Fluconazole For Non-Resistant Candida Auris? Preclinical PK/PD

New preclinical PK/PD model-based data suggest that while fluconazole is unlikely to be a useful treatment option for most isolates of the hyper-resistant pathogen Candida auris, it may have a potential role for the treatment of a minority of C auris isolates that test as non-resistant. Currently, most cases of C auris are managed with initial therapy with echinocandins or other intravenous antifungal agents due to high rates of resistance to fluconazole. However, new preclinical PK/PD data generated using a C auris isolates with human-equivalent exposures to fluconazole, predict that some C auris isolates with low MICs could be treated, with confirmation of susceptibility, optimal dosing and close monitoring of patients. These data do not suggest that fluconazole is “back in play”, but it may be an option for treating a minority of patients with C auris infections under very controlled circumstances. Verification of MICs in a reliable laboratory, thoughtful patient selection, awareness of potential drug interactions and monitoring of hepatic function are critical. Patients treated with fluconazole should have a low threshold for escalating therapy if they are not demonstrating clinical improvement.

Why It Matters

Candida auris is an emerging worldwide fungal pathogen with challenging features for transmission and development of resistance. C. auris can be transmitted from person to person in healthcare facilities, and persists on surfaces and equipment for months. Many C. auris isolates have been shown to be resistant to multiple classes of antifungal drugs. Because of these characteristics, C. auris outbreaks require significant resources to rapidly implement screening, infection control measures (such as isolation or contact precautions) and use of disinfection products specifically labeled for use against fungal pathogens. Delays in appropriate treatment can be fatal for patients with bloodstream or deep tissue infections. These challenges of C. auris transmission affect patient care, staffing, bed distribution and public health strategy. These factors all have to be taken into consideration during treatment decisions.

Even a small proportion of C. auris isolates amenable to oral, inexpensive therapy could make a large difference. Oral therapy is generally easier to administer to patients than parenteral therapy, and fluconazole is a well-known, widely available and stocked medication. For patients with confirmed or suspected C. auris infection, the use of oral fluconazole could allow for a step-down to less expensive, oral therapy sooner, avoid the unnecessary placement of a central line, and allow for earlier hospital discharge, benefiting both the hospital and long-term care settings. This could relieve pressure to administer IV infusions, decrease overall cost of care, and support good antimicrobial stewardship practices.

We added a PK/PD signal to the project that translates Susceptible in the lab to Likely treatable in the patient. For many of the antifungals under development, achieving appropriate exposure is as important as choosing the right antifungal. The PK/PD for fluconazole can be described as exposure (AUC) over 24 hours in relation to MIC. Our preclinical studies to date suggest that for some isolates with very low MICs, higher daily doses may be required to achieve the amount of exposure associated with 100% survival in the model. This would define a possible treatment window that is currently left to chance, hope or history.

What the preclinical PK/PD work adds

This study translates well to clinical and stewardship practice as it forces the clinician to think in probabilities rather than absolute certainty. The “dose-to-MIC” framework presented in this manuscript suggests that, on average, standard or moderately increased daily doses are likely to achieve optimal PK/PD targets only at very low MICs. As MICs increase, higher exposures are required for optimal outcomes. This trend is consistent with other forms of Candida infection due to fluconazole and some of the MIC ranges presented in this manuscript are simply not realistic for safe and effective treatment.

Of course, “non-resistant” doesn’t necessarily mean “good candidate for fluconazole”. While many laboratories and interim interpretive criteria will call an isolate “non-resistant” at a wide range of MICs, only the lower end of this range is actually achievable and safe in clinical practice according to PK/PD modeling.

Why caution remains essential

The vast majority of C. auris isolates from around the world have been found to be highly resistant to fluconazole, so this approach is not usually effective for C. auris. In several countries, surveillance for C. auris has found resistance to fluconazole to be the norm, not the exception, and empiric treatment for suspected C. auris infection remains a high-risk decision in most hospitals.

Despite limitations in our ability to diagnose candidiasis, many practitioners rely on a diagnosis of candidiasis and a course of fluconazole regardless of the antifungal susceptibility test results. The consequences of such actions include prolongation of fungemia, development of metastatic complications, and prolongation of hospitalization and mortality for patients who would otherwise be treated with effective therapy. On a population level, such selective pressure can promote the development of resistance, particularly in a time in which our antifungal armamentarium is shrinking to near zero and we are struggling to control ongoing outbreaks of candidal disease.

