In this article an infectious diseases pharmacist discusses five practical considerations for using antifungal drugs for invasive candidiasis.
Authored By: Sunish Shah, Pharm.D., BCIDP
[Last Updated: 31 May 2020]
While Candida species are commensals of normal flora, the organism’s implementation in human pathogenicity ranges from benign local infections such as oropharyngeal candidiasis to invasive candidiasis. Candidemia (i.e, Candida in the bloodstream) is the most common form of invasive candidiasis and is associated with up to 47% attributable mortality rate.1 Less common manifestations of invasive candidiasis include infective endocarditis, peritonitis, meningitis, osteomyelitis, and endophthalmitis.
Over 90% of invasive disease is caused by either C. albicans, C. glabrata, C. tropicalis, C. parapsilosis, or C. krusei.1 Antifungal drugs represent a crucial aspect in the modern management of invasive candidiasis secondary to these pathogens which each have their own unique antifungal resistance profile. Our limited arsenal of antimycotic agents used in the treatment of candidemia consists of echinocandins, azoles, and polyenes.
The clinician is faced with several clinical challenges when utilizing antifungal therapy which even further limit our armamentarium of useful antifungal agents. Given the considerations for toxicity, drug-drug interactions, adverse effects, pharmacokinetics, and spectrum of activity, I propose asking the five following questions when treating a patient with invasive candidiasis to allow for a systematic approach.
Question #1. What are we treating?
This is perhaps the most important question to ask before administering therapy for any disease state. In fact, a core element of antimicrobial stewardship is appropriate documentation of the indication.2 Therapy for candidiasis should adhere to this core element as requiring the clinician to define the indication for therapy may subsequently lead to improved prescribing.
For instance, within my health-system’s electronic medical record (EMR), “Candida Pneumonia” is not listed as an indication for the ordering antifungal therapy. This is because while Candida are frequently isolated in respiratory cultures, it typically represents colonization. This was shown in a randomized, double-blind trial that found no benefit to initiating antifungal therapy to critically ill patients with a clinical suspicion of ventilator-associated pneumonia and positive airway secretion cultures for Candida species.3
On the other hand, Candida species isolated in the bloodstream should always be treated. Guidance from the Infectious Diseases Society of America (IDSA), recommend starting with an echinocandin.1 However, if source control can be assured and the isolated Candida species is susceptible to an azole antifungal (e.g., fluconazole), narrowing therapy to an azole has been shown to be safe in an observational propensity score-adjusted analysis.3 This often allows for an oral option and limits the development of echinocandin (e.g., micafungin) resistance.
When Candida are isolated in the bloodstream, the IDSA guidelines recommend the patient undergo funduscopic examination.1 This is because one of the most devastating complications of candidemia is subsequent ophthalmologic seeding resulting in endophthalmitis. Less commonly, endophthalmitis secondary to Candida species can result from trauma or a surgical procedure. The optimal approach to choosing pharmacologic therapy for this disease state requires an understanding of ocular tissue invasion in addition to pharmacokinetic properties. Systemically administered voriconazole and fluconazole are noted to achieve excellent aqueous humor and vitreous concentrations and are therefore regarded as first line agents. Conversely, echinocandins have demonstrated undetectable ocular compartment concentrations and are not recommended.5 A serious concern is the increasing incidence of fluconazole and voriconazole resistant Candida species. For patients with endophthalmitis with these pathogens, systemic amphotericin B can be considered, however, ocular penetration is poor.6 Treatment should always be systemic; however adjunctive intravitreal amphotericin B or voriconazole should be added for macular or vitreous involvement as these manifestations are sight-threatening and adjunctive intravitreal therapy allows for immediate therapeutic vitreal concentrations.7 Further information on the management of fungal endopthalmitis can be found in the excellent review by Riddell et al. 8
Candiduria is common in hospitalized patients but unusual in healthy ambulatory patients. For symptomatic cystitis secondary to Candida species, the number of useful agents is limited to those that achieve adequate concentrations in the urine. Fluconazole is considered the drug of choice for these infections given the drug’s efficacy and favorable side-effect profile. Unfortunately, the other systemic azole antifungals do not achieve adequate concentration in the urine to demonstrate efficacy. In cases of fluconazole non-susceptible isolates, amphotericin B is the most reliable agent. However, the liposomal formulation does not achieve adequate urine concentration and therefore, the conventional formulation needs to be utilized. While the IDSA guidelines suggest up to a 7-day course, experimental models have noted amphotericin to be present in the urine weeks after administration.1 Clinical success has been noted with a single amphotericin B dose and toxicity may be mitigated by not redosing the drug.9 An alternative strategy to mitigating toxicity would be the utilization of an amphotericin B bladder irrigation. Generally, echinocandins are not recommended for cystitis secondary to Candida species given they are characterized as having poor urinary concentrations; however, their accumulation in renal parenchyma is high. Furthermore, it should be noted that an observational, multicenter study noted echinocandins to demonstrate comparable clinical success to fluconazole when treating patients for candidemia from a urinary source.10 Finally, flucytosine has been utilized for Candida cystitis.11 However, many clinicians typically avoid this agent as monotherapy due to the potential for rapid emergence of resistance.
