Candida antifungal treatment

Candida antifungal treatment DEFAULT

Candida infections of the mouth, throat, and esophagus

About

Candidiasis is an infection caused by a yeast (a type of fungus) called Candida. Candida normally lives on the skin and inside the body, in places such as the mouth, throat, gut, and vagina, without causing any problems.1 Sometimes, Candida can multiply and cause an infection if the environment inside the mouth, throat, or esophagus changes in a way that encourages fungal growth.

Candidiasis in the mouth and throat is also called thrush or oropharyngeal candidiasis. Candidiasis in the esophagus (the tube that connects the throat to the stomach) is called esophageal candidiasis or Candida esophagitis. Esophageal candidiasis is one of the most common infections in people living with HIV/AIDS.2

Symptoms

Candida infection illustration

Candidiasis in the mouth and throat can have many different symptoms, including:

  • White patches on the inner cheeks, tongue, roof of the mouth, and throat (photo showing candidiasis in the mouth)
  • Redness or soreness
  • Cotton-like feeling in the mouth
  • Loss of taste
  • Pain while eating or swallowing
  • Cracking and redness at the corners of the mouth

Symptoms of candidiasis in the esophagus usually include pain when swallowing and difficulty swallowing.

Contact your healthcare provider if you have symptoms that you think are related to candidiasis in the mouth, throat, or esophagus.

Risk and Prevention

Who gets candidiasis in the mouth or throat?

Candidiasis in the mouth, throat, or esophagus is uncommon in healthy adults. People who are at higher risk for getting candidiasis in the mouth and throat include babies, especially those younger than 1 month of age, and people with at least one of these factors:3-7

  • Wear dentures
  • Have diabetes
  • Have cancer
  • Have HIV/AIDS
  • Take antibiotics or corticosteroids, including inhaled corticosteroids for conditions like asthma
  • Take medications that cause dry mouth or have medical conditions that cause dry mouth
  • Smoke

Most people who get candidiasis in the esophagus have weakened immune systems, meaning that their bodies don’t fight infections well. This includes people living with HIV/AIDS and people who have blood cancers such as leukemia and lymphoma. People who get candidiasis in the esophagus often also have candidiasis in the mouth and throat.

How can I prevent candidiasis in the mouth or throat?

Ways to help prevent candidiasis in the mouth and throat include:

  • Maintain good oral health
  • Rinse your mouth or brush your teeth after using inhaled corticosteroids

Sources

Candida normally lives in the mouth, throat, and the rest of the digestive tract without causing any problems. Sometimes, Candida can multiply and cause an infection if the environment inside the mouth, throat, or esophagus changes in a way that encourages its growth.

This can happen when:

  • a person’s immune system becomes weakened,
  • if antibiotics affect the natural balance of microbes in the body,
  • or for a variety of other reasons in other groups of people.

Diagnosis and Testing

Healthcare providers can usually diagnose candidiasis in the mouth or throat simply by looking inside.8 Sometimes a healthcare provider will take a small sample from the mouth or throat. The sample is sent to a laboratory for testing, usually to be examined under a microscope.

Healthcare providers usually diagnose candidiasis in the esophagus by doing an endoscopy. An endoscopy is a procedure to examine the digestive tract using a tube with a light and a camera. A healthcare provider might prescribe antifungal medicine without doing an endoscopy to see if the patient’s symptoms get better.

Treatment

Candidiasis in the mouth, throat, or esophagus is usually treated with antifungal medicine.6 The treatment for mild to moderate infections in the mouth or throat is usually an antifungal medicine applied to the inside of the mouth for 7 to 14 days. These medications include clotrimazole, miconazole, or nystatin. For severe infections, the most common treatment is fluconazole (an antifungal medication) taken by mouth or through a vein. If patient does not get better after taking fluconazole, healthcare providers may prescribe a different antifungal. The treatment for candidiasis in the esophagus is usually fluconazole. Other types of prescription antifungal medicines can also be used for people who can’t take fluconazole or who don’t get better after taking fluconazole.

If you are a healthcare provider, click here to see the Infectious Diseases Society of America’s Clinical Practice Guidelines for the Management of CandidiasisExternalexternal icon.

Statistics

The exact number of cases of candidiasis in the mouth, throat, and esophagus in the United States is difficult to determine. This is because there is no national surveillance for these infections. The risk of these infections varies based on the presence of certain underlying medical conditions. For example, candidiasis in the mouth, throat, or esophagus is uncommon in healthy adults. However, they are some of the most common infections in people living with HIV/AIDS.2 In one study, about one-third of patients with advanced HIV infection had candidiasis in the mouth and throat.9

Sours: https://www.cdc.gov/fungal/diseases/candidiasis/thrush/index.html

Guidelines for Treatment of Candidiasis

Executive Summary

Candida species are the most common cause of fungal infections. Candida species produce infections that range from non—life-threatening mucocutaneous illnesses to invasive processes that may involve virtually any organ. Such a broad range of infections requires an equally broad range of diagnostic and therapeutic strategies. These guidelines summarize current knowledge about treatment of multiple forms of candidiasis for the Infectious Diseases Society of America (IDSA). Throughout this document, treatment recommendations are rated according to the standard scoring scheme used in other IDSA guidelines to illustrate the strength of the supporting evidence and quality of the underlying data (table 1). This document covers the following 4 major topical areas.

Table 1

Infectious Diseases Society of America—United States Public Health Service grading system for rating recommendations in clinical guidelines.

Table 1

Infectious Diseases Society of America—United States Public Health Service grading system for rating recommendations in clinical guidelines.

The role of the microbiology laboratory. To a greater extent than for other fungi, treatment of candidiasis can now be guided by in vitro susceptibility testing. However, susceptibility testing of fungi is not considered a routine testing procedure in many laboratories, is not always promptly available, and is not universally considered as the standard of care. Knowledge of the infecting species, however, is highly predictive of likely susceptibility and can be used as a guide to therapy. The guidelines review the available information supporting current testing procedures and interpretive breakpoints and place these data into clinical context. Susceptibility testing is most helpful in dealing with deep infection due to non—albicans species of Candida. In this setting, especially if the patient has been treated previously with an azole antifungal agent, the possibility of microbiological resistance must be considered.

Treatment of invasive candidiasis. In addition to acute hematogenous candidiasis, the guidelines review strategies for treatment of 15 other forms of invasive candidiasis (table 2). Extensive data from randomized trials are available only for therapy of acute hematogenous candidiasis in the nonneutropenic adult. Choice of therapy for other forms of candidiasis is based on case series and anecdotal reports. In general, amphotericin B–based preparations, the azole antifungal agents, and the echinocandin antifungal agents play a role in treatment. Choice of therapy is guided by weighing the greater activity of amphotericin B–based preparations and the echinocandin antifungal agents for some non—albicans species (e.g., Candida krusei) against the ready availability of oral and parenteral formulations for the azole antifungal agents. Flucytosine has activity against many isolates of Candida but is infrequently used.

Treatment of mucocutaneous candidiasis. Therapy for mucosal infections is dominated by the azole antifungal agents. These drugs may be used topically or systemically and are safe and efficacious. A significant problem with mucosal disease is the propensity for a small proportion of patients to have repeated relapses. In some situations, the explanation for such a relapse is obvious (e.g., recurrent oropharyngeal candidiasis in an individual with advanced and uncontrolled HIV infection), but in other patients, the cause is cryptic (e.g., relapsing vaginitis in a healthy woman). Rational strategies for these situations are discussed in the guidelines and must consider the possibility of induction of resistance with prolonged or repeated exposure.

Prevention of invasive candidiasis. Prophylactic strategies are useful if the risk of a target disease is sharply elevated in a readily identified patient group. Selected patient groups undergoing therapy that produces prolonged neutropenia (e.g., some bone marrow transplant recipients) or who receive a solid-organ transplant (e.g., some liver transplant recipients) have a sufficient risk of invasive candidiasis to warrant prophylaxis.

Introduction

Relationship between epidemiology of candidal infections and therapy. Although Candida albicans remains the most common pathogen in oropharyngeal and cutaneous candidiasis, non-albicans species of Candida are increasingly associated with invasive candidiasis [1–5]. This shift is particularly problematic in patients with acute life-threatening invasive candidal infections. Although the susceptibility of Candida to the currently available antifungal agents can be predicted if the species of the infecting isolate is known (table 3) [1, 4, 6, 11–17, 20–24], individual isolates do not necessarily follow the general pattern. For example, C. albicans is usually susceptible to all major agents. However, azole resistance for this species is now well described among HIV-infected individuals with recurrent oropharyngeal candidiasis and is also reported sporadically in critically ill adults with invasive candidiasis [25] or in healthy adults [26]. For this reason, susceptibility testing for azole resistance is increasingly used to guide the management of candidiasis in patients, especially in situations where there is failure to respond to the initial empirical therapy. On the other hand, most Candida isolates appear to remain susceptible to amphotericin B, although recent data suggest that isolates of Candida glabrata and C. krusei may require maximal doses of amphotericin B (see next section).

Susceptibility testing and drug dosing. Intensive efforts to develop standardized, reproducible, and clinically relevant susceptibility testing methods for fungi have resulted in the development of the NCCLS M27-A methodology (now updated with the essentially identical M27-A2 methodology) for susceptibility testing of yeasts [27, 28]. Data-driven interpretive breakpoints using this method are available for testing the susceptibility of Candida species to fluconazole, itraconazole, and flucytosine [28–31]. Several features of these breakpoints are important. First, these interpretive breakpoints should not be applied to other methods without extensive testing. Although the M27-A2 methodology is not the only possible way to determine an MIC, use of the M27-A2 interpretive breakpoints with other methods should be approached with caution—even small methodological variations may produce results that are not correctly interpreted by means of these breakpoints. Second, these interpretive breakpoints place a strong emphasis on interpretation in the context of the delivered dose of the azole antifungal agent. The novel category “susceptibility—dose/delivery dependent” (S-DD) indicates that maximization of dosage and bioavailability are critical to successful therapy (table 4). In the case of fluconazole, data for both human beings and animals suggest that S-DD isolates may be treated successfully with a dosage of 12 mg/kg per day [30, 32]. Although trials to date have not used this method, administration of twice the usual daily dose of fluconazole as a loading dose is a pharmacologically rational way to more rapidly achieve higher steady-state blood concentrations. In the case of itraconazole, oral absorption is somewhat unpredictable, and achieving blood levels of ⩾0.5 µg/mL (as determined by high-performance liquid chromatography) appears to be important to successful therapy. Finally, these breakpoints were developed on the basis of data from 2 groups of infected adult patients: patients with oropharyngeal and esophageal candidiasis (for fluconazole and itraconazole) and patients with invasive candidiasis (mostly nonneutropenic patients with candidemia; for fluconazole only) [30] and are supported by subsequent reports [27, 31, 33, 34]. Although these limitations are similar to those of interpretive breakpoints for antibacterial agents [27], and extrapolation of these results to other diagnostic settings appears to be rational on the basis of data from in vivo therapy models, it is still prudent to consider the limitations of the data when making use of the breakpoints. Pharmacology, safety, published reports, drug interactions, and isolate susceptibility [27] must be considered when selecting a therapy. For example, most isolates of Candida are susceptible to itraconazole, but this agent only recently became available as a parenteral preparation and has not been studied intensively for candidiasis, except for treatment of mucosal disease.

Reliable and convincing interpretive breakpoints are not yet available for amphotericin B. The NCCLS M27-A2 methodology does not reliably identify amphotericin B–resistant isolates [6]. Variations of the M27-A2 methodology using different media [6], agar-based MIC methods [12, 35, 36], and measurements of minimum fungicidal concentrations [11] appear to enhance detection of resistant isolates. Although these methods are as yet insufficiently standardized to permit routine use, several generalizations are becoming apparent. First, amphotericin B resistance appears uncommon among isolates of Candida albicans, Candida tropicalis, and C. parapsilosis. Second, isolates of Candida lusitaniae most often demonstrate readily detectable and clinically apparent amphotericin B resistance. Not all isolates are resistant [11, 23, 37], but therapeutic failure of amphotericin B is well documented [38]. Third, a growing body of data suggests that a nontrivial proportion of the isolates of C. glabrata and C. krusei may be resistant to amphotericin B [4, 11, 20–22]. Of importance, delivery of additional amphotericin B by use of a lipid-based preparation of amphotericin B may be inadequate to overcome this resistance [22]. Also, because of in vitro effects of the lipid, tests for susceptibility to amphotericin B should always use the deoxycholate rather than the lipid formulation [39]. Unfortunately, the clinical relevance of these observations is uncertain. Most rational current therapy of infections due to these species (C. lusitaniae, C. glabrata, and C. krusei) thus involves (1) awareness of the possibility of true microbiological resistance among the species and (2) judicious and cautious use of susceptibility testing. When amphotericin B deoxycholate is used to treat infections due to C. glabrata or C. krusei, doses of at least 1 mg/kg per day may be needed, especially in profoundly immunocompromised hosts.

Meaningful data do not yet exist for other compounds. This includes specifically the newer expanded-spectrum triazoles (voriconazole, posaconazole, and ravuconazole) and the echinocandins (caspofungin, micafungin, and anidulafungin). Although MIC data for these compounds are available for all major Candida species (table 3), the interpretation of those MICs in relation to achievable blood levels is uncertain [29]. This is particularly true for the echinocandin antifungal agents.

