The Use of Fluconazole to Treat Candida Infections of the Nipple and Breast Ducts, A Synopsis for Health Providers

David A. Lee, MD, November 2001

Introduction:

Candida infections in the oral cavity of infants and of the nipples and milk ducts of breastfeeding women have been sited as causes for pain leading to cessation of breastfeeding¹.

Treat of such infections usually starts with topical treatment with antifungal agents such as nystatin suspension for oral thrush and nystatin or clotrimazole cream for the nipples.  The treatment of recurring or persistent infections is more controversial.  Treatment options include the continued use of oral nystatin and nystatin or clotrimazole cream, oral nystatin for the baby and oral fluconazole for the woman and oral fluconazole for both the woman and the baby.

There are no published studies that document the efficacy and safety of the current oral fluconazole regimen suggested (a single 200 or 400 mg dose and then 100 mg doses once or twice a day for 2-3 weeks) for the treatment of nipple/milk duct candida infections.  Fluconazole is not FDA approved for this indication.  Because this use would be "off-label" some physicians have been uncomfortable prescribing fluconazole for their breastfeeding patients with candidal infections in the nipples and or milk ducts.

This situation is not unique to fluconazole.  Many medications are routinely used for "off-label" regimens and indications.  This, however, does not mean there is no information available for the use of fluconazole to treat persistent candida infections.  We certainly have an obligation to our patients to examine and weigh this information prior to our own "off-label" use of this medication.

Where does the dosing regimen come from?

Jack Newman, a neonatologist with a strong interest in breastfeeding issues discussed the problem of persistent candida infections in the nipple and ducts with an infectious diseases colleague, Dr. Stanley Reid².  Dr. Reid, who's specialty is the treatment of patients with HIV, extrapolated the regimen from one that is used in patients with candida infections in other organs where medications do not have the best penetrance.  The regimen was100 mg once a day for a total treatment period of 7-14 days.  Dr. Newman found that 10 days was usually very effective, but had fewer recurrences if women were treated for at least a week after all symptoms had disappeared and if a loading dose of 200 mg was used.  His regimen has been widely used over the last 5-6 years and though there are still no randomized or blinded studies, many pediatricians, obstetricians and family practitioners have been using this regimen with good success and a very low rate of side effects.  Dr. Newman states that he has treated thousands of women himself without problems.  The regimen with the initial dose of 400 mg with subsequent doses of 100-200 mg twice a day was recently started by Dr. Newman when he began to see treatment failures with the earlier regimen³.  The need for these higher doses may be geographically specific as many others still use the lower dose regimen with continued success.

Who uses this regimen?

While precise documentation is not available, it seems that the use of fluconazole for this indication is widespread.  Dr. Jack Newman is an internationally recognized authority on breastfeeding and breastfeeding related issues.  Oral fluconazole is the treatment he advocates for persistent candida nipple/milk duct infections in the breastfeeding woman (he initially uses topical treatment with 1% gentian violet and or antifungal ointments).  In informal discussions with physicians across the United States, oral fluconazole is cited as the treatment used when topical treatment fails. 

Brent¹ recently published a survey that looked at how pediatricians, obstetricians and family practitioners treated candida infections in the breastfeeding dyad.  The survey was sent to 432 pediatricians, obstetricians and family practitioners who were members of the Academy of Breastfeeding Medicine. 111 of 312 (35%) respondents stated that oral fluconazole was their regimen of choice for recurrent candida infections and 144/312 (46%) treated persistent candida infections with oral fluconazole.  In the same survey, 54/312 (17%) used oral fluconazole for the mother (and oral nystatin for the baby) as their initial treatment.

Does fluconazole successfully treat candida infections?