Question #2: Is the antifungal agent appropriate for the pathogen?
When cultures return with growth of a Candida species, and antifungal therapy is indicated, it is important to predict susceptibility patterns based on the species since antifungal susceptibilities may take several days to return.
While, Table 1 provides a general overview, several other factors should be considered. For instance, it should be recognized for most Candida species, fluconazole tends to be less active in-vitro compared to posaconazole, itraconazole, or isavuconazole. Conversely, for most Candida species, voriconazole tends to be more active in-vitro compared to posaconazole, itraconazole, or isavuconazole.12 Therefore, while C. krusei is intrinsically resistant to fluconazole and C. glabrata is commonly resistant to fluconazole, it may be worth obtaining susceptibilities to voriconazole for these pathogens as voriconazole may represent an oral option.
While echinocandins tend to be recommended interchangeably, it is important to recognize that caspofungin is less active against Candida species compared to anidulafungin or micafungin. Therefore, if an isolated Candida species is reported as susceptible to caspofungin, it can be interpreted as susceptible to anidulafungin and micafungin. For C. parapsilosis, an FKS1 hot spot alteration is responsible for elevated echinocandin minimum inhibitory concentrations (MICs) and therefore fluconazole remains the drug of choice.13 Similarly, C. guilliermondii also harbors this mutation resulting in higher echinocandin MICs and while resistance to fluconazole has been well documented in the literature, I have yet to see this organism demonstrate fluconazole resistance in my health-system.13
Although amphotericin B has been in medical use since 1958, it is uncommonly used for the treatment of candidiasis in modern medicine given its toxicities. Nevertheless, it is important to recognize that C. lusitaniae is commonly resistant to amphotericin B and C. haemulonii is intrinsically resistant to amphotericin B.
Question #3: Is the fluconazole dose appropriate based on pathogen MIC?
Although CLSI breakpoints and FDA dosing recommendations exist, pharmacokinetically, efficacy of triazole antifungals can be predicted by the area under the concentration–time curve to MIC ratio (AUC/MIC). In a patient with normal renal function, the AUC of fluconazole, expressed as milligrams (mg) per hour per liter is identical to the daily dose of fluconazole in mg.14 Clinically, fluconazole dose to MIC ratios > 25-50 have been shown to be associated with treatment success.15,16
For instance, consider a patient with C. glabrata candidemia secondary to a central line that was removed. The isolated C. glabrata is susceptible to anidulafungin but has a fluconazole MIC of 16. In this situation, it would be appropriate to narrow the patient to 400mg to 800mg of fluconazole daily instead of continuing the patient on broad spectrum therapy with anidulafungin. A second benefit to this is fluconazole offers an oral alternative, while echinodandins are available only for intravenous use.
Question #4: Are there any drug interactions or adverse effects?
Prior to the administration of systemic azole antifungal drugs, the clinician should identify any clinically significant drug interactions. Since many of the azole antifungals are metabolized through cytochrome p450 as noted in Table 2, several enzymatic drug interactions exist. In addition to enzymatic interactions, the absorption for many azole antifungals are altered based on the gastrointestinal environment. For example, absorption of itraconazole capsules, unlike itraconazole solution, requires an acidic environment and therefore should not be administered with H2 receptor antagonists (e.g., famotidine) or proton pump inhibitors (e.g., lansoprazole). In fact, to ensure adequate absorption efficacy, itraconazole requires therapeutic drug (TDM) monitoring with a target level of > 0.5 mg/L. On the contrary, absorption of posaconazole suspension, unlike posaconazole delayed-release tablets, also requires an acidic environment and therefore should not be administered with H2 receptor antagonists or proton pump inhibitors. Similarly, posaconazole TDM is indicated to ensure adequate absorption and my health-system recommends a target level of > 0.7 mg/L.