The safety of fluconazole, particularly at high doses in complicated patients, has to be considered. Many common drugs prescribed in the ICU and oncology units are metabolized by the cytochrome P450 system and the effect of high-dose fluconazole on the concentration of many of these drugs can be significant. In addition to hepatotoxicity, fluconazole at high doses can also cause QT interval prolongation, a potential effect that may be additive to that seen with other drugs that also prolong the QT interval.

Who It Affects

The vast majority of individuals for whom C. auris would be a particularly dangerous illness are those with a serious or rapidly progressing underlying illness for whom delay in effective therapy could jeopardize their survival. In addition to antifungal susceptibility testing, prioritization of effective therapy is particularly important for patients with invasive C. auris disease who are gravely ill with conditions such as bloodstream infection, deep-seated disease (e.g. fungemia with Candida auris, cutaneous Candida auris, urinary tract Candida auris, or respiratory Candida auris), or severe sepsis, and for whom treatment must be initiated expeditiously. The majority of C. auris cases to date have been in patients who are medically fragile, including ICU patients, with central venous catheters, who are dialysis dependent or on continuous renal replacement therapy, or have other serious underlying conditions in which their immune systems have been suppressed. There may be only a few days for a treatment misstep before a patient takes a turn for the worse.

Residents of long-term care facilities and patients for whom healthcare exposure is frequent can be at risk for infection and prolonged colonization and transmission of C. auris. Many people may be asymptomatic carriers of C. auris. Colonization is typically prolonged and both colonized and infected patients are sources of persistent surface and device contamination that can facilitate transmission of C. auris to others. Transition care issues, shared staffing, and adequate environmental cleaning, regardless of the chosen antifungal, should be considered in assessing risk for C. auris transmission.

Clinicians and clinical microbiology laboratories

Uncertainty handling approaches for fluconazole susceptibility test results that have been submitted to the PSO need to be simplified for clinical providers. C. auris testing methods are largely still under development and are significantly less well established than those for more common species such as C. albicans. Significant uncertainty is therefore present in reports for this species. Providers should be aware of methods used for testing, whether or not confirmatory tests have been performed, and interpretation of MIC values in context of pharmacokinetics and severity of illness.

Laboratories are key in this battle against C. auris and must produce accurate MICs for C. auris to ensure that fluconazole is used therapeutically correctly. For widespread use of fluconazole for C. auris to occur, a reliable MIC method with appropriate quality controls must be available in the laboratory, often requiring referral testing, method validation, or specialized training and workflow adjustments to complete results in a timely fashion. Also important is helping clinicians to step down therapy.

Stewardship programs, payers, and public health

Guidelines for use of fluconazole for treatment of candidal infections will need to be very strict in defining which patients would be appropriate for treatment with this drug, in order to make sure that the benefits outweigh the risks for the individual patient. In addition, the stewardship teams will have to make decisions about which Candida species are susceptible to fluconazole, determine criteria for stable clinical improvement, and monitor for complications. Furthermore, as more information becomes available, there will be a tendency to increase the dose (“dose drift”).

For those paying for treatment of cryptococcal meningitis, the cost will be felt by payers and health systems through the cost of facility infusions, duration of in hospital stay, and readmissions. Effective oral step-down regimens may reduce health system costs. However, the cost of bad treatment Policy (failures) in terms of morbidity and mortality can be very high. As use of fluconazole for treatment of cryptococcal meningitis increases, public health programs need to increase surveillance for development of antifungal resistance and treatment failures.

What Changes

Fluconazole is considered a conditional therapy for select indications and not as first-line alternative for initial therapy of suspected or confirmed invasive C. auris infection. Management algorithms suggest echinocandins serve as initial therapy for suspected or confirmed invasive C. auris infection, with transition to or switch of other medications for indications of treatment failure (resistance), intolerance, or ongoing severe disease. For patients with confirmed low-MIC C. auris who are clinically stable, fluconazole may be used as step-down therapy following successful parenteral therapy.

The ACP-ASPC recommendations for hospitalized patients with pulmonary infections include several changes in clinical practice. “

Our indications for oral step-down therapy are evolving, but currently the most realistic indication would be a patient who is clinically improving, has obtained source control, and has evidence of effective therapy based on a reliable MIC from a trustworthy assay. Thus, a patient with clearing blood cultures and evidence of clinical stabilization would be an appropriate candidate for step-down therapy, whereas ongoing fungemia, complicating endocarditis, or therapy for CNS infection would not, due to the potential for serious consequences with failure.

