Erlandsen JE, Kirkpatrick WR, et al. The changing epidemiology of oropharyngeal candidiasis in patients with HIV/AIDS in the era of antiretroviral therapy. AIDS Res Treat. 2012;2012:262471. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22970352.
7. Thanyasrisung P, Kesakomol P, Pipattanagovit P, Youngnak-Piboonratanakit P, Pitiphat W, Matangkasombut O. Oral Candida carriage and immune status in Thai human immunodeficiency virus-infected individuals. J Med Microbiol. 2014;63(Pt 5):753-759. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24591706.
8. Mushi MF, Mtemisika CI, Bader O, et al. High oral carriage of non-albicans Candida spp. among HIV-infected individuals. Int J Infect Dis. 2016;49:185-188. Available at: http://www.ncbi.nlm.nih.gov/pubmed/27401585.
9. Clark-Ordóñez I, Callejas-Negrete OA, Aréchiga-Carvajal ET, Mouriño-Perez RR. Candida species diversity and antifungal susceptibility patterns in oral samples of HIV/AIDS patients in Baja California, Mexico. Med Mycol. 2016. Available at: http://www.ncbi.nlm.nih.gov/pubmed/27630251.
10. Klein RS, Harris CA, Small CB, Moll B, Lesser M, Friedland GH. Oral candidiasis in high-risk patients as the initial manifestation of the acquired immunodeficiency syndrome. N Engl J Med. 1984;311(6):354-358. Available at: http://www.ncbi.nlm.nih.gov/pubmed/6738653.
11. Bonacini M, Young T, Laine L. The causes of esophageal symptoms in human immunodeficiency virus infection. A prospective study of 110 patients. Arch Intern Med. 1991;151(8):1567-1572. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1651690.
12. Brion LP, Uko SE, Goldman DL. Risk of resistance associated with fluconazole prophylaxis: systematic review. J Infect. 2007;54(6):521-529. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17239952.
13. Salem M, Reichlin T, Fasel D, Leuppi-Taegtmeyer A. Torsade de pointes and systemic azole antifungal agents: analysis of global spontaneous safety reports. Glob Cardiol Sci Pract. 2017;2017(2):11. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29644223.
14. Pappas PG, Kauffman CA, Andes DR, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1-50. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26679628.
15. Vazquez JA, Patton LL, Epstein JB, et al. Randomized, comparative, double-blind, double-dummy, multicenter trial of miconazole buccal tablet and clotrimazole troches for the treatment of oropharyngeal candidiasis: study of miconazole Lauriad(R) efficacy and safety (SMiLES). HIV Clin Trials. 2010;11(4):186-196. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20974574.
16. Vazquez JA. Optimal management of oropharyngeal and esophageal candidiasis in patients living with HIV infection. HIV AIDS (Auckl). 2010;2(1):89-101. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22096388.
17. Vazquez JA, Skiest DJ, Nieto L, et al. A multicenter randomized trial evaluating posaconazole versus fluconazole for the treatment of oropharyngeal candidiasis in subjects with HIV/AIDS. Clin Infect Dis. 2006;42(8):1179-1186. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16575739.
18. Krishna G, Ma L, Martinho M, Preston RA, O’Mara E. A new solid oral tablet formulation of posaconazole: a randomized clinical trial to investigate rising single- and multiple-dose pharmacokinetics and safety in healthy volunteers. J Antimicrob Chemother. 2012;67(11):2725-2730. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22833639.
19. Jung DS, Tverdek FP, Kontoyiannis DP. Switching from posaconazole suspension to tablets increases serum drug levels in leukemia patients without clinically relevant hepatotoxicity. Antimicrob Agents Chemother. 2014;58(11):6993-6995. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25199774.
20. Viljoen J, Azie N, Schmitt-Hoffmann AH, Ghannoum M. A phase 2, randomized, double-blind, multicenter trial to evaluate the safety and efficacy of three dosing regimens of isavuconazole compared with fluconazole in patients with uncomplicated esophageal candidiasis. Antimicrob Agents Chemother. 2015;59(3):1671-1679. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25561337.
21. de Wet N, Llanos-Cuentas A, Suleiman J, et al. A randomized, double-blind, parallel-group, dose-response study of micafungin compared with fluconazole for the treatment of esophageal candidiasis in HIV-positive patients. Clin Infect Dis. 2004;39(6):842-849. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15472817.
22. Krause DS, Simjee AE, van Rensburg C, et al. A randomized, double-blind trial of anidulafungin versus fluconazole for the treatment of esophageal candidiasis. Clin Infect Dis. 2004;39(6):770-775. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15472806.