Yes, fluconazole is a widely used treatment for many types of candida infections.  It is used to treat vaginal infections.  It is also used to treat and suppress candida infections in patients with artificial implants⁴ (eye, joint, breast and heart), and chronic renal conditions⁵.  Fluconazole has become the drug of choice to treat and suppress systemic infections in transplant recipients⁶, cancer patients^7,8 and immunocompromised (AIDS) patients⁸.  Dosing regimens in many of these patients are similar to that used for the treatment of nipple and duct candidiasis.

Is it safe for the patient who takes the fluconazole?

No medication is without the risk of side effects.  The safety profile of fluconazole is good and well established.  There are numerous studies that looked at both the efficacy and the safety of fluconazole at the doses suggested for nipple and ductal infections as well as regimens that used higher doses and longer treatment periods.  Representative studies are summarized below.

Sobel⁵ et al reported a randomized, double blinded placebo study looking at the treatment of candiduria with fluconazole in 316 patients.  The dose of fluconazole was 400 mg the first day and then 100 mg twice a day thereafter for 14 days.  The fluconazole did treat the candida and there were equal numbers of side effects in both groups.

Drew⁴ et al reported a study on the use of fluconazole in liver transplant recipients.  It was a randomized, double blinded, placebo controlled trial.  The dose of fluconazole was 400 mg/day for 10 weeks after liver transplant.  There were 212 patients in the study.  Fluconazole was able to prevent candida infection in the treatment group significantly better than placebo.  The rate of side effects was barely significantly higher in the fluconazole group (p= 0.05).  Most of the side effects were gastrointestinal (diarrhea, nausea, vomiting or abdominal pain) or neurologic (headaches or seizures).  The fluconazole group did have patients that suffered seizures (5/108) however these patients also had elevated cyclosporine levels.  The authors felt that the elevated cyclosporine levels were the cause of the seizures, not the fluconazole.

A similar study was done by Young et al⁷ comparing the safety and efficacy of oral fluconazole to nystatin suspension with respect to preventing candida infections in patients with leukemia.  There were 164 patients in the study.  The dose of fluconazole was 200 mg/d.  The average treatment duration was 4 weeks.  There was no difference in side effects between the two groups.  The majority of side effects were gastrointestinal.  No one had seizures.

Penk and Pittrow⁴ reported a series of 56 patients with candida infections associated with artificial implants.  Fluconazole was used in doses from 100 mg/d to 400 mg/d to suppress documented candidal infections in these patients. Recorded regimens lasted from 6 weeks to "lifelong" with the longest recorded actual time treatment to be 4.5 years.  Infections were effectively suppressed in all 56 patients and no major adverse events were seen.

Martin⁸ published an extensive review of the efficacy and safety of fluconazole.  He states in his review "Clinical experience is extensive, with over 16 million patient days of treatment with fluconazole since its introduction in the UK and 300 million patient-days world-wide.  The incidence of side effects is low and the symptoms are generally mild and do not require discontinuation from therapy… Tolerability is high even in special patient groups including children and severely ill patients with AIDS or cancer.  Although not licensed, high doses of fluconazole (up to 800 mg/d) are well tolerated in the treatment of immunocompromised patients with severe systemic mycoses.  Doses of up to 1600 mg fluconazole have been shown to be well tolerated in studies of AIDS patients with histoplasmosis and cryptococcal meningitis."

While there are certainly reports of side effects, fluconazole has been shown to be very safe even in very sick or debilitated patients.  Very few side effects have been reported in otherwise healthy patients.  This does not mean that side effects should not be watched for or cautioned against.  There is, however, a good deal of data that indicate that the likelihood of a healthy woman having a serious adverse reaction is very low.

Is it safe for the breastfeeding baby?

Yes it is safe.  Fluconazole does come through breastmilk (after all, it does need to get into the ducts to kill the candida causing the infection).  The amounts shown to come through, however, are small compared to the doses used to treat candida infections in newborns⁹.  Fluconazole is used routinely in the intensive care nursery to treat candida infections in both premature and term newborns at much higher doses and for much longer periods of time with little to no evidence of any adverse effects^10-14.  Fluconazole is listed as approved for breastfeeding by the American Academy of Pediatrics¹⁵.