Practical clinical use of antifungal susceptibility testing. Antifungal susceptibility testing has not achieved the status of a standard of care and is not widely available, and results of testing may not be available for days. The strongest data to date are for fluconazole, an agent for which the issues of resistance are most compelling. The greatest concern for fluconazole resistance relates to C. glabrata, for which rates of resistance as high as 15% have been reported [40]. Testing is most often used in 1 of 2 ways [27]. First, susceptibility is useful in the evaluation of the possible causes of lack of clinical response. Second, the data may be used to support a change in therapy from a parenteral agent of any class to oral fluconazole. This consideration is most relevant when considering outpatient therapy and for treating infections that require protracted therapy (e.g., meningitis, endocarditis, and osteomyelitis).

Available Drugs and Drug Use

The rapid pace of antifungal drug development has resulted in the recent licensure of 2 new antifungal drugs (voriconazole and caspofungin), along with the active development of 4 others (ravuconazole, posaconazole, micafungin, and anidulafungin). In addition, new data continue to accumulate for itraconazole and the lipid-associated preparations of amphotericin B. Although all these compounds appear to have significant activity against Candida species, the size of the published clinical database for these compounds for treatment of candidiasis is limited. In an effort to integrate these agents into the guidelines, the available data on the newly licensed agents will be summarized here.

Itraconazole. An intravenous preparation of itraconazole in hydroxy-propyl-β-cyclodextrin has been licensed. This formulation is administered at a dosage of 200 mg q12h for a total of 4 doses (i.e., 2 days) followed by 200 mg/day and was licensed on the basis of evidence that this dosing regimen achieves adequate blood levels more rapidly and with less patient-to-patient variability than do oral preparations of the drug [41–44]. Itraconazole is well known to be active against mucosal forms of candidiasis (see Nongenital Mucocutaneous Candidiasis, below), but the availability of an intravenous form of itraconazole allows for treatment of invasive disease. Although itraconazole would be expected to have activity broadly similar to that of fluconazole, the 2 compounds have quite different pharmacological properties and clinical activities for other mycoses [45]. Moreover, formal studies of intravenous itraconazole for invasive candidiasis are not available. Therefore, the discussion of therapy for invasive candidiasis will generally not address intravenous itraconazole.

Voriconazole and the newer azole antifungal agents. Voriconazole is available in both oral and parenteral preparations. It is as active as fluconazole against esophageal candidiasis, although it was associated with more adverse events in a recent study [46]. Among 4 pediatric patients who received voriconazole as salvage therapy, candidemia cleared in 2 of 2 patients and disseminated candidiasis resolved in 1 of 2 patients [47]. It is notable that voriconazole appears to have the potential to be active against some fluconazole-resistant isolates. Of 12 HIV-infected subjects with fluconazole-refractory esophageal candidiasis due to C. albicans, 7 were cured and the conditions of 3 improved because of treatment with voriconazole [48]. Consistent with its activity against C. krusei in a guinea pig model [49], recent experience from open-label protocols reported response in 7 (70%) of 10 patients with invasive disease due to this species [19]. On the basis of these data, voriconazole received an indication in the European Union for “treatment of fluconazole-resistant serious invasive Candida infections (including C. krusei).” Voriconazole is not currently licensed for this indication in the United States, awaiting an analysis of a recently completed worldwide study of its activity in candidemia.

The in vitro anti-Candida activity of the other azoles under active development (posaconazole and ravuconazole) also appears to be good [50]. The available clinical data for posaconazole include reports of successful salvage therapy for invasive candidiasis [51], successful salvage therapy of azole-refractory oropharyngeal candidiasis in HIV-infected individuals [52], and 2 randomized comparisons showing efficacy comparable with that of fluconazole for non—azole-refractory esophageal candidiasis [53, 54]. The available data for ravuconazole include a randomized phase II dose-ranging study showing efficacy comparable with that of fluconazole for non—azole-refractory esophageal candidiasis [55].

Caspofungin and the echinocandin antifungal agents. Caspofungin is the first of the echinocandin antifungal agents to be licensed. As with all of the agents of this class, this agent is only available as a parenteral preparation, and its spectrum is largely limited to Candida and Aspergillus species. Of particular relevance for use as empirical treatment, the agents of this class do not appear to have significant activity against Cryptococcus neoformans or against filamentous fungi other than Aspergillus [56].

Caspofungin has been shown to be as effective as both amphotericin B deoxycholate and fluconazole when used as therapy for oropharyngeal and esophageal candidiasis [57–60]. Likewise, Mora-Duarte et al. [17] found that caspofungin (70-mg loading dose followed by 50 mg/day in adults) was equivalent to but better tolerated than was amphotericin B deoxycholate (0.6–1.0 mg/kg per day) for cases of invasive candidiasis (83% of which were candidemia, 10% of which were peritonitis, and 7% of which were miscellaneous cases). Finally, caspofungin was effective in 72% of patients with fluconazole-resistant esophageal candidiasis [61]. This agent appears to be active against all Candida species; however, the MICs for some isolates of C. parapsilosis and Candida guilliermondii are relatively higher. The meaning of these higher MICs is still being investigated, but the data from the aforementioned study by Mora-Duarte et al. [17] hint at their possible clinical relevance [62]. Although C. parapsilosis caused only 19% of cases of fungemia in the caspofungin-treated group in that study, it was associated with 42% cases of persistent fungemia. Conversely, the species distribution of cases of persistent fungemia for amphotericin B–treated patients more closely paralleled the distribution of infecting species. It must be emphasized, however, that the total number of cases is very small and that the overall success rates for treatment of infections due to C. parapsilosis were similar between the study arms. Thus, these data suggest that echinocandins may be used successfully for treatment of C. parapsilosis fungemia but that the physician should be aware of the possibility that this species might respond less readily to this class of agents.

The in vitro activity of the other 2 agents in this category (anidulafungin and micafungin) against Candida species appears quite similar to that of caspofungin, and clinical data are expected to support similar patterns of utility. However, available clinical data for these agents are as yet limited to open-label dose-ranging studies of micafungin for treatment of esophageal candidiasis [63–65], open-label studies of anidulafungin for esophageal candidiasis [66], open-label data on micafungin administered to patients with candidemia [67, 68], and a randomized, double-blind comparison of micafungin with fluconazole as prophylaxis during the period of risk for neutropenia following bone marrow transplantation [69].

Amphotericin B deoxycholate and the lipid-associated formulations of amphotericin B. The majority of the experience with amphotericin B is with its classic deoxycholate preparation. However, 3 lipid-associated formulations of amphotericin B have been developed and approved for use in humans: amphotericin B lipid complex (ABLC) (Abelcet; Enzon), amphotericin B colloidal dispersion (ABCD) (Amphotec [in the United States] and Amphocil [elsewhere]; InterMune), and liposomal amphotericin B (AmBisome; Vestar). The names of these compounds, along with the requirement for use of the lipid-associated formulations at much higher doses than the deoxycholate preparation, have led to much confusion. The reader should note carefully that (1) “liposomal amphotericin B” is the name of a specific lipid-associated product, (2) a useful general term for the class is “lipid-associated formulations of amphotericin B,” (3) the 3 lipid-associated formulations of amphotericin B have different pharmacological properties and rates of treatment-related adverse events and thus should not be interchanged without careful consideration, (4) the typical intravenous dose for amphotericin B deoxycholate is 0.6–1.0 mg/kg per day, and (e) the typical dosage for the lipid-associated formulations when used for candidiasis is 3–5 mg/kg per day.

In this document, a reference to “intravenous amphotericin B” without a specific dose or other discussion of form should be taken to be a reference to the general use of any of the preparations of amphotericin B, with the understanding that the clinical experience is greatest with amphotericin B deoxycholate for essentially all forms of candidiasis and classes of patients. On the other hand, references to a specific formulation and dosage indicate more-specific data. We are not aware of any forms of candidiasis for which a lipid-associated formulation of amphotericin B is superior to amphotericin B deoxycholate [70], but we are also not aware of any situations in which a lipid-associated formulation would be contraindicated. The only possible exception is urinary candidiasis in which the protection of the kidney afforded by the altered pharmacological properties of the lipid-associated preparations of amphotericin B [71] has the theoretical potential to reduce delivery of amphotericin B and thus slow the pace of response [72]. The relative paucity of organized clinical data does, however, produce uncertainty regarding the optimal dose and duration of therapy with these agents.

Only ABLC and liposomal amphotericin B have been approved for use in proven cases of candidiasis. These approvals are for second-line therapy for patients who are intolerant of or have an infection refractory to therapy with conventional amphotericin B deoxycholate; these circumstances were defined in one study in which ABLC was administered as failure of therapy with amphotericin B deoxycholate (⩾500 mg), initial renal insufficiency (creatinine level of ⩾2.5 mg/dL or creatinine clearance of <25 mL/min), a significant increase in creatinine level (up to 2.5 mg/dL in adults or 1.5 mg/dL in children [73]), or severe, acute, administration-related toxicity. Patients with invasive candidiasis also have been treated successfully with ABCD [74, 75]. Both in vivo and clinical studies indicate that these compounds are less toxic but as effective as amphotericin B deoxycholate when used in appropriate dosages [76, 77]. Nevertheless, their higher cost and the paucity of randomized trials of their efficacy against proven invasive candidiasis limit their front-line use for treatment of these infections. These agents dramatically alter the pharmacology of amphotericin B, and the full implications of these changes are not yet known [78, 79].

Although amphotericin B deoxycholate has long been the standard agent for treatment of invasive candidiasis, the toxicity of this preparation is increasingly appreciated. Lipid-associated preparations have previously been considered primarily for patients who are intolerant of or have an infection refractory to the deoxycholate preparation. However, data showing that amphotericin B–induced nephrotoxicity may be associated with an up to 6.6-fold increase in mortality [80] makes consideration of initial use of lipid-associated amphotericin B appropriate for individuals who are at high risk of being intolerant of amphotericin B deoxycholate (e.g., those who require prolonged therapy; have preexisting renal dysfunction; or require continued concomitant use of another nephrotoxic agent, such as cis-platinum, an aminoglycoside, or cyclosporine [81, 82]). Some authors have also suggested that residence in an intensive care unit (ICU) or an intermediate care unit at the time of initiation of amphotericin B deoxycholate therapy is an additional risk factor for renal failure [82]. Additional work is required to help identify those individuals who can safely tolerate the deoxycholate preparation. The lipid-associated agents are licensed to be administered at the following dosages: ABLC, 5 mg/kg per day; ABCD, 3–6 mg/kg per day; and liposomal amphotericin B, 3–5 mg/kg per day. The optimal dosages of these compounds for serious Candida infections is unclear, and the agents appear generally equipotent. Dosages of 3–5 mg/kg would appear suitable for treatment of most serious candidal infections [83, 84].

Appropriate dosages in pediatric patients. The topic of the pharmacological properties of antifungal agents in children and infants has been reviewed in detail [85]. Data on dosing for the antifungal agents in pediatric patients are limited. Amphotericin B deoxycholate appears to have similar kinetics in neonates and adults [86]. A phase I and II study of ABLC (2–5 mg/kg per day) in the treatment of hepatosplenic candidiasis in children found that the area under the curve and the maximal concentration of drug were similar to those of adults and that steady-state concentration appeared to be achieved after ∼7 days of therapy [83]. Anecdotal data suggest that liposomal amphotericin B can be used in neonates [87]. Because clearance of flucytosine is directly proportional to glomerular filtration rate, infants with very low birth weight may accumulate high plasma concentrations because of immature renal function [88].

The pharmacokinetics of fluconazole vary with age [89–92]. Because of its more rapid clearance in children (plasma half-life, ∼14 h) [89], fluconazole at a dosage of 6 mg/kg q12h should be administered for treatment of life-threatening infections. In comparison with the volume of distribution seen in adults (0.7 L/kg), neonates may have a 2–3-fold higher volume of distribution that falls to <1 L/kg by 3 months of age. In comparison with the half-life of fluconazole in adults (30 h), the half-life in neonates is 55–90 h [93]. Despite this prolonged half-life, once-daily dosing seems prudent in infants with low or very low birth weight who are being treated for disseminated candidiasis. A dosage of 5 mg/kg per day has been used safely and successfully in this population [94].

Itraconazole cyclodextrin oral solution (5 mg/kg per day) administered to infants and children was found to provide potentially therapeutic concentrations in plasma [95]. The levels were, however, substantially lower than those attained in adult patients with cancer, particularly in children aged between 6 months and 2 years. A recent study of itraconazole cyclodextrin oral solution (2.5 mg/kg per day and 5 mg/kg per day) in HIV-infected children documented its efficacy for treating oropharyngeal candidiasis in pediatric patients [96]. The newly licensed intravenous formulation of itraconazole has not been studied in pediatric patients.

The published data on the use of the echinocandins in pediatric or neonatal patients includes small numbers of patients treated with caspofungin and micafungin [97–99]. The data suggest safety and efficacy in such patients.