Side effects of antifungal azoles vary significantly by agent.
While fluconazole is generally well tolerated, reversible alopecia has been reported with chronic use. While I commonly see warnings for fluconazole for prolongation of the QT interval, it should be noted that daily fluconazole doses of 1200mg only prolong the QTc by about 10msec in the absence of other QT prolonging factors.17
Itraconazole is noted to have a negative inotropic effect and therefore should not be administered in patients with congestive heart failure.
While voriconazole TDM is indicated for both safety and toxicity, hallucinations, photosensitivity, and hepatotoxicity may still occur despite voriconazole troughs within the target range of 1-4 ug/mL. In one study of oncology patients, the mean QTc during voriconazole therapy (448.0 ± 52.9 msec) was significantly longer compared to the mean QTc off voriconazole (421.8 ± 42.2 msec; p = 0.002).18 The intravenous formulations, but not the oral formulations, of both voriconazole and posaconazole contain a cyclodextrin vehicle which may cause nephrotoxicity. However, this may only be an issue in patients with baseline renal disease and in those receiving prolonged therapy.19 Similar to voriconazole, posaconazole can also cause QTc prolongation and hepatoxicity but to a lesser extent tan voriconazole. However, posaconazole has also been implicated in causing hypokalemia and hypertension due to a mineralocorticoid effect.20
Isavuconazole is generally well tolerated but has been noted to cause QTc shortening. Therefore, patients with familial short QT syndrome, a rare disease predominantly reported in young adult males and infants, should not receive isavuconazole. Otherwise, the clinical implications of QTc shortening remain unclear.
Few drug-drug interactions and adverse effects exist with the echinocandins. Through OATP1B1 mediation, rifampin has been shown to initially increase caspofungin concentrations prior to 14 days of concurrent therapy, but then to decrease caspofungin concentrations following 14 days of therapy. Therefore, the package insert recommends use of an increased caspofungin dose of 70 mg daily in adults when coadministered with known inducers of caspofungin drug clearance. Although a mechanism remains unclear, some clinicians recommend avoiding cyclosporine with caspofungin due to unacceptably high liver function tests that have been reported with this combination. While few clinically relevant drug interactions exist with anidulafungin and micafungin, some clinicians will exhibit caution and closer monitoring when micafungin, a weak CYP3A4 inhibitor, is administered with sirolimus.
Echinocandins are relatively well tolerated; however, it is noted that these agents may result in a histamine-mediated infusion related reaction. Nevertheless, this adverse effect may be overcome by slowing the infusion rate.
While enzymatic drug-drug interactions are not clinically relevant with amphotericin B, drugs that pose additive risk of toxicity should be minimized. Amphotericin B possesses a broad toxicity profile consisting of hepatotoxicity, nephrotoxicity, hypokalemia, hypomagnesemia, and infusion related reactions.21 Infusion-related reactions may be mitigated with prophylactic acetaminophen and diphenhydramine.22 In addition, prophylactic administration of fluids may be utilized to decrease the risk of renal toxicity and meperidine has been used to manage rigors (beware use in patients with renal dysfunction). Furthermore, the lipid and liposomal formulations of amphotericin B have decreased risk of renal toxicity and infusion related reactions as compared to conventional amphotericin B. Despite this broad toxicity profile, it should be noted that in pregnancy, amphotericin B is deemed the least teratogenic systemic antifungal. More information on antifungal use in pregnancy can be found in the comprehensive review by Pilmis et al.23
For additional information on antifungal drug interactions and adverse effects, I recently had the fortune of being invited to collaborate on the antifungal drugs chapter of Side Effects of Drugs Annual.24
Question #5: Am I practicing antifungal stewardship?
It is imperative that we protect the few agents available for the treatment of fungal infections. Given the numerous toxicities associated with amphotericin, this agent cannot be routinely used for invasive candidiasis. In addition to azole resistance in Candida species, echinocandin resistance is also emerging. For instance, one center in the United States reported that resistance in C. glabrata bloodstream infections increased to echinocandins from 4.9% to 12.3% and to fluconazole from 18% to 30% between 2001 and 2010, respectively.25 Therefore, since echinocandins are more broad-spectrum, it is recommended to narrow to fluconazole when possible for candidiasis since, unsurprisingly, use of echinocandins is a risk factor for the development of invasive candidiasis that is echinocandin resistant.26 Prior to initiating systemic antifungal therapy, any concomitant topical therapy is typically duplicative and can usually be discontinued.