23. Martens MG, Maximos B, Degenhardt T, et al. Phase 3 study evaluating the safety and efficacy of oteseconazole in the treatment of recurrent vulvovaginal candidiasis and acute vulvovaginal candidiasis infections. Am J Obstet Gynecol. 2022;227(6):880 e881-880 e811. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35863457.
24. Sobel JD, Donders G, Degenhardt T, et al. Efficacy and safety of oteseconazole in recurrent vulvovaginal candidiasis. NEJM Evid. 2022;1(8):1-13. Available at: https://evidence.nejm.org/doi/full/10.1056/EVIDoa2100055.
25. Schwebke JR, Sobel R, Gersten JK, et al. Ibrexafungerp versus placebo for vulvovaginal candidiasis treatment: a phase 3, randomized, controlled superiority trial (VANISH 303). Clin Infect Dis. 2022;74(11):1979-1985. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34467969.
26. Nyirjesy P, Schwebke JR, Angulo DA, Harriott IA, Azie NE, Sobel JD. Phase 2 randomized study of oral ibrexafungerp versus fluconazole in vulvovaginal candidiasis. Clin Infect Dis. 2022;74(12):2129-2135. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34555149.
27. SCYNEXIS presents positive data from its pivotal phase 3 CANDLE study of oral ibrexafungerp for prevention of recurrent vaginal yeast infections during the 2022 IDSOG annual meeting [press release]. Jersey City, NJ. SCYNEXIS, Inc. 2022. Available at: https://d1io3yog0oux5.cloudfront.net/_b74ab29ee08f7c716ae5e6710e5dba4b/scynexis/news/2022-08-04_SCYNEXIS_Presents_Positive_Data_from_Its_Pivotal_298.pdf.
28. BREXAFEMME® (ibrexafungerp tablets), for oral use [package insert]. U.S. Food and Drug Administration. 2021. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214900s002lbl.pdf.
29. Sucher AJ, Thai A, Tran C, Mantena N, Noronha A, Chahine EB. Ibrexafungerp: a new triterpenoid antifungal. Am J Health Syst Pharm. 2022;79(24):2208-2221. Available at: https://www.ncbi.nlm.nih.gov/pubmed/36083109.
30. Chang YL, Yu SJ, Heitman J, Wellington M, Chen YL. New facets of antifungal therapy. Virulence. 2017;8(2):222-236. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27820668.
31. Thambuchetty N, Mehta K, Arumugam K, Shekarappa UG, Idiculla J, Shet A. The epidemiology of IRIS in southern India: an observational cohort study. J Int Assoc Provid AIDS Care. 2017;16(5):475-480. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28399724.
32. Ramirez-Amador V, Patton LL, Naglik JR, Nittayananta W. Innovations for prevention and care of oral candidiasis in HIV-infected individuals: are they available?-A workshop report. Oral Dis. 2020;26 Suppl 1:91-102. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32862535.
33. Skiest DJ, Vazquez JA, Anstead GM, et al. Posaconazole for the treatment of azole-refractory oropharyngeal and esophageal candidiasis in subjects with HIV infection. Clin Infect Dis. 2007;44(4):607-614. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17243069.
34. Villanueva A, Gotuzzo E, Arathoon EG, et al. A randomized double-blind study of caspofungin versus fluconazole for the treatment of esophageal candidiasis. Am J Med. 2002;113(4):294-299. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12361815.
35. Ally R, Schurmann D, Kreisel W, et al. A randomized, double-blind, double-dummy, multicenter trial of voriconazole and fluconazole in the treatment of esophageal candidiasis in immunocompromised patients. Clin Infect Dis. 2001;33(9):1447-1454. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11577374.
36. Dentinger PJ, Swenson CF, Anaizi NH. Stability of amphotericin B in an extemporaneously compounded oral suspension. Am J Health Syst Pharm. 2001;58(11):1021-1024. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11402476.
37. Powell A, Ghanem KG, Rogers L, et al. Clinicians’ use of intravaginal boric acid maintenance therapy for recurrent vulvovaginal candidiasis and bacterial vaginosis. Sex Transm Dis. 2019;46(12):810-812. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31663976.
38. Nyirjesy P, Brookhart C, Lazenby G, Schwebke J, Sobel JD. Vulvovaginal candidiasis: a review of the evidence for the 2021 Centers for Disease Control and Prevention of sexually transmitted Infections treatment guidelines. Clin Infect Dis. 2022;74(Suppl_2):S162-S168. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35416967.