Treatment Guidelines Overview

These practice guidelines provide recommendations for treatment of various forms of candidiasis. For each form, we specify objectives; treatment options; outcomes of treatment; evidence; values; benefits, harms, and costs; and key recommendations. Please see the discussion above with regard to available therapeutic agents: the amount of data on the newest agents (caspofungin and voriconazole) is quite limited, and they will be mentioned below only in reference to selected presentations of candidiasis.

Candidemia and Acute Hematogenously Disseminated Candidiasis

Objective. To resolve signs and symptoms of associated sepsis, to sterilize the bloodstream and any clinically evident sites of hematogenous dissemination, and to treat occult sites of hematogenous dissemination.

Treatment options. Intravenous amphotericin B, intravenous or oral fluconazole, intravenous caspofungin, or the combination of fluconazole plus amphotericin B (with the amphotericin B administered for the first 5–6 days only). Flucytosine could be considered in combination with amphotericin B for more-severe infections (C-III; see table 1 and Sobel [100] for definitions of categories reflecting the strength of each recommendation for or against its use and grades reflecting the quality of evidence on which recommendations are based). Removal of existing intravascular catheters is desirable, if feasible, especially in nonneutropenic patients (B-II).

Outcomes. Clearance of bloodstream and other clinically evident sites of infection, symptomatic improvement, absence of retinal findings of Candida endophthalmitis, and adequate follow-up to ensure that late-appearing symptoms of focal hematogenous spread are not overlooked.

Evidence. Candida bloodstream infections are increasingly frequent [101, 102] and are often associated with clinical evidence of sepsis syndrome and high associated attributable mortality [103, 104]. In addition, hematogenous seeding may compromise the function of ⩾1 organ. Two large randomized studies [105, 106] and 2 large observational studies [107, 108] have demonstrated that fluconazole (400 mg/day) and amphotericin B deoxycholate (0.5–0.6 mg/kg per day) are similarly effective as therapy. A large randomized study has demonstrated that caspofungin (70 mg on the first day followed by 50 mg/day) is equivalent to amphotericin B deoxycholate (0.6–1.0 mg/kg per day) for invasive candidiasis (mostly candidemia) [17]. Caspofungin was better tolerated and had a superior response rate in a predefined secondary analysis of evaluable patients. A comparison of fluconazole (800 mg/day) with the combination of fluconazole (800 mg/day) plus amphotericin B deoxycholate (∼0.7 mg/kd per day for the first 5–6 days) as therapy for candidemia was confounded by differences in severity of illness between the study groups, but the study found the regimens to be comparable and noted a trend toward better response (based principally on more-effective bloodstream clearance) in the group receiving combination therapy. The randomized studies are largely limited to nonneutropenic patients, whereas the observational studies provide data suggesting that fluconazole and amphotericin B are similarly effective in neutropenic patients. ABLC and liposomal amphotericin B are indicated for patients intolerant of or with infection refractory to conventional antifungal therapy. Open-label therapy of candidemia with ABCD (2–6 mg/kg per day) has been successful [75]. In a randomized trial, ABLC (5 mg/kg per day) was found to be equivalent to amphotericin B deoxycholate (0.6–1.0 mg/kg per day) as therapy for nosocomial candidiasis [109].

Values. Without adequate therapy, endophthalmitis, endocarditis, and other severe disseminated forms of candidiasis may complicate candidemia. Given the potential severity of the clinical syndrome, it is important that the initial empirical choice be adequate to address the most likely species and their associated susceptibility to the various agents. Candidemia due to C. parapsilosis has increased in frequency in pediatric populations and appears to be associated with a lower mortality rate than is candidemia due to other species of Candida [110–113]. Candidemia due to C. glabrata may be associated with increased mortality in patients with cancer [113]. In neonates, a duration of candidemia of ⩾5 days has been linked to the likelihood of ophthalmologic, renal, and cardiac involvement [114].

Benefits, harms, and costs. Effective therapy is potentially lifesaving. Amphotericin B–induced nephrotoxicity can complicate management of critically ill patients.

Key recommendations. If feasible, initial nonmedical management should include removal of all existing central venous catheters (B-II). The evidence for this recommendation is strongest for the nonneutropenic patient population [108, 115, 116] and includes data in which catheter removal was associated with reduced mortality in adults [108, 116] and neonates [117]. In neutropenic patients, the role of the gut as a source for disseminated candidiasis is evident from autopsy studies, but, in an individual patient, it is difficult to determine the relative contributions of the gut and a catheter as primary sources of fungemia [107, 108, 118]. An exception is made for fungemia due to C. parapsilosis, which is very frequently associated with use of catheters (A-II) [107]. There are, however, no randomized studies of this topic, and a recent exhaustive review [119] clearly demonstrates the limitations of the available data. However, the consensus opinion is that existing central venous catheters should be removed, when feasible [120]. Anecdotal reports of successful in situ treatment of infected catheters by instillation of antibiotic lock solutions containing as much as 2.5 mg/mL of amphotericin B deoxycholate [121–125] suggest this as an option in selected cases, but the required duration of therapy and the frequency of relapse are not known.

Initial medical therapy should involve caspofungin, fluconazole, an amphotericin B preparation, or combination therapy with fluconazole plus amphotericin B. The choice between these treatments depends on the clinical status of the patient, the physician's knowledge of the species and/or antifungal susceptibility of the infecting isolate, the relative drug toxicity, the presence of organ dysfunction that would affect drug clearance, available knowledge of use of the drug in the given patient population, and the patient's prior exposure to antifungal agents. Experience with caspofungin (a 70-mg loading dose followed by 50 mg daily) is, as yet, limited, but its excellent clinical activity [17], its broad-spectrum activity against Candida species, and a low rate of treatment-related adverse events make it a suitable choice for initial therapy in adults (A-I). For clinically stable patients who have not recently received azole therapy, fluconazole (⩾6 mg/kg per day; i.e., ⩾400 mg/day for a 70-kg patient) is another appropriate choice (A-I) [126, 127]. For clinically unstable patients infected with an unspeciated isolate, fluconazole has been used successfully, but many authorities prefer amphotericin B deoxycholate (⩾0.7 mg/kg per day) [126, 127] because of its broader spectrum. If a lipid-associated formulation of amphotericin B is selected, a dosage of at least 3 mg/kg/d appears suitable (C-III). A combination of fluconazole (800 mg/day) plus amphotericin B deoxycholate (0.7 mg/kg per day for the first 5–6 days) is also suitable (A-I).

Neonates with disseminated candidiasis are usually treated with amphotericin B deoxycholate because of its low toxicity and because of the relative lack of experience with other agents in this population. Fluconazole (6–12 mg/kg per day) has been used successfully in small numbers of neonates [128–131]. There are currently no data on the pharmacokinetics of caspofungin in neonates.

Antifungal susceptibility can be broadly predicted once the isolate has been identified to the species level (see the subsection Susceptibility testing and drug dosing, in the Introduction). Infections with C. albicans, C. tropicalis, and C. parapsilosis may be treated with amphotericin B deoxycholate (0.6 mg/kg per day), fluconazole (6 mg/kg per day), or caspofungin (70-mg loading dose followed by 50 mg/day) (A-I). Because C. glabrata often has reduced susceptibility to both azoles and amphotericin B, opinions on the best therapy are divided [127]. Both C. krusei and C. glabrata appear susceptible to caspofungin, and this agent appears to be a good alternative (A-I). Although fungemia due to C. glabrata has been treated successfully with fluconazole (6 mg/kg per day) [105, 132], many authorities prefer amphotericin B deoxycholate (⩾0.7 mg/kg per day) (B-III) [127]. On the basis of pharmacokinetic predictions [133], fluconazole (12 mg/kg per day; 800 mg/day for a 70-kg patient) may be a suitable alternative, particularly in less-critically ill patients (C-III). If the infecting isolate is known or likely to be C. krusei, available data suggest that amphotericin B deoxycholate (1.0 mg/kg per day) is preferred (C-III). On the basis of data on open-label salvage therapy, voriconazole is licensed in Europe (but not the United States) for “treatment of fluconazole-resistant serious invasive Candida infections (including C. krusei)” [19] and could be considered as an alternative choice (B-III). Many, but not all, isolates of C. lusitaniae are resistant to amphotericin B. Therefore, fluconazole (6 mg/kg per day) is the preferred therapy for this species (B-III). Both voriconazole and caspofungin would be expected to be active against this species (C-III). Issues associated with selection and dosage of the lipid amphotericin preparations are discussed in the Introduction. As discussed above and elsewhere, susceptibility testing may be used to identify isolates that are less likely to respond to fluconazole (A-II) or amphotericin B (B-II) (table 3) [27, 30].

For candidemia, therapy should be continued for 2 weeks after the last positive blood culture result and resolution of signs and symptoms of infection (A-III). Amphotericin B or caspofungin may be switched to fluconazole (intravenous or oral) for completion of therapy (B-III). Patients who are neutropenic at the time of developing candidemia should receive a recombinant cytokine that accelerates recovery from neutropenia (granulocyte colony-stimulating factor or granulocyte-monocyte colony-stimulating factor) [134]. Other forms of immunosuppression should be modified, when possible (e.g., by reduction of a corticosteroid dosage).

Breakthrough (or persistence of) candidemia in the face of ongoing antifungal therapy suggests the possibility of an infected intravascular device [135], significant immunosuppression [136], or microbiological resistance. Therapy with an agent from a different class should be started, the isolate should be promptly identified to the species level, and susceptibility testing should be considered. Infected intravascular devices should be removed, when feasible, and immunosuppression should be ameliorated.

Finally, all patients with candidemia should undergo at least 1 ophthalmological examination to exclude the possibility of candidal endophthalmitis (A-II). Although some authors have suggested that examinations should be conducted for 2 weeks after negative findings of an initial examination [137], these recommendations are based on small numbers of patients. The results of large prospective therapy studies that included careful ophthalmological examinations suggest that onset of retinal lesions is rare following an otherwise apparently successful course of systemic therapy (there were no such cases in 441 successfully treated subjects [17, 105, 132]. We thus conclude that candidemic individuals should have at least 1 careful ophthalmological examination, preferably at a time when the candidemia appears controlled and new spread to the eye is unlikely (B-III). These data and recommendations are based almost entirely on experience in the treatment of nonneutropenic patients—neutropenic patients may not manifest visible endophthalmitis until recovery from neutropenia, and, therefore, ophthalmological examination should be performed after recovery of the neutrophil count.

Empirical Treatment of Suspected Disseminated Candidiasis in Febrile Nonneutropenic Patients

Objective. To treat early occult Candida infection.

Treatment options. Intravenous amphotericin B or intravenous or oral fluconazole.

Outcomes. Reduction in fever and prevention of development of overt candidal bloodstream infection and the complications associated with hematogenously disseminated candidiasis.

Evidence. Although Candida is now the fourth most common bloodstream isolate and is the most common invasive fungal infection in critically ill nonneutropenic patients, accurate early diagnostic tools for invasive candidiasis are lacking. One study found that candidemia increased the length of hospitalization by 22 days and increased costs by $34,000–$44,000 [138]. Colonization by Candida of multiple nonsterile sites, prolonged use of antibacterial antibiotics, presence of central venous catheters, hyperalimentation, surgery (especially surgery that transects the gut wall), and prolonged ICU stay have all been linked to increased risk of invasive candidiasis [139–141]. Although empirical therapy is intuitively attractive, colonization does not always imply infection [142], and compelling data that define appropriate subsets of patients for such therapy are lacking.

Values. Prevention of clinically evident invasive candidiasis could potentially reduce morbidity and mortality.

Benefits, harms, and costs. Given the ill-defined nature of this syndrome, preference is often given to therapies with lesser toxicity. Widespread use of inappropriate antifungal therapy may have deleterious epidemiological consequences, including selection of resistant organisms.

Key recommendations. The utility of antifungal therapy for this syndrome has not been defined. If therapy is given, its use should be limited to patients with (1) Candida species colonization (preferably at multiple sites [139, 143]), (2) multiple other risk factors, and (3) absence of any other uncorrected causes of fever (C-III) [127]. The absence of colonization by Candida species indicates a lower risk for invasive candidiasis and warrants delaying empirical therapy.

Empirical Antifungal Treatment of Neutropenic Patients with Prolonged Fever Despite Antibacterial Therapy

Objective. To treat early occult fungal infection and prevent fungal infection in high-risk patients.

Treatment options. Empirical therapy should address both yeast and mould infections. Until recently, amphotericin B was the only sufficiently broad-spectrum agent available in a reliable parenteral form. Itraconazole has an adequate antifungal spectrum of activity and has been shown to have activity equivalent to that of amphotericin B [144]. If itraconazole is used, initiation of therapy with the intravenous formulation is appropriate, because the bioavailability of the current oral formulations of itraconazole (including the cyclodextrin solution) is unpredictable [145, 146]. Fluconazole may be inappropriate because of prior exposure and its limited spectrum. Voriconazole has been shown to be active in high-risk patients (e.g., allogeneic bone marrow transplant recipients and individuals with relapsed leukemia) for prevention of breakthrough fungal infections [147]. The role of caspofungin and the other echinocandin antifungal agents in the treatment of such patients is uncertain.

Outcomes. Resolution of fever and prevention of development of clinically overt infection.