Oral Fluconazole Regimen^3,9:

·        Fluconazole is available only by prescription

·        The first dose of Fluconazole is usually 200 mg. 

·        Subsequent doses will usually be 100 mg once or twice daily for at least two weeks.  The patient should generally be symptom free for at least a week before stopping the medication. This seems to prevent most relapses. However, this means that although most women require only two weeks of treatment, some need longer treatment.  (Note: The mother’s two-week prescription is likely to cost between $300 and $350.)

·        Fluconazole is generally well tolerated, but side effects can occur. Vomiting, diarrhea, abdominal pain and skin rashes are the most common side effects. These are not usually severe, and only occasionally is it necessary to stop the medication because of these side effects. Allergic reactions are possible but uncommon.  There have been reports of hepatotoxicity and neurologic effects, but these seem to occur only in patients with other medical conditions or in those taking other medications (like cyclosporine).

·        Pregnant women should not take oral fluconazole.

·        For recurrent or persistent infections longer periods of treatment or prophylactic treatment after acute infections have been cured may be necessary.

·        Be sure to treat both the baby (oral nystatin is usually sufficient) and the mother simultaneously to insure the highest chance of success in eradicating the mother's infection.

References:

1.               Brent, N, Thrush in the Breastfeeding Dyad: Results of a Survey on Diagnosis and Treatment, Clin Pediatrics, 40:503-506, 2001.

2.               Newman, Jack, personal communication, 2001.

3.               Newman, Jack, Candida Protocol posted at breastfeedingonline.com, 2000.

4.               Penk A, Pittrow, L, Role of fluconazole in the long-term suppressive therapy of fungal infections in patients with artificial implants, Mycoses, 42(supple 2): 91-96, 1999.

5.               Sobel, JD, Kauffman, CA, McKinsey, D, et al, Candiduria: A Randomized Double-Blind Study of Treatment with Fluconazole and Placebo, Clinical Inf Diseases, 30:19-24, 2000.

6.               Drew, W, Pakrasi, A, Busuttil, R, Prophylactic Fluconazole in Liver Transplant Recipients: a Randomized Double-Blind Placebo-Controlled Trial, Ann Internal Medicine, 131(10): 729-737, 1999.

7.               Young, GAR, Bosley, A, Gibbs, DL et al, A Double-blind Comparison of Fluconazole and Nystatin in the Prevention of Candidiasis in Patients with Leukaemia, Eur J of Cancer, 35(8): 1208-1213, 1999.

8.               Martin, MV, The use of fluconazole and itraconazole in the treatment of Candida albicans infections: a review, J Antimicrobial Chemotherapy, 44:429-437, 1999.

9.               Hale, TW, In Medications and Mothers' Milk, Pharmsoft Publishing, TX, Ninth Ed, pp266-270, 2000.

10.          Wainer, S, Cooper, PA et al, Prospective study of fluconazole therapy in systemic neonatal fungal infection, Ped Inf Dis J, 16(8):763-767

11.          Wiest, DB, Fowler, SL, et al, Fluconazole in neonatal disseminated candidiasis,  Arch Dis Child, 66(8):1002

12.          Gurses, N, Kalayci, AG, Fluconazole monotherapy for candidal meningitis in a premature infant, Clinical Inf Diseases, 23:645-646, 1996.

13.          Driessen, M, Ellis, JB et al, Fluconazole vs. amphotericin B for the treatment of neonatal fungal septicemia: a prospective study, Ped Inf Dis J, 15:1107-1112, 1996.

14.          Huttova, M, Hartmanova, I et al, Candida fungemia in neonates treated with fluconazole: report of forty cases, including eight with meningitis, Ped Inf Dis J, 17:1012-1015, 1998.

15.          American Academy of Pediatrics, The Transfer of Drugs and Other Chemicals into Human Milk, Pediatrics, 108(3): 776-789, 2001