In addition, C. auris is an emerging pathogen identified as an urgent threat by the CDC and some strains harbor resistance to all three available classes of antifungals.27 Unfortunately, it is unclear if ibrexafungerp (not yet FDA approved), a novel first-in-class antifungal agent targeting glucan synthase, will be clinically useful against C. auris.28 The only other novel antifungal agent in the pipeline with utility against Candida species is rezafungin, which is suspected to have comparable activity to anidulafungin and micafungin.28
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REFERENECES / READINGS
1. 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.
3. Albert M, Williamson D, Muscedere J, et al. Candida in the respiratory tract secretions of critically ill patients and the impact of antifungal treatment: a randomized placebo controlled pilot trial (CANTREAT study). Intensive Care Med. 2014; 40(9):1313-22.
4. Garnacho-Montero J, Díaz-Martín A, Cantón-Bulnes L, et al. Initial Antifungal Strategy Reduces Mortality in Critically Ill Patients With Candidemia: A Propensity Score-Adjusted Analysis of a Multicenter Study. Crit Care Med. 2018; 46(3):384-93.
5. Groll AH, Mickiene D, Petraitiene R, et al. Pharmacokinetic and pharmacodynamic modeling of anidulafungin (LY303366): reappraisal of its efficacy in neutropenic animal models of opportunistic mycoses using optimal plasma sampling. Antimicrob Agents Chemother 2001; 45(10):2845–55.
9. Fisher JF, Woeltje K, Espinel-Ingroff A, Stanfield J, DiPiro JT. Efficacy of a single intravenous dose of amphotericin B for Candida urinary tract infections: further favorable experience. Clin Microbiol Infect. 2003; 9(10):1024-7.
10. Cuervo G, Garcia-Vidal C, Puig-Asensio M, et al. Echinocandins Compared to Fluconazole for Candidemia of a Urinary Tract Source: A Propensity Score Analysis. Clin Infect Dis. 2017; 64(10):1374-1379.
12. Sanglard D, Coste AT. Activity of Isavuconazole and Other Azoles against Candida Clinical Isolates and Yeast Model Systems with Known Azole Resistance Mechanisms. Antimicrob Agents Chemother. 2015; 60(1):229-38.
14. Louie A, Liu QF, Drusano GL, et al. Pharmacokinetic studies of fluconazole in rabbits characterizing doses which achieve peak levels in serum and area under the concentration-time curve values which mimic those of high-dose fluconazole in humans. Antimicrob Agents Chemother. 1998; 42(6):1512‐14.
15. Clancy CJ, Yu VL, Morris AJ, Snydman DR, Nguyen MH. Fluconazole MIC and the fluconazole dose/MIC ratio correlate with therapeutic response among patients with candidemia. Antimicrob Agents Chemother. 2005; 49(8): 3171–7.
18. Gueta I, Loebstein R, Markovits N, et al. Voriconazole-induced QT prolongation among hemato-oncologic patients: clinical characteristics and risk factors. Eur J Clin Pharmacol. 2017; 73(9):1181-5.
19. Yasu T, Konuma T, Kuroda S, Takahashi S, Tojo A. Effect of Cumulative Intravenous Voriconazole Dose on Renal Function in Hematological Patients. Antimicrob Agents Chemother. 2018; 62(9): e00507-18.
25. Alexander BD, Johnson MD, Pfeiffer CD, et al. Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations. Clin Infect Dis. 2013; 56(12):1724-32.
26. Lortholary O, Desnos-Ollivier M, Sitbon K, et al. French Mycosis Study Group. Recent exposure to caspofungin or fluconazole influences the epidemiology of candidemia: a prospective multicenter study involving 2,441 patients. Antimicrob Agents Chemother. 2011; 55(2):532-8.
DISCLAIMER: The views expressed in this article represent that of the author and do not necessarily reflect the position or policy of any previous, current, or potential future employers or other organizations in which he serves. This material is provided for general information only and should not be relied upon or used as the sole basis for making decisions without consulting primary, more accurate, more complete or more timely sources of information. Any reliance on the material is done so at your own risk.
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