Evidence. This clinical condition has recently been reviewed, and there is a related guideline from the IDSA [134]. Randomized, prospective clinical trials have demonstrated that neutropenic patients with persistent fever despite receipt of broad-spectrum antimicrobial therapy have an ∼20% risk of developing an overt invasive fungal infection [148, 149]. Empirical antifungal therapy reduces the frequency of development of clinically overt invasive fungal infection in this high-risk population [148–150].

Values. Early antifungal therapy is more likely to succeed in neutropenic patients. Advanced infection is associated with high morbidity and mortality.

Benefits, harms, and costs. Early treatment of fungal infections should reduce fungal infection—associated morbidity.

Key recommendations. Antifungal therapy is appropriate in neutropenic patients who have persistent unexplained fever, despite receipt of 4–7 days of appropriate antibacterial therapy. Once begun, therapy is continued until resolution of neutropenia. Amphotericin B deoxycholate (0.5–0.7 mg/kg per day) has traditionally been the preferred agent (A-II). When compared with amphotericin B deoxycholate (median dose, 0.6 mg/kg per day), liposomal amphotericin B (median dose, 3 mg/kg per day) showed similar overall clinical efficacy but demonstrated superior safety and a decreased rate of documented breakthrough fungal infections, particularly in recipients of bone marrow transplants (A-I) [151]. When compared with amphotericin B deoxycholate (mean daily dose, 0.7 mg/kg), itraconazole (200 mg iv q12h for 2 days, 200 mg iv per day for 12 days, and then 400-mg solution po per day) showed similar breakthrough fungal infection rates and mortality but significantly less toxicity (A-I) [144]. Although the data are controversial because some analyses show that voriconazole was, overall, slightly inferior to liposomal amphotericin B [147, 152–155], voriconazole has been shown to be superior to liposomal amphotericin B in the prevention of breakthrough fungal infections in high-risk patients (A-I). Thus, use of this compound should be limited to allogeneic bone marrow transplant recipients and individuals with relapsed leukemia. Fluconazole (400 mg/day) has been used successfully for selected patients (A-I) [156–158] and could be considered as an alternative strategy [127] if (1) the patient is at low risk for invasive aspergillosis, (2) the patient lacks any other signs or symptoms suggesting aspergillosis, (3) local epidemiologic data suggest that the patient is at low risk for infection with azole-resistant isolates of Candida, and (4) the patient has not received an azole antifungal agent as prophylaxis.

Chronic Disseminated Candidiasis (Hepatosplenic Candidiasis)

Objective. To eradicate foci of chronic disseminated candidiasis.

Treatment options. Intravenous amphotericin B or intravenous or oral fluconazole. Flucytosine in combination with one of these agents could be considered for more-refractory infections.

Outcomes. Resolution of clinical signs and symptoms of infection and resolution of radiographic findings of visceral involvement.

Evidence. Open-label and observational studies have evaluated the utility of amphotericin B deoxycholate [159, 160], lipid-associated amphotericin B [83], and fluconazole [161, 162]. A recent case report suggests that caspofungin might have activity against this form of candidiasis [163].

Values. This syndrome is not acutely life-threatening but does require prolonged therapy to produce a cure. Thus, importance is placed on use of a convenient and nontoxic long-term regimen.

Benefits, harms, and costs. Amphotericin B, although efficacious, must be administered intravenously. Fluconazole can be given orally.

Key recommendations. Fluconazole (6 mg/kg per day) is generally preferred for clinically stable patients (B-III). Amphotericin B deoxycholate (0.6–0.7 mg/kg per day) or a lipid-associated formulation of amphotericin B (3–5 mg/kg per day) may be used in acutely ill patients or patients with refractory disease. Some experts recommend an initial 1–2-week course of amphotericin B for all patients, followed by a prolonged course of fluconazole [126]. Therapy should be continued until calcification or resolution of lesions, particularly in patients receiving continued chemotherapy or immunosuppression. Premature discontinuation of antifungal therapy may lead to recurrent infection. Patients with chronic disseminated candidiasis may continue to receive chemotherapy, including ablative therapy for recipients of bone marrow and/or stem cell transplants. Treatment of chronic disseminated candidiasis in such patients continues throughout chemotherapy [160].

Disseminated Cutaneous Neonatal Candidiasis

Objective. To treat infants with disseminated cutaneous neonatal candidiasis (also known as congenital candidiasis) who are at high risk for developing acute disseminated candidiasis.

Treatment options. In healthy infants with normal birth weight, treatment of primary cutaneous candidiasis with topical agents is generally appropriate. In patients at risk for acute bloodstream or visceral dissemination, therapies used for acute disseminated candidiasis are appropriate.

Outcomes. The neonatal candidiasis syndrome is a unique syndrome in which widespread dermatitis due to Candida infection is seen in neonates. This syndrome is thought to be secondary to contamination of the amniotic fluid, and, in healthy-term infants, this process is usually limited to the skin and resolves with topical therapy [164]. However, neonates born prematurely or infants with low birth weight and prolonged rupture of cutaneous membranes, the cutaneous process may become invasive and produce acute disseminated candidiasis [165].

Evidence. Essentially all data are derived from small case series and individual reports. Most reports have been limited to use of amphotericin B.

Values. If not treated, acute disseminated candidiasis may develop, which can be lethal.

Benefits, harms, and costs. Amphotericin B deoxycholate therapy is generally well tolerated in neonates. Fluconazole has not been as well studied. In particular, the pharmacological properties of fluconazole vary with neonatal age, making the choice of dosage somewhat difficult [86, 90, 91].

Key recommendations. Prematurely born neonates, neonates with low birth weight, or infants with prolonged rupture of membranes who demonstrate the clinical findings associated with disseminated neonatal cutaneous candidiasis should be considered for systemic therapy. Amphotericin B deoxycholate (0.5–1 mg/kg per day, for a total dose of 10–25 mg/kg) is generally used (B-III). Fluconazole may be used as a second-line agent (B-III). Dosing issues for neonates are discussed in the subsection Appropriate dosages for pediatric patients, in the section Available Drugs and Drug Use (above).

Urinary Candidiasis

Objective. To eradicate signs and symptoms associated with parenchymal infection of the urinary collecting system. In select patients, such therapy might reduce the risk of ascending or disseminated infection.

Treatment options. Fluconazole (oral or intravenous), amphotericin B (intravenous), or flucytosine (oral). Because of bladder irrigation, amphotericin B fails to treat disease above the level of the bladder.

Outcome. Clearance of infection in urine.

Evidence. Urinary candidiasis includes an ill-defined group of syndromes [166]. The most common risk factors for candiduria include urinary tract instrumentation, recent receipt of antibiotic therapy, and advanced age [167]. Candida species are now the organisms most frequently isolated from the urine of patients in surgical ICUs. In most patients, isolation of Candida species represents only colonization as a benign event. In individuals with candidemia, Foley catheter change alone rarely results in clearance of candiduria (<20%). However, discontinuation of catheter use alone may result in eradication of candiduria in almost 40% of patients [168] (B-III). A recently completed placebo-controlled trial found that fluconazole (200 mg/day for 14 days) hastened the time to negative results of urine culture but that the frequency of negative urine culture results was the same in both treatment groups 2 weeks after the end of therapy (∼60% for catheterized patients and ∼73% for noncatheterized patients) [168]. The minimal utility of antifungal therapy against urinary candidiasis is also supported by a recent large observational study [169]. On the other hand, candidal urinary tract infections that were accompanied by radiographic evidence of a bezoar have responded to fluconazole alone [131]. In other patients (e.g., those with obstructive uropathy), candiduria may rarely be the source of subsequent dissemination [170] or a marker of acute hematogenous dissemination [166]. These concerns are especially applicable to neutropenic patients, patients without current or recent placement of medical instruments in the urinary tract, and infants with low birth weight. Data on the outcome of therapy are limited by the heterogeneity of the underlying diseases and by the lack of clear definitions.

Values. Treatment of asymptomatic candiduria in nonneutropenic catheterized patients has never been shown to be of value. Treatment with fluconazole will briefly clear funguria in approximately one-half of treated patients, but recurrence is prompt, selection of resistant Candida species is possible, and therapy does not appear to alter clinical outcome [168]. Candiduria in neutropenic patients, critically ill patients in ICUs, infants with low birth weight, and recipients of a transplant may be an indicator of disseminated candidiasis.

Benefits, harms, and costs. Treatment of appropriately selected patients may reduce the risk of ascending and/or hematogenously disseminated disease. Treatment of persistently febrile patients who have candiduria but who lack evidence for infection at other sites may treat occult disseminated candidiasis. Inappropriate therapy may select for resistant organisms.

Key recommendations. Determination of the clinical relevance of candiduria can be difficult [171]. Asymptomatic candiduria rarely requires therapy (D-III). Candiduria may, however, be the only microbiological documentation of disseminated candidiasis. Candiduria should be treated in symptomatic patients, patients with neutropenia, infants with low birth weight, patients with renal allografts, and patients who will undergo urologic manipulations (B-III). However, short courses of therapy are not recommended; therapy for 7–14 days is more likely to be successful. Removal of urinary tract instruments, including stents and Foley catheters, is often helpful. If complete removal is not possible, placement of new devices may be beneficial. Treatment with fluconazole (200 mg/day for 7–14 days) and with amphotericin B deoxycholate at widely ranging doses (0.3–1.0 mg/kg per day for 1–7 days) has been successful [172] (B-II). In the absence of renal insufficiency, oral flucytosine (25 mg/kg q.i.d.) may be valuable for eradicating candiduria in patients with urologic infection due to non-albicans species of Candida (C-III). However, emergence of resistance may occur rapidly when this compound is used as a single agent [173]. Bladder irrigation with amphotericin B deoxycholate (50–200 µg/mL) may transiently clear funguria [174] but is rarely indicated (C-III), except as a diagnostic localizing tool [175]. Even with apparently successful local or systemic antifungal therapy for candiduria, relapse is frequent, and this likelihood is increased by continued use of a urinary catheter. Persistent candiduria in immunocompromised patients warrants ultrasonography or CT of the kidney (C-III).

Lower Respiratory Tract Candidiasis (Pulmonary and Laryngeal Candidiasis)

Objective. To eradicate infection and prevent airway obstruction and loss of pulmonary reserve.

Treatment options. Intravenous amphotericin B or oral or intravenous fluconazole.

Outcomes. For pneumonia, treatment clears local sites of infection along with any associated sites of systemic infection. For laryngitis, early clinical detection and documentation by fiberoptic or indirect laryngoscopy demonstrates localization of lesions and assessment of airway patency, permits acquisition of samples for culture, and enables rapid initiation of antifungal therapy. Impending airway obstruction is managed by endotracheal intubation. Successful medical therapy resolves laryngeal stridor, prevents airway obstruction, and reduces the risk of aspiration.

Evidence. Observational reports and case series have shown that proven Candida pneumonia is associated with high mortality among patients with malignancies [176]. No convincing data for any particular form of therapy exist. Data for laryngitis are based on small series and individual case reports [177, 178]. Most cases have been managed with amphotericin B therapy, but milder cases been successfully managed with fluconazole therapy [179, 180].

Values. Candida pneumonia seems to exist in 2 forms. Rarely, after aspiration of oropharyngeal material, primary pneumonia due to Candida may develop [176, 181,182]. More commonly, hematogenously disseminated candidiasis produces pulmonary lesions, along with involvement of multiple additional organs. Firm diagnosis of these disease entities is elusive and requires histopathological confirmation. Benign colonization of the airway with Candida species and/or contamination of the respiratory secretions with oropharyngeal material is much more common than either form of true Candida pneumonia. Thus, diagnoses of Candida pneumonia that are based solely on microbiological data are often incorrect [183, 184] (B-III).

If not diagnosed and treated promptly, laryngitis may lead to airway obstruction and respiratory arrest.

Benefits, harms, and costs. Injudicious use of antifungal therapy for patients with tracheobronchial colonization or oropharyngeal contamination of respiratory secretions may lead to selection of resistant organisms. Definitive diagnosis of Candida pneumonia requires histopathological confirmation. In contrast, because of the severe morbidity and potential mortality associated with laryngeal candidiasis, rapid clinical diagnosis and prompt initiation of therapy are important and outweigh any adverse effects of antifungal therapy.

Key recommendations. Most patients with primary Candida pneumonia and laryngeal candidiasis have been treated with amphotericin B (0.7–1.0 mg/kg per day) (B-III). In cases of secondary pneumonia associated with hematogenously disseminated infection, therapy directed at disseminated candidiasis, rather than at Candida pneumonia in particular, is indicated (see the section Candidemia and Acute Hematogenously Disseminated Candidiasis, above). For candidal laryngitis, fluconazole is a suitable alternative in milder cases (B-III).

Candidal Osteomyelitis (Including Mediastinitis) and Arthritis

Objective. To relieve symptoms and eradicate infection.

Treatment options. After open or arthroscopic debridement or drainage, both intravenous amphotericin B and oral or intravenous fluconazole have been used.

Outcomes. Eradication of infection and symptoms and return of joint function.

Evidence. Multiple observational studies have been reported, most of which have used intravenous amphotericin B as the primary therapy, sometimes followed by a course of treatment with an azole antifungal agent. A few reports have described initial therapy with an azole.

Values. Untreated disease leads to crippling disability.