39. Goldman M, Cloud GA, Wade KD, et al. A randomized study of the use of fluconazole in continuous versus episodic therapy in patients with advanced HIV infection and a history of oropharyngeal candidiasis: AIDS Clinical Trials Group Study 323/Mycoses Study Group Study 40. Clin Infect Dis. 2005;41(10):1473-1480. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16231260.
40. Powderly WG, Finkelstein D, Feinberg J, et al. A randomized trial comparing fluconazole with clotrimazole troches for the prevention of fungal infections in patients with advanced human immunodeficiency virus infection. NIAID AIDS Clinical Trials Group. N Engl J Med. 1995;332(11):700-705. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7854376.
41. Schuman P, Capps L, Peng G, et al. Weekly fluconazole for the prevention of mucosal candidiasis in women with HIV infection. A randomized, double-blind, placebo-controlled trial. Terry Beirn Community Programs for Clinical Research on AIDS. Ann Intern Med. 1997;126(9):689-696. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9139554.
42. Havlir DV, Dube MP, McCutchan JA, et al. Prophylaxis with weekly versus daily fluconazole for fungal infections in patients with AIDS. Clin Infect Dis. 1998;27(6):1369-1375. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9868644.
43. Vazquez JA, Skiest DJ, Tissot-Dupont H, Lennox JL, Boparai N, Isaacs R. Safety and efficacy of posaconazole in the long-term treatment of azole-refractory oropharyngeal and esophageal candidiasis in patients with HIV infection. HIV Clin Trials. 2007;8(2):86-97. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17507324.
44. Johnson EM, Warnock DW, Luker J, Porter SR, Scully C. Emergence of azole drug resistance in Candida species from HIV-infected patients receiving prolonged fluconazole therapy for oral candidosis. J Antimicrob Chemother. 1995;35(1):103-114. Available at: https://www.ncbi.nlm.nih.gov/pubmed/7768758.
45. Marty F, Mylonakis E. Antifungal use in HIV infection. Expert Opin Pharmacother. 2002;3(2):91-102. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11829723.
46. Alsaad AM, Kaplan YC, Koren G. Exposure to fluconazole and risk of congenital malformations in the offspring: a systematic review and meta-analysis. Reprod Toxicol. 2015;52:78-82. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25724389.
47. Molgaard-Nielsen D, Pasternak B, Hviid A. Use of oral fluconazole during pregnancy and the risk of birth defects. N Engl J Med. 2013;369(9):830-839. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23984730.
48. Lopez-Rangel E, Van Allen MI. Prenatal exposure to fluconazole: an identifiable dysmorphic phenotype. Birth Defects Res A Clin Mol Teratol. 2005;73(11):919-923. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16265639.
49. Molgaard-Nielsen D, Svanstrom H, Melbye M, Hviid A, Pasternak B. Association between use of oral fluconazole during pregnancy and risk of spontaneous abortion and stillbirth. JAMA. 2016;315(1):58-67. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26746458.
50. Berard A, Sheehy O, Zhao JP, et al. Associations between low- and high-dose oral fluconazole and pregnancy outcomes: 3 nested case-control studies. CMAJ. 2019;191(7):E179-E187. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30782643.
51. Pasternak B, Wintzell V, Furu K, Engeland A, Neovius M, Stephansson O. Oral fluconazole in pregnancy and risk of stillbirth and neonatal death. JAMA. 2018;319(22):2333-2335. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29896619.
52. SPORANOX® (itraconazole) oral solution [package insert]. U.S. Food and Drug Administration. 2003. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/020657s038lbl.pdf.
53. De Santis M, Di Gianantonio E, Cesari E, Ambrosini G, Straface G, Clementi M. First-trimester itraconazole exposure and pregnancy outcome: a prospective cohort study of women contacting teratology information services in Italy. Drug Saf. 2009;32(3):239-244. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19338381.
54. NOXAFIL Highlights of prescribing information [package insert]. U.S. Food and Drug Administration. 2015. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022003s018s020,0205053s002s004,0205596s001s003lbl.pdf.
55. VFEND® [package insert]. U.S. Food and Drug Administration. 2010. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021266s032lbl.pdf.
56. Pilmis B, Jullien V, Sobel J, Lecuit M, Lortholary O, Charlier C. Antifungal drugs during pregnancy: an updated review. J Antimicrob Chemother. 2015;70(1):14-22. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25204341.
57. Oteseconazole. Am J Health Syst Pharm. 2022;79(23):2083-2085. Available at: https://www.ncbi.nlm.nih.gov/pubmed/36173878