Benefits, harms, and costs. The high morbidity associated with untreated disease makes aggressive surgical and medical therapy appropriate. The presentation of candidal mediastinitis may be indolent and delayed [185]. Surgical debridement, biopsy, and drainage also serve to provide more-definitive histopathological and microbiological documentation before initiation of the prolonged therapy required for this class of infection.

Key recommendations. Osteomyelitis is best treated with combined surgical debridement of the affected area, especially in the case of vertebral osteomyelitis, and antifungal therapy [186]. Courses of amphotericin B deoxycholate (0.5–1 mg/kg per day for 6–10 weeks) have been used successfully [187–189]. Fluconazole has been used successfully as initial therapy for susceptible isolates in 3 reports in which doses of 6 mg/kg per day for 6–12 months were effective [190–192]. Addition of amphotericin B deoxycholate to bone cement appears safe and may be of value in complicated cases [193]. Taken together, these data suggest that surgical debridement and an initial course of amphotericin B for 2–3 weeks followed by fluconazole, for a total duration of therapy of 6–12 months, would be rational (B-III).

Definitive information on treatment of native joint arthritis is limited. Adequate drainage is critical to successful therapy [194]. In particular, management of Candida arthritis of the hip requires open drainage. Case reports have documented cures with administration of intravenous amphotericin B [195] and with fluconazole when administered in conjunction with adequate drainage. Fluconazole has occasionally been used alone successfully [196]. As parenteral administration of these agents produces substantial synovial fluid levels, the utility of intra-articular therapy is discouraged. Prolonged courses of therapy similar to those used for treating osteomyelitis appear to be required (C-III).

Although success with medical therapy alone has been described [197], Candida arthritis that involves a prosthetic joint generally requires resection arthroplasty [198]. Subsequent medical therapy mirrors that for native joint disease, and a new prosthesis may be inserted after successful clearance of the local infection (C-III).

On the basis of a small number of cases, Candida mediastinitis may be treated successfully with surgical debridement followed by either amphotericin B or fluconazole therapy [185, 199] (III-C). Irrigation of the mediastinal space with amphotericin B is not recommended, because it may cause chemical mediastinitis. Prolonged courses of therapy, similar to those needed for osteomyelitis at other sites, appear to be appropriate (C-III).

Candidal Infections of The Gallbladder, Pancreas, and Peritoneum

Objective. To eradicate Candida infection and prevent recurrence of infection.

Treatment options. Intravenous amphotericin B or oral or intravenous fluconazole.

Outcome. Clearance of infection, as judged by resolution of local signs and symptoms along with sterilization of cultures.

Evidence. Treatment of Candida infection of the pancreas and biliary tree has been described in case reports and small series. Successful therapy with either amphotericin B or fluconazole has been described.

Values. There are 2 major syndromes of peritoneal candidiasis. In disease associated with use of catheters for peritoneal dialysis, catheter removal is often required for successful therapy [200–203]. Both systemic amphotericin B and fluconazole therapies have been used successfully [201–203].

Candida peritonitis may also develop in association with surgical or traumatic injury to the gut wall. Others at risk include patients who recently received chemotherapy for neoplasm or immunosuppressive therapy for transplantation or to those with inflammatory diseases [204]. Candida is usually part of a polymicrobial infection, and case series suggest that therapy directed toward Candida species is indicated, particularly when Candida organisms are isolated as part of a complex infection or in an immunocompromised patient [205–209]. Uncontrolled Candida superinfection has been associated with significant mortality in patients with acute necrotizing pancreatitis [210–213]. A recent small but placebo-controlled trial demonstrated that fluconazole (400 mg/day) reduced the likelihood of developing symptomatic Candida peritonitis in surgical patients with recurrent gastrointestinal perforations or anastomotic leakage [214].

Benefits, harms, and costs. Routine treatment of Candida isolated following prompt and definitive repair of an acutely perforated viscus in otherwise healthy patients without signs of sepsis is probably not needed and could lead to selection of resistant organisms.

Key recommendations. Disease of the biliary tree should be treated by mechanical restoration of functional drainage, combined with therapy with either amphotericin B or fluconazole (C-III). Both agents achieve therapeutic biliary concentrations, and local instillation is not needed [215]. Catheter-associated peritonitis is treated with catheter removal and systemic treatment with amphotericin B or fluconazole (B-III). After removal of the peritoneal dialysis catheter and a delay of at least 2 weeks, a new catheter may be placed (B-III) [200]. Intraperitoneal amphotericin B has been associated with painful chemical peritonitis and should, in general, be avoided. Candida peritonitis related to intra-abdominal leakage of fecal material is treated with surgical repair, drainage, and therapy with either amphotericin B or fluconazole (C-III). The required duration of therapy for all forms of Candida peritonitis is not well defined and should be guided by the patient's response. In general, 2–3 weeks of therapy seems to be required. Surgical patients with recurrent gastrointestinal perforation are at increased risk for Candida peritonitis and may benefit from prophylactic antifungal therapy (B-I).

Candidal Endocarditis, Pericarditis, Suppurative Phlebitis, and Myocarditis

Objective. To eradicate Candida infection and prevent recurrence of infection.

Treatment options. Intravenous amphotericin B or oral or intravenous fluconazole. Oral flucytosine may be added to amphotericin B.

Outcome. Clearance of infection, as judged by sterilization of the bloodstream and preservation of cardiac function.

Evidence. All data are derived from individual case reports and case series.

Values. Although the available data are limited [216], combined medical and surgical therapy generally appears to be the key for treatment of candidal endocarditis, pericarditis, and suppurative phlebitis. As emphasized by a report of a native valve that was not sterilized after 160 days of amphotericin B deoxycholate therapy [217], removal of infected valves, resection of infected peripheral veins, and debridement of infected pericardial tissue are almost always required for successful therapy [218, 219]. Suppurative phlebitis of the central veins has responded to prolonged medical therapy with amphotericin B [220–222]. Suppurative peripheral thrombophlebitis responds to surgical resection of the infected vein and antifungal therapy with amphotericin B or fluconazole [223]. The utility of anticoagulation as part of such purely medical therapy is uncertain. Candidal myocarditis is usually part of the syndrome of disseminated candidiasis, is clinically silent, and is treated as part of the therapy of disseminated disease [224]. However, candidal myocarditis may cause complete atrioventricular block, necessitating placement of a pacemaker [225].

Benefits, harms, and costs. These infections are associated with high morbidity and mortality, justifying aggressive medical and surgical therapy.

Key recommendations. Both native valve and prosthetic valve infection should be managed with surgical replacement of the infected valve. Medical therapy with amphotericin B with or without flucytosine at maximal tolerated doses has most often been used (B-III). Total duration of therapy should be at least 6 weeks after surgery, but possibly much longer (C-III). Candida endocarditis has a propensity for relapse and requires careful follow-up for at least 1 year [227]. If valve replacement is not possible, long-term (possibly life-long) suppressive therapy with fluconazole may be used (C-III) [216, 228, 229]. Successful primary therapy with fluconazole [105] and liposomal amphotericin B [230] has been described for patients with native valve infections.

Candidal pericarditis requires surgical debridement and/or resection, depending on the extent of the disease [231, 232]. Cardiac tamponade is possible and may require an emergency procedure to relieve hemodynamic compromise. Prolonged therapy with amphotericin B [219] or fluconazole should be used (C-III).

Suppurative Candida thrombophlebitis of a peripheral vein is best managed with surgical resection of the involved vein segment, followed by antifungal therapy for 2 weeks (B-III). After vein resection, the general approach to this disease is similar to that for other forms of acute hematogenous dissemination.

Candidal Meningitis

Objective. To achieve rapid clearance of the infection and the return of normal neurological function.

Treatment options. Intravenous amphotericin B or fluconazole. Flucytosine may be added to the course of amphotericin B.

Outcomes. Sterilization of the CSF often precedes eradication of parenchymal infection. Thus, therapy should be continued until normalization of all CSF analysis findings, normalization of radiological findings, and stabilization of neurological function.

Evidence. Most data are based on observational reports of use of amphotericin B deoxycholate [233, 234]. Liposomal amphotericin B was used successfully in 5 of 6 cases of Candida meningitis in newborn infants [235]. Because of its ability to penetrate the blood-brain barrier, flucytosine is often added to the course of therapy [236]. Fluconazole with flucytosine was used successfully in 1 case [237].

Values. Candida meningitis often follows candidemia in newborn infants [234] and has a high propensity for relapse. Untreated disease is lethal.

Benefits, harms, and costs. Because of the high morbidity and mortality associated with this infection, very aggressive therapy is warranted.

Key recommendations. Amphotericin B deoxycholate (0.7–1 mg/kg per day) plus flucytosine (25 mg/kg q.i.d.) is appropriate as initial therapy (B-III). The flucytosine dose should be adjusted to produce serum levels of 40–60 µg/mL [173]. Very few data exist on fluconazole for the treatment of candidal meningitis—it has been used as both follow-up therapy and long-term suppressive therapy. Because of the tendency for this disease to relapse, therapy should be administered for a minimum of 4 weeks after resolution of all signs and symptoms associated with the infection. Treatment of Candida meningitis associated with neurosurgical procedures should also include removal of prosthetic devices [238, 239].

Sours: https://academic.oup.com/cid/article/38/2/161/286280
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Antifungal treatment for invasive Candida infections: a mixed treatment comparison meta-analysis

CRD summary

This review evaluated antifungal therapy on infection response rates, mortality and safety in adults with confirmed systemic fungal infection. The authors concluded that azoles and echinocandins were equally effective for treating invasive candidiasis and similar within-class effects were evident. Due to unclear study quality and concerns about the chosen method of synthesis, the reliability of these conclusions is unclear.

Authors' objectives

To evaluate the effects of antifungal therapy on infection response rates, mortality and safety in adults with confirmed systemic fungal infection.

Searching

MEDLINE, EMBASE, Cochrane Central Database of Controlled Trials (CENTRAL), AMED, CINAHL, TOXNET, Development and Reproductive Toxicology, Hazardous Substances Data Bank, PsycINFO, Web of Science and other databases that included full-text journals were searched from inception to May 2009. Search terms were reported. Bibliographies of systematic reviews and retrieved papers were searched for additional studies, including unpublished material.

Study selection

Randomised controlled trials (RCTs) that compared different antifungal treatments for patients aged at least 18 years with confirmed invasive candidiasis were eligible for inclusion in the review. The primary outcome of interest was clinical response rate. Secondary outcomes of interest were all-cause mortality, fungal-attributable death and adverse events. Trials were excluded if they reported only on dose-comparison or dosage form, single-site fungal infections and aspergillosis, cryptococcosis and endemic mycoses.

Most included trials compared azole-class drugs to amphotericin B. The included azoles were fluconazole, itraconazole and voriconazole. Other trials assessed echinocandins (anidulafungin, micafungin and caspofungin). Patients were mostly those with hematologic cancers infected with candida species. Mixed clinical populations were included. Median participant age was 57 years. Dosage, timing and definitions of response varied across included trials.

Two independent reviewers selected trials for inclusion in the review..

Assessment of study quality

Trial quality was assessed on allocation sequence generation, allocation concealment, blinding, loss to follow-up and intention-to-treat analysis.

Two reviewers independently performed quality assessment. Disagreements were resolved by consensus.

Methods of synthesis

The analysis was twofold. For the analysis of study outcomes across classes of drugs (azole interventions versus all amphotericin B), relative risks and 95% CIs were pooled in a fixed-effect meta-analysis. Where there were zero events in one arm of a trial, the Haldane method was used and 0.5 was added to each arm. Multivariate meta-regression (amphotericin delivery and allocation concealment as covariates) was applied to assess the impact of individual azoles and delivery methods of amphotericin B on the overall estimates. The I2 statistic was used to assess statistical heterogeneity. The relative effectiveness of each drug was evaluated by combining direct and indirect evidence in a fixed-effect analysis of mixed-treatment comparisons using a Bayesian approach that reported posterior means and 95% credible intervals.

Results of the review

Eleven RCTs (n=965) were included in the review. Overall trial quality was considered to be moderate; individual quality assessment results were not reported.

For global clinical response, a statistically significant pooled effect was found for azoles versus amphotericin B (RR 0.87, 95% CI 0.78 to 0.96, I2=43%; seven trials). Similar effect estimates were reported when fluconazole (five trials), itraconazole (one trial) and voriconazole (one trial) were compared with amphotericin B; only the first of these analyses was statistically significant. Results for anidulafungin compared with fluconazole were also statistically significant (RR 1.26 95% CI 1.06 to 1.51; one trial).

For all-cause mortality, there was no statistically significant effect in the comparison of azoles versus amphotericin B. Similar results were reported for fluconazole (five trials), itraconazole (one trial) and voriconazole (one trial). There were no statistically significant effects in any of the analyses of micafungin versus caspofungin and anidulafungin versus fluconazole.

There were no statistically significant associations for deaths attributable to fungal infection.

Azoles were found to be favourable to amphotericin B in terms of a lower incidence of serious adverse events (RR 0.67, 95% CI 0.55 to 0.81; two trials). Echinocandins were similarly favourable to amphotericin B (RR 0.49, 95% CI 0.37 to 0.66; two trials). Micafungin and caspofungin had similar safety profiles. Azoles were favourable to amphotericin B on nephrotoxicity (RR 0.22, 95% CI 0.15 to 0.32; I2=74%), as were echinocandins (RR 0.31, 95% CI 0.17 to 0.57). The only statistically significant result for hepatic enzyme elevations was in favour of anidulafungin over fluconazole (RR 0.21, 95% CI 0.05 to 0.83).

Mixed-treatment comparison analysis showed that within-class effects were similar across all drug interventions. Absolute response rates ranged from 63% (fluconazole) to 77.49% (anidulafungin). Absolute treatment efficacy in terms of mortality ranged from 20.75% (anidulafungin) to 39.99% (amphotericin B liposomal).

Sensitivity analysis on the dose of amphotericin B did not alter the main results.

Authors' conclusions

Azoles and echinocandins were equally effective for treating invasive candidiasis and similar within-class effects were evident. Amphotericin B was an effective alternative, but was more toxic.

Implications of the review for practice and research

Practice: The authors stated that this review confirmed the guidelines from the Infectious Disease Society of America, which recommended azoles or echinocandins as the first-line treatment for candida infections.

Research: The authors stated that future research should aim for more consistency in endpoint definitions to facilitate comparisons across trials.

Bibliographic details

Mills EJ, Perri D, Cooper C, Nachega JB, Wu P, Tleyjeh I, Phillips P. Antifungal treatment for invasive Candida infections: a mixed treatment comparison meta-analysis. Annals of Clinical Microbiology and Antimicrobials 2009; 8:23. [PMC free article: PMC2713200] [PubMed: 19558681]

Indexing Status

Subject indexing assigned by NLM

MeSH

Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B /adverse effects /therapeutic use; Antifungal Agents /adverse effects /therapeutic use; Azoles /adverse effects /therapeutic use; Candidiasis /drug therapy /mortality; Echinocandins /adverse effects /therapeutic use; Fluconazole /adverse effects /therapeutic use; Humans; Middle Aged; Randomized Controlled Trials as Topic; Treatment Outcome; Young Adult

Database entry date

15/09/2010

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

Sours: https://www.ncbi.nlm.nih.gov/books/NBK77422/
Candida Esophagitis

Treatment for Invasive Candidiasis

How is invasive candidiasis treated?

Image of IV of antifungal solution

The specific type and dose of antifungal medication used to treat invasive candidiasis usually depends on the patient’s age, immune status, and location and severity of the infection. For most adults, the initial recommended antifungal treatment is an echinocandin (caspofungin, micafungin, or anidulafungin) given through the vein (intravenous or IV). Fluconazole, amphotericin B, and other antifungal medications may also be appropriate in certain situations.

How long does the treatment last?

For candidemia, treatment should continue for 2 weeks after signs and symptoms have resolved and Candida yeasts are no longer in the bloodstream. Other forms of invasive candidiasis, such as infections in the bones, joints, heart, or central nervous system, usually need to be treated for a longer period of time.

Healthcare providers can click here for the Infectious Diseases Society of America’s Clinical Practice Guidelines for the Management of Candidiasisexternal icon.

Sours: https://www.cdc.gov/fungal/diseases/candidiasis/invasive/treatment.html

Treatment candida antifungal

Antifungal agents commonly used in the superficial and mucosal candidiasis treatment: mode of action and resistance development

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Candida Treatments That Actually Work

Antifungal Drugs for Invasive Candida Infections (ICI) in Neonates: Future Perspectives

Introduction

Fungal Infections

Yeasts are commensal organisms which normally colonize mucosal surfaces and skin. However, they display a variety of virulence factors which may potentially allow for the infection of the host organism.

Fungal adhesion to host tissues is of primary importance for tissue colonization. Yeasts exploit either specific (ligand-receptor interactions) or non-specific mechanisms to adhere with different tissue types and inanimate surfaces. The production of the so-called “adhesins,” proteins able to interact specifically with molecules of the extracellular matrix, is essential for fungal adhesion, while the non-specific mechanisms include electrostatic charge, and van der Waals forces (1). In the case of damaged epithelium, higher amounts of extracellular matrix proteins are exposed, thus allowing for an easier fungal adhesion. A further virulence factor is the production of enzymes, such as secreted aspartyl proteases (SAP), phospholipases, lipases, and hydrolytic enzymes, which allow the lysis of the cellular membrane and, therefore, the entrance into the host cells (2). The fungal ability to form intraluminal catheter biofilms also plays a primary role in the colonization of epithelial surfaces and subsequent dissemination. Moreover, Candida's ability to form hyphae is crucial for its virulence and dissemination (3).

Besides fungal virulence factors, a number of host features may facilitate fungal colonization and infection. Candida infections develop more easily if the host has impaired defense mechanisms. In preterm neonates, Candida represents the third most common causative agent of late-onset sepsis and has a high burden of morbidity and mortality (4, 5). Candida infection (ICI) occurs in 4–18% of critically ill neonates, with higher incidence among extremely low birth weight (ELBW) infants (birth weight ≤ 1,000 grams) (4, 6–10). Between 20 and 30% of these infants are likely to die. The mortality rate is comparable between neonates with positive blood cultures and neonates with positive urine cultures (4, 11, 12). Moreover, Candida is able to invade virtually all body tissues and possible complications such as blindness, impaired neurodevelopment, and need for surgical corrective procedures may develop after severe ICI in neonates who survive (11, 12). In case of ICI, the central nervous system (CNS) is frequently involved and the higher risk is described in ELBW infants, presenting neurologic involvement in 50–64% of cases (4, 12). When CNS is affected, the mortality rate increases to 30–60% and survivors may develop significant long-term neurological disorders (6–8, 12). In addition to the low birth weight (BW), further risk factors for Candida infections include fungal colonization of more than two body sites, the exposure to total parenteral nutrition and to H2 receptor antagonists, to antenatal and postnatal antibiotics, and to corticosteroids (4, 11). Among invasive procedures, the presence of indwelling catheters, the exposure to mechanical ventilation and to abdominal surgery are well-known risk factors in the preterm infants (11).

Fungal burden varies between different countries and hospitals (4, 13–16), and much of this variability is explained by the variability of procedures, drugs, and feeding practices used in different clinical contexts (10).

At least 15 different species of pathogen Candida are detectable in humans, although >90% of ICI are caused by the five most frequent pathogen species, i.e., Candida albicans, Candida parapsilosis, Candida glabrata, Candida tropicalis, and Candida krusei. Candida albicans and Candida parapsilosis are more frequently associated with disease in neonates (17, 18). Each Candida species may vary in terms of virulence properties (19–24). Possible virulence factors include the ability to undergo phenotypic switching, the expression of adhesion molecules on cell surface allowing a higher attachment to host structures, and the production of hydrolytic enzymes (19). Some fungal strains also show a high propensity to form biofilms on the surface of devices, such as central line catheters, making these strains particularly difficult to treat (25).

The diagnosis of ICI is challenging. Signs and symptoms of IC may be non-specific and are often subtle, therefore a combination of clinical, radiological, and mycological assessments is required. Besides culture isolation (blood, urine, cerebrospinal fluid, peritoneal fluid, tracheal aspirate), other microbiologic techniques to diagnose an ICI include direct microscopic examination, histologic examination of the involved tissues, assessment of fungal antibodies, and of fungal antigens (galactomannan, 1,3-β-D-glucan) by enzyme-linked immunosorbent assay (ELISA) test or immunofluorescence and molecular diagnosis by real-time Polymerase Chain Reaction determination of fungal DNA. Although fungal strains usually easily grow in culture medium, their identification requires large volumes of blood, which are difficult to collect in the preterm neonate. This may explain why, in this special population of patients, blood cultures may be negative for a large number of fungal bloodstream infections. Furthermore, 50% of fungal sepsis with negative blood cultures show a positive culture of the cerebrospinal fluid, underlying the complexity of an ICI diagnosis (12).

New Options For Antifungal Therapy in the Neonatal Age

The cell membrane and cell wall of fungi consist of a phospholipid bilayer, including ergosterol, chitin and chitosan, beta 1,3 and beta 1,6 glucans, mannoproteins, and other components, in various combinations.

Antifungal drugs act by means of different mechanisms, such as interference with cell membrane synthesis, with cell wall synthesis and stability, and with fungal DNA/RNA synthesis (26).

The target of Polyenes and Azoles is ergosterol, the predominant sterol in many pathogenic fungi. Echinocandins block cell wall synthesis by inhibiting the enzyme 1,3 beta glucan synthase, antimetabolites inhibit the protein syntesis.

Safe and effective therapeutic strategies for the treatment of ICI in the neonatal period are limited (10, 27, 28), and Polyenes, Azoles and Echinocandins represent the three classes of antifungal drugs more commonly used in infants [Table 1; (34)].

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Table 1. Antifungal drugs currently used in infants with ICI.

Conventional Amphotericin B deoxycholate (D-AMPH-B), and fluconazole, represented the only therapeutic choice for candidiasis in neonates and infants for many years. In recent years, due to the resistance of some Candida spp. against fluconazole (although with difference rates worldwide), the use of echinocandins has progressively increased, thanks also to the more specific mechanism of action, which limits the side effects of the therapy. Nevertheless, most of the available data refer to infants (35), and only a minority of them refer specifically to the neonatal period. Furthermore, the newer therapies are sometimes more expensive than the traditional ones.

The administration of the most appropriate drug and at the optimal dosing is obviously crucial (Figure 1) (28). However, for most of the antifungal drugs, the appropriate dosages in neonates are still discussed [Table 1; (26, 29–33)].

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Figure 1. AmB deoxycholate should be started at 1 mg/kg intravenous daily and can be increased up to 1.5 mg/Kg/die. An alternative option is liposomal AmB that should be started at 3–5 mg/kg daily. The addition of 5-flucytosine 25 mg/kg four times daily at should be considered as salvage therapy in patients not responsive to initial AmB therapy or with End Organ Dissemination (EOD). Fluconazole, 12 mg/kg daily, is recommended for Candida strains that are susceptible to fluconazole, in babies who had not a previous fluconazole prophylaxis. Algorithm for the initial treatment of Invasive Candida Infections in neonates [from (28), modified].

Polyenes

Conventional amphotericin B deoxycholate (D-AMPH-B) has represented the standard of care for the IC therapy since 1950, when it was introduced in the current clinical management of fungal infections, in adults, and children. D-AMPH-B is a polyene macrolide antifungal drug isolated from Streptomyces nodosus (34, 36) By its interaction with ergosterol, residing on the fungal cell wall, D-AMPH-B depolarizes the cell membrane and causes the formation of pores, which increase the permeability to proteins and electrolytes, leading to cell death (34). The efficacy correlates with the dose, following the maximum concentration (Cmax)/Minimal Inhibiting Concentration (MIC) ratio and ranging from 4 to 10. D-AMPH-B has fungicidal effects against a spectrum of fungi such Candida species, Aspergillus species, Zygomycetes, and dimorphic fungi (37). In addition, its action is enhanced by the release of reactive oxygen species (ROS) (36). Sporadic resistance against D-AMPH-B has been reported for some fungal strains, but clinically relevant resistance is uncommon (37).

Since D-AMPH-B is poorly absorbed through the gastrointestinal tract, it is administered intravenously. D-AMPH-B decreases renal blood flow and glomerular filtration rate, thus it has a potential nephrotoxicity that limits the total dose that can be given to neonates (38). As D-AMPH-B is mostly protein-bound, its penetration into the extracellular spaces, such as the cerebrospinal fluid, is poor (34).

To decrease the incidence of adverse effects, including hypokalemia or nephrotoxicity described after long lasting D-AMPH B administration, Amphotericin B was combined with lipids and a new antifungal drug was developed. Three formulations of lipid amphotericin B are currently available: (1) amphotericin B lipid complex-ABLC, complexed with dimyristoyl-phosphatidylcholine, and phosphatidylglycerol, whose configuration is ribbon-like; (2) amphotericin B colloidal dispersion (ABCD), complexed with cholesteryl sulfate, that has a disk-like structure; (3) liposomal amphotericin B (L-AMPH-B), complexed with hydrogenated soy phosphatidylcholine, distearil-phosphtidyl-glycerol, and cholesterol. Unlike the other lipid formulations, L-AMPH-B is a true liposome composed of mono-lamellar lipid vesicles, allowing the drug to reach targeted tissue. To date, L-AMPH-B is currently used also in infants and children (39). Its antifungal activity is effective against many clinically aggressive agents, including Candida spp., Aspergillus spp., and filamentous molds such as Zygomycetes (39, 40). The newer lipid formulations release L-AMPH-B exactly into its action site on the fungal cell membrane. Furthermore, a lower toxicity was detected in mammalian cells, thanks to the higher stability of the lipid formulation, allowing higher dosages of L-AMPH-B to be administered (34), regardless of birth weight, gestational age or chronological age of the newborn (41).

Due to the association of L-AMPH-B with liposomes, the risk for nephrotoxicity and infusion-related toxicity is lower compared to conventional amphotericin B (40). Moreover, it has higher tissue concentrations, with the highest levels detected in the liver, spleen, kidneys, and lungs (42).

The recommended dose for L-AMPH-B is 3–5 mg/Kg/day, whereas for D-AMPH-B the dose starts from 0.5 to 0.7 mg/Kg/die to 1.5 mg/Kg/day (4, 17, 43). A recent study demonstrated that a high dose of L-AMPH-B is effective and well-tolerated in very low birth weight (VLBW) neonates affected by candidiasis (44). Although L-AMPH-B is the most widely used antifungal agent in infants and D-AMPH-B the most used in newborns, there are no available prospective randomized trials in neonates, providing information about the pharmacokinetic properties of these drugs and their safety.

Azoles

The second major class of antifungal agents available for the treatment of preterm infants with invasive fungal infection is the azole group. This includes triazoles (fluconazole voriconazole and imidazoles for topical use (miconazole ketoconazole). Triazoles, in particular fluconazole, are used more commonly in neonatal practice, and appear to be a safe treatment for newborn infants (34). Agents of the triazole class, including the recently issued isavuconazole®, exert antifungal activity through the inhibition of sterol 14-a-demethylase (Erg11p). This enzyme of the cytochrome P450 family is responsible for a key demethylation step in the ergosterol biosynthetic pathway. Ergosterol is typically the predominant sterol found in the membranes of fungi, including Aspergillus, Candida, and Mucorales. It is responsible for the regulation of membrane integrity, fluidity, and permeability. Inhibition of Erg11p blocks the production of ergosterol, diverting ergosterol precursors toward alternative biosynthetic pathways. A portion of these averted intermediates converts to toxic 14-a-methylsterols, which pack more loosely into lipid bilayers leading to leaky and unstable membranes (45). All of the azole antifungals inhibit cytochrome P450 enzymes to some degree. Thus, clinicians must carefully consider the influence on a patient's drug regimen, when adding or removing an azole. Common polymorphisms in the gene encoding the primary metabolic enzyme for voriconazole result in wide variability of serum levels. Drug–drug interactions are common with voriconazole and should be considered when initiating and discontinuing treatment with this compound (27). The most frequently reported side effect is a transient elevation of plasma levels of creatinine or hepatic enzymes, described in about 5% of infants treated with fluconazole (34). Fluconazole is readily absorbed, with oral bioavailability resulting in concentrations equal to ~90% of those achieved by intravenous administration. Absorption is not affected by food consumption, gastric pH, or disease state. Among the triazoles, fluconazole has the greatest penetration into the cerebrospinal fluid (CSF) and vitreous, achieving concentrations of >70% of those in serum. This is the reason why it is often used in the treatment of CNS and intraocular Candida infections (27). The efficacy correlates with the dose/24 h, following the Area Under the Curve (AUC)/MIC ratio, that should be higher or equal to 25 for a successful therapy. In neonates, the dosage is 12 mg/Kg/die for 3 weeks (46, 47) regardless of birth weight or gestational age. Blood level measurements might be of help to monitor fluconazole concentrations during the treatment period. In term neonates, fluconazole plasma half-life is ~70 h (30 h in adults) whereas in preterms it is 73 h at birth, 53 h at 6 days of age, and 46 h at 12 days of age. These pharmacokinetic characteristics make fluconazole an attractive candidate for the prevention of ICI, mainly in premature infants, allowing for infrequent administration (48). Moreover, fluconazole is minimally (12%) bound to plasma proteins, penetrates CSF, and achieves saliva and lung concentrations that are 1.3 and 1.2 times the plasma levels, respectively, thereby providing higher concentrations at key areas of colonization (32, 48–53).

Voriconazole is available in oral and intravenous formulations and is the primary therapy for invasive aspergillosis. Consistent with voriconazole time-dependent effect, Cmin >1–2 mg/L is a good predictor of successful clinical outcome in both adults and children. Voriconazole side effects include visual disturbances, elevated hepatic transaminases, and skin photosensitization (13–30%). In adults, concentrations above 4–5.5 mg/L correlate with toxicity (39). Voriconazole must be taken before or after a meal. In children (2–12 years), voriconazole is administered intravenously at 9 mg/kg once every 12 h for the 1st day, then at 8 mg/kg once every 12 h. Orally it should be administered at 9 mg/kg twice in a day (max: 350 mg each dose) for ages ranging 2–14 years (32). However, voriconazole is not recommended in children <2 years and infants.

Isavuconazole is a recently approved expanded-spectrum triazole with excellent in vitro activity against Candida species. Available in both oral and cyclodextrin-free intravenous formulations, isavuconazole has a broad spectrum of activity including yeast, dimorphic fungi, and various molds, as well as a favorable adverse effect profile and less substantial drug-drug interactions than other triazoles. Isavuconazole is currently indicated for the treatment of invasive aspergillosis and invasive mucormycosis, and the agent is currently being investigated for an indication in the treatment of candidemia and ICI (39). Preliminary analysis of the recently completed large international double-blind trial comparing isavuconazole to an echinocandin for ICI suggests that isavuconazole does not meet criteria for non-inferiority (personal communication, Astellas US) (50). Although much of the role of isavuconazole remains to be revealed by phase IV experience, a broad spectrum of activity, minimal safety concerns, and proven efficacy in the treatment of invasive mold infections, certainly make this latter triazole a welcome addition to the antifungal armamentarium (39).

Fluconazole Prophylaxis

Candida species colonize the skin and mucous membranes of about 77.1% of preterm infants within 4 weeks of admission to the NICU and can progress to fungal invasive infection (51). The colonization of more than one body site by Candida is one of the well-known risk factors for ICI in preterm neonates. Then, critically ill neonates benefit greatly from antifungals administered for prophylaxis, which seems to limit fungal colonization and the progression of systemic infections. The use of fluconazole as antifungal prophylaxis is supported by robust studies showing the efficacy and safety of this drug (52–56). Taken together, all data suggest that prophylactic administration of fluconazole, 3–6 mg/kg/dose twice weekly, is appropriate for all neonates and results in a reduction in Candida colonization and a 91% decrease of ICI. Since 2001, Kaufmann and colleagues have demonstrated the efficacy of intermittent administration of fluconazole at a low dose in the prevention of ICI in high risk infants. (53). In a prospective, randomized, clinical trial, Kaufmann evaluated the efficacy of fluconazole prophylaxis vs. placebo in 100 preterm infants. Fungal infection developed in 20% of the infants in the placebo group and in none of those in the fluconazole group. These results have been confirmed in 2007 by an elegant study by Paolo Manzoni. The authors showed that fluconazole administered as prophylaxis twice in a week to very low birth weight infants reduced the incidence of ICI by up to 4% compared to 13.2% in the placebo group (55). Although in this last study the effect on the Candida colonization was not clear, the decrease of ICI was surprising. Fluconazole's long half-life in neonates allows an intermittent administration for the prophylactic treatment. In neonates the mean serum peak concentration of fluconazole increases during the first week but decreases during the second week of life (48). Therefore, fluconazole prophylactic dosage varies according to the chronological age. The dose scheme is 3–6 mg/Kg/dose once a day, 2 times a week in the first 2 weeks of life whereas, from the third week of life, prophylaxis should be administered every day. The benefit of prophylaxis may be less evident in care settings where the incidence of ICI is <2%. In this context the recommendation is to decide to start prophylaxis case by case, in relation to the presence of risk factors for ICI. When the incidence of infections is at least 5% it is advisable to administer fluconazole prophylaxis as a routine treatment to babies of extremely low birth weight or to those of higher birth weight with specific risk factors (32).

Echinocandins

The possible occurrence of adverse reactions in neonates and the development of fungi resistance to conventional antifungal drugs led to the exploration of new molecules as alternative therapies against systemic fungal infections (56). Although partially studied in neonates, Echinocandins are more and more frequently used in the treatment of disseminated candidiasis in such delicate patients. Echinocandins are semisynthetic cyclic lipopeptides, that block the synthesis of the fungal cell wall, by inhibiting the enzyme (1 → 3)-β-D-glucan synthase complex. The result is a glucan-depleted cell wall susceptible to osmotic lysis (57–60). This target is unique to fungi, as the 1,3-β-D-glucan is not present in mammalian cells, thus contributing to the favorable toxicity profile of the drug and minimal adverse effects (61). The enzyme complex (1 → 3)-β-D-glucan synthetase, contained within the fungal cell wall, is composed of the catalytic subunits FKS1p, FKS2p, and the Rho1p protein. FKS1p is the major subunit, which determines the remodeling of the cell wall in fungi. Mutations in the genes FKS1 and FKS2, encoding proteins, are responsible for fungal drug-resistance. Rho1p is a protein that regulates or stops the synthesis of (1 → 3) -β-D-glucan (61). The proportion of glucan in the fungal cell wall varies widely between fungal species and is predictive of fungicidal activity of echinocandins against Candida spp., including fluconazole-resistant spp. Echinocandins have a fungistatic action on the Aspergillus spp. and are not active against Candida neoformans, Zygomycetes, and dimorphic fungi (61, 62).

The three Echinocandins currently available are caspofungin, anidulafungin, and micafungin, and are only available as parenteral preparations. All of them have an optimal spectrum activity against various Candida spp. (61–63). Caspofungin represents an appropriate alternative for the therapy of systemic candidiasis in preterm neonates when there is lack of response, resistance or toxicity to other antifungal agents such as D-AMPH-B, or fluconazole (64). Its action is fungicidal against Candida spp. and many fungal strains resistant to AMPH-B and triazoles. Plasma concentrations in neonates are slightly more elevated compared to older pediatric patients and adults, and is without any observed adverse safety outcomes. At 25 mg/m2 daily, caspofungin is generally well-tolerated in neonates (65) but pharmacokinetics, safety, and efficacy data are lacking until now (31, 64, 65). Anidulafungin is currently not registered and authorized for pediatric use, although pharmacokinetic studies in pediatric and neonatal populations have already been conducted and this Echinocandin may be an option in the future.

Among the Echinocandins, micafungin is the most studied Echinocandin in neonates and the only approved by both European Medicine Agency (EMA) and United States Food and Drug Administration (US-FDA) for younger children (66–71). The few data available in the literature on neonatal pharmacokinetics of micafungin limit the possibility of recommending it as a first-choice drug in the therapy of systemic candidiasis. Moreover, recommendations for the optimal dosage of micafungin in neonates are still not clarified, though, the U.S. FDA approved a dosage of 2 mg/kg/day in infants 4 months of age or older (72). Similar dosing is recommended by the EMA-approved label, although a warning about the potential hepatotoxicity of micafungin has been issued (73). Nevertheless, according to preclinical models and bridging studies about CNS-related candidiasis (74, 75), in neonates the administration of doses higher than 2 mg/kg/day seems to be necessary. Babies younger than 4 months and neonates with VLBW (<1,500 g) seem to require doses from 7 to 15 mg/kg/day to achieve therapeutic plasma levels, compared to 1–4 mg/kg/day, which is the optimal dosage in older children and adults. Although micafungin levels in CSFare relatively low, the daily administration of 8–10 mg/kg/day of micafungin seems suitable, according to pharmacokinetics/pharmacodynamic models in neonates and very preterm neonates, also in the presence of Candida localizations in the CNS (76). The clearance of micafungin seems greater in neonates than in adults, due to an unclear mechanism (67). The low level of plasma proteins, characteristic of the preterm infant, could be one of the reasons for the increased micafungin clearance. The micafungin molecule has a high molecular weight and is highly bound to plasma proteins. This binding seems about 8 times lower in neonates than in adults, with an increase in the proportion of free drug, that can be quickly eliminated (67).

Our group analyzed 18 preterm neonates and infants with ICI, three with Candida meningitis, who received, for at least 14 days, 8 to 15 mg/kg/day of intravenous micafungin. Overall, 78.2% of neonates had clinical resolution of their infection. High doses of micafungin were well-tolerated and showed pharmacokinetic profiles predictive of a positive effect. A significant increase in alkaline phosphatase levels was observed. Increased gamma-glutamyl-transferase (GGT) levels were also recorded in three patients treated with 10- to 15- mg/kg/day of micafungin, and improvement of the GGT level was achieved after dose reduction (30).

Clinical efficacy and safety data with newly proposed dosing in neonates needs further evaluation (30), since major discrepancies exist concerning the optimal dosage of micafungin (10, 66–68, 77) for the treatment of systemic candidiasis in the neonatal age. Micafungin is metabolized mainly in the liver, by arylsulfatase, catechol-O-methyltransferase, and by isoenzymes (3A4, 1A2, 2B6, and 2C) belonging to cytochrome P450 system and interactions with other drugs are few (66, 68, 69). The major route of elimination is non-enzymatic degradation (27). The excretion is mainly via feces. Differences in the hepatic metabolism of micafungin between infants and adults have not been demonstrated. Drug levels in urine are relatively low.

The most frequent adverse events include neutropenia, jaw and joint pain, rash, increased hepatic enzymes, abnormal Liver Function Tests, and two serious adverse events: hyperbilirubinemia and increased serum creatinine (66). Due to its hepatic metabolism (68), micafungin use should be avoided in cases of liver diseases, whereas it should represent the first-line choice in case of renal impairment. Micafungin displays concentration-dependent fungicidal killing, and in animal models, efficacy correlates best with AUC:MIC ratios (78). Analysis of adult clinical data for the treatment of systemic candidiasis found that an AUC:MIC ratio over 3,000 predicts better mycological response (79).

Considering the ability of Candida strains to develop catheters intraluminal biofilms, micafungin has also been used to perform the catheter lock therapy (72, 73). Compared to amphotericin B or fluconazole, micafungin seems to be preferable for this procedure, thanks to its ability to penetrate the biofilm (63).

Antifungal Lock Therapy of Central Venous Catheters (CVC)

When a systemic candidiasis is diagnosed, prompt catheter removal is recommended both in adults and in children (80). In neonates, a delayed CVC removal when fungal infections occur seems to be associated with significantly increased mortality (80). A delay in CVC removal (more than 1 day after initiation of systemic antifungal treatment) was also associated with impaired neurodevelopment compared with infants in which CVC was promptly removed at the onset of infection (4). Moreover, the timing of catheter removal also affects candidemia duration. Benjamin et al. showed that the time to clear Candida from the blood was equal to 5 days in neonates in whom the CVC was removed immediately after diagnosis of candidemia vs. 7.3 days in those with late removal (4). However, catheter removal may be problematic in very ill neonates requiring CVCs for long-term parenteral nutrition and/or life-saving therapies, and CVC reinsertion may be challenging. Therefore, the need for CVC salvage may sometimes outweigh the risk of a delayed removal. In such cases, the so-called “lock therapy” (LT) has been suggested as a possible therapeutic strategy (81, 82), although, there is still insufficient experience concerning its use in neonates, and its actual efficacy and safety are still discussed by authors. The LT consists of high concentrations of antibiotic drugs instilled into the lumen of the catheter and left in situ for few hours. LT with antifungal drugs has been suggested as a possible therapeutic option for central venous catheter (CVC)-related fungal infections, whenever critical clinical conditions of a neonate make it difficult, or dangerous to remove the catheter (82). In neonates, infections due to the use of CVC are mostly related to the development of biofilms inside the catheter surface (83). Biofilms are made up of microbial cells embedded in a self-secreted polymeric matrix (made of water, polysaccharides, proteins, lipids, and extracellular DNA) released in the extracellular space (84). This matrix provides a protective barrier able to decrease the penetration of antimicrobials and to provide the fungal colonies protection against mechanisms of host immune defense (10). Therefore, biofilms may become a reservoir for systemic spread to other sites of the body.

The optimal antimicrobial drug to be used for a LT should be identified according to the specific antibiogram. Very high concentrations of antimicrobial drugs, 100 to 1,000 times the microorganisms' MIC, should be instilled into CVC lumen for a determined dwell-time. If the antibiogram is unavailable, a LT with ethanol 70% could be performed. In case of Candida infection, micafungin should be preferred to other antifungal drugs such as amphotericin B or fluconazole, thanks to its ability to penetrate the biofilm (63). However, a recent Cochrane review concluded that, although preventive LT appeared to be effective in decreasing the incidence of catheter-related bloodstream infections, the evidence was still insufficient to recommend it, considering the limited number of trials and the heterogeneity of antimicrobial drugs administered and about the optimal LT dosage and timing (85). Piersigilli et al. described the case of a preterm infant with critical CVC-related Candida albicans infection unresponsive to the systemic therapy. The infant received a combined LT [1:1 mixture of 70% ethanol and micafungin sodium 5 mg/L], which allowed for the resolution of the infection and the preservation of his long-term CVC (67). However, further studies are required to confirm the efficacy and safety of the LT in neonates and to design the most appropriate dosage and dwell times.

Therapeutic Strategies for the Treatment of Fungal Abscesses

Hepatic fungal abscesses are uncommon in neonates. They usually occur in the course of fungal sepsis, due to the localization of the germ within the hepatic parenchyma. Candida albicans is the most common fungal organism isolated (74). Cases of hepatic fungal abscesses described in the literature are sporadic (75, 76, 86–88) and they mainly involve preterm infants due to the functional immaturity of the immune system and the invasive procedures necessary for preterm babies to survive. Among the recognized risk factors, the strongest is the presence of vascular catheters, especially umbilical catheters. Other important risk factors are the presence of bowel diseases requiring surgery, such as isolated intestinal perforation, necrotizing enterocolitis, and the concomitant presence of sepsis (74). Diagnosis of fungal abscesses is challenging. The optimal therapeutic approach is still uncertain and mortality is high, due to the ineffectiveness of medical therapy alone. In adults, hepatic abscesses are treated by percutaneous needle aspiration or by percutaneous catheter drainage, associated with medical therapy. Patients who fail to respond to such a treatment undergo surgery. In preterm infants, especially those with a very low birth weight, the extreme difficulty in performing needle aspirations should be considered (89). Abscess culture is recommended to assess microbiological sensitivity pattern of the organism, and start the most appropriate therapy. Auriti et al. reported the case of a Candida albicans hepatic abscess in a severely ill preterm neonate, successfully treated by intralesional administration of L-AMPH-B (1 mg/ml, in isotonic water) (90). Further investigations are required to confirm such practice.

Shunt Lock Therapy With Antifungal Drugs in Neonates With Hydrocephalus

In case of hydrocephalus, potential complications such as shunt-associated fungal infections may occur, representing a challenging situation of the early life periods. Such infections are currently treated with systemic antifungal drugs. As already mentioned above in the text, recent studies measuring micafungin concentrations in CSF demonstrated that this drug, particularly in patients treated with high doses, has enough penetration in the CNS to have a good antifungal effect (30, 68, 73). International guidelines, however, recommended shunt replacement, whenever possible, because of the ability of fungi to form, inside the lumen, a biofilm resistant to antifungal therapy, with lasting CSF positive cultures despite optimal therapy (91). Considering the ability of echinocandins to eliminate fungal biofilms from CVCs (92), Auriti et al. successfully treated a shunt-associated Candida albicans meningitis by means of systemic antifungal therapy combined with micafungin LT of the external ventricular drain (EVD) in a seriously ill, preterm infant with posthaemorrhagic hydrocephalus (68). The use of shunt LT needs a larger validation to determine the optimal duration and number of locks to sterilize the shunt or to prevent recolonization after new EVD insertion.

Conclusions

Fungal infections represent severe complications of the neonatal period, associated with high morbidity, and mortality. Diagnosis is challenging and requires long-lasting diagnostic testing such as cultures. As such infections are difficult to eradicate by means of the traditional treatments, specific therapeutic strategies developed in the last years, such as catheter LT and shunt LT in association with the systemic therapy may provide additional efficacy of antifungal treatments. Further investigations are required to confirm this hypothesis.

Author Contributions

All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Keywords: neonate, fungal infection, sepsis, lock therapy, polyenes, azoles, echinocandins, candidemia

Citation: Bersani I, Piersigilli F, Goffredo BM, Santisi A, Cairoli S, Ronchetti MP and Auriti C (2019) Antifungal Drugs for Invasive Candida Infections (ICI) in Neonates: Future Perspectives. Front. Pediatr. 7:375. doi: 10.3389/fped.2019.00375

Received: 09 May 2019; Accepted: 02 September 2019;
Published: 20 September 2019.

Reviewed by:

Aakash Pandita, Sanjay Gandhi Post Graduate Institute of Medical Sciences, India
Daniel Vijlbrief, University Medical Center Utrecht, Netherlands

Copyright © 2019 Bersani, Piersigilli, Goffredo, Santisi, Cairoli, Ronchetti and Auriti. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Cinzia Auriti, cinzia.auriti@opbg.net

Sours: https://www.frontiersin.org/articles/471151

Now discussing:

Candidiasis of the Skin (Cutaneous Candidiasis)

What is candidiasis of the skin?

Different types of bacteria and fungi live and grow on your skin. Most of them aren’t dangerous. Your body requires the majority of them to carry out normal functions. However, some can cause infections when they begin to multiply uncontrollably.

The Candida fungus is one of these potentially harmful organisms. When an overgrowth of Candida develops on the skin, an infection can occur. This condition is known as candidiasis of the skin, or cutaneous candidiasis.

Candidiasis of the skin often causes a red, itchy rash to form, most commonly in the folds of the skin. This rash may also spread to other areas of the body. While the symptoms are often bothersome, they can usually be treated with improved hygiene and antifungal creams or powders.

What are the symptoms of candidiasis of the skin?

The main symptom of candidiasis of the skin is a rash. The rash often causes redness and intense itching. In some cases, the infection can cause the skin to become cracked and sore. Blisters and pustules may also occur.

The rash can affect various parts the body, but it’s most likely to develop in the folds of the skin. This includes areas in the armpits, in the groin, between the fingers, and under the breasts. Candida can also cause infections in the nails, edges of the nails, and corners of the mouth.

Other conditions that may resemble candidiasis of the skin include:

What causes candidiasis of the skin?

Candidiasis of the skin develops when the skin becomes infected with Candida. A small amount of Candida fungi naturally live on the skin. When this type of fungus begins to multiply uncontrollably, however, it can cause an infection. This may occur because of:

  • warm weather
  • tight clothing
  • poor hygiene
  • infrequent undergarment changes
  • obesity
  • the use of antibiotics that kill harmless bacteria that keep Candida under control
  • the use of corticosteroids or other medications that affect the immune system
  • a weakened immune system as a result of diabetes, pregnancy, or another medical condition
  • incomplete drying of damp or wet skin

Candida fungi thrive and grow in warm, moist areas. This is why the condition often affects areas where there are folds of skin.

Babies can also develop candidiasis of the skin, especially on the buttocks. A diaper tends to provide an ideal environment for Candida.

Candidiasis of the skin usually isn’t contagious. However, people with weakened immune systems may develop the condition after touching the skin of an infected person. Those with compromised immune systems are also more likely to develop a severe infection as a result of candidiasis.

How is candidiasis of the skin diagnosed?

Your doctor will likely be able to make a diagnosis simply by performing a physical examination. During the exam, they’ll inspect the location of your rash and the appearance of your skin.

Your doctor may also want to perform a skin culture before making a diagnosis of candidiasis of the skin. During a skin culture, your doctor will rub a cotton swab over the affected area and collect a skin sample. The sample will then be sent to a laboratory to be tested for the presence of Candida.

How is candidiasis of the skin treated?

Candidiasis of the skin can usually be prevented with home remedies, the most important of which is proper hygiene. Washing the skin regularly and drying the skin thoroughly can prevent the skin from becoming too moist. This is vital to keeping Candida infections at bay.

There are many lifestyle changes you can make to both prevent and treat a candidiasis infection.

Since abnormal blood sugar levels can contribute to the development of Candida infections, keeping your blood sugar under control may also help relieve symptoms. You may be able to lower your blood sugar by reducing the amount of sugar in your diet and by exercising for 30 minutes at least three times per week. If you have diabetes, it’s important to continue following your doctor’s instructions as you may need to start receiving oral medications or an increased amount of insulin.

In severe or persistent cases of candidiasis, your doctor may recommend using an antifungal cream or powder that can be applied to your skin. Over-the-counter antifungal creams that are often recommended include clotrimazole (Mycelex), miconazole (Monistat), and tioconazole (Vagistat). This type of treatment can kill Candida and reduce the spread of the infection.

Your doctor may prescribe an antifungal cream such as nystatin or ketoconazole if the over-the-counter treatments aren’t effective. If the infection has already spread to areas inside your body, such as your throat or mouth, you may need to take an oral antifungal to get rid of it.

Cutaneous candidiasis in babies

Cutaneous candidiasis (or candidiasis present on skin, nails, or hair) is a common occurrence in infants and babies.

Candidiasis-related diaper rash is one of the most frequently occurring candidiasis infections in babies. This rash is typically red with a well-defined border, and normally lasts more than three days. Treatment includes changing the infant’s diaper frequently and allowing them to wear loose-fitting clothes on top of the diaper. The antifungal nystatin may be prescribed.

Oral thrush is another common occurrence in newborns and infants under 6 months old. Symptoms can include cracked skin in the corners of the mouth and whitish patches on the lips, tongue, or inside of the cheeks. Your doctor can prescribe an antifungal medication that’s applied to the infant’s mouth several times a day.

If candidiasis infection is left untreated, it can enter the bloodstream and spread. See your doctor if you believe your baby has candidiasis.

Learn more: Oral thrush »

Cutaneous candidiasis in children

Although healthy children have strong immune systems, found that the rate of topical fungal infections among children is increasing rapidly. Children sometimes develop candidiasis infections after receiving antibiotics that treat another condition. Children who suck their thumbs may be prone to developing candidiasis infections in or around their nail beds.

If your child is 9 months or older and has reoccurring thrush or skin infections, this could point to an underlying health concern, such as HIV or another problem with the immune system. Older children with frequent or severe skin infections should also be tested for diabetes.

What is the outlook for someone with candidiasis of the skin?

Candidiasis of the skin usually goes away with treatment, and most people make a full recovery without complications. If treated, the candidiasis typically resolves within one to two weeks. Without prescription treatment, recovery can take anywhere from a few days to a few weeks, depending on the severity of the infection.

Even with treatment, it is possible for the infection to return in the future. People with compromised immune systems, especially people who are undergoing chemotherapy and those with HIV or AIDS, are at a much higher risk of severe or life-threatening Candida infections. If you’re undergoing chemotherapy or you have HIV or AIDs and you develop severe throat pain, headache, or high fevers, you should see your doctor immediately.

Sours: https://www.healthline.com/health/skin/cutaneous-candidiasis


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