Strategy for monitoring should not be random. A thoughtful approach should be implemented for step-down antibiotics with clear criteria for discontinuation (repeat cultures, clinical response, time to response, etc.). A high index of suspicion for failure should exist for indicators of fever, hemodynamic instability, increase in inflammatory markers, or new positive cultures and patients should be rapidly switched back to broader empirical therapy and consulted with infectious diseases specialists.

Dosing and pharmacology: “Exposure is the point”

When using fluconazole, the dose must be chosen to achieve exposure and should not be based solely on standard dosing for Candida in the heavy weight or critically ill patient. Critically ill patients experience marked variability in pharmacokinetics due to patient specific factors such as fluid shifts, organ dysfunction, and the need for renal replacement therapy. Therefore, standard dosing may not be sufficient to attain adequate exposure. An appropriate loading dose should be administered followed by weight-adjusted maintenance dosing based on function and clinical scenario.

As the required doses of fluconazole increase to achieve adequate therapy, the need for therapeutic drug monitoring increases. While the monitoring of fluconazole levels is not a standard practice in most clinical settings, selective monitoring of particular patients may be clinically helpful for a variety of reasons including variability in absorption, patients on renal replacement therapy and pharmacokinetic interactions with other drugs. In the absence of monitoring, either all patients could be selected for therapy with very close follow-up for adverse effects or alternative dosing strategies for prevention could be employed.

Safety considerations need to be made explicit. A clinician should consider these issues before beginning a course of therapy with diazepam and in treating a patient who is already on this medication. Every patient, especially the older adult with potentially life-threatening medical illness, has QT-prolonging medications in his or her armamentarium that must be considered. The clinician also should determine a patient’s liver enzymes before initiating therapy with diazepam. In addition, consideration should be given to potential dangerous interactions with anticoagulants, antiepileptic medications, and with common immunosuppressive medications such as mycophenolate motifell and azathioprine. Given the fact that a patient with a serious psychiatric disorder is likely to be on multiple other medications, a therapist needs to have ready access to complete and accurate lists of a patient’s current prescription medications and over the counter medications.

Laboratory and diagnostics: “Method matters”

As more clinical isolates are found to be susceptible to fluconazole, there will be an increased need for validated susceptibility testing methods. Clinical laboratories will require methods, confirmatory procedures, and effective communication with physicians to provide accurate and timely information. A critical component of good practice would be to link the interpretation of “susceptible” to specific methods or quality control profiles and to verify unusual results.

Clear reporting language can help prevent misuse by informing healthcare providers about the quality of the result and the evidence base upon which treatment recommendations are based. Labs can help prevent inappropriate therapy by including interpretive comments that highlight uncertainty when breakpoints are tentative, and by clearly stating whether an isolated MIC is or is not within a range that is realistically treatable based on current knowledge of PK/PD.

Stewardship and policy: “Guardrails first”

Selecting this option requires that health systems use responsibly with guardrails in place. Species identification, evidence of low MICs in an established method of measurement, infectious diseases consultation for severe or invasive illness, step-down hospitalization for stable patients, and ability to perform follow-up checkpoints are all examples of effective guardrails to ensure that this agent is used appropriately in settings for which there is evidence. Outcomes, failures, and resistance patterns should also be monitored by the stewardship program.

Patients previously treated for invasive C. auris infection should not have infection control measures relaxed. People can remain colonized for months after successful treatment. Contact precautions or facility recommended enhanced use of barrier precautions, thorough environmental disinfection with C. auris-active cleaning products or agents, and careful communication during patient transfer or release from healthcare facility are all necessary. Oral therapy does not reduce the environmental persistence of C. auris and does not eliminate the need for rigorous cleaning and screening of patient environments and contact and transmission-based precautions.

Research priorities: “From models to patients”

There is a lack of evidence which defines the optimal drug regimen for MRSA infection outcomes. Future research should take the form of a series of observational studies and randomised trials conducted on confirmed low-MIC strains of MRSA, using adequate dosing regimens and outcome measures. In- and community-based data from real-life situations should be collected, and side effects of high doses monitored in more detail. Therapeutic drug monitoring could help to optimise the effect of the currently used treatment. Studying the relapse phenomenon might also provide more insight into optimal treatment.

Standardized interpretive criteria will be important for safe and effective use of fluconazole for C. auris. In turn, clinicians and laboratories will require knowledge of C. auris MICs and standardized methods for testing. Until such time, the use of fluconazole for C. auris should be exceptional and closely monitored.

References:

https://pmc.ncbi.nlm.nih.gov/articles/PMC10986320/ https://journals.asm.org/doi/10.1128/aac.00549-21 https://pmc.ncbi.nlm.nih.gov/articles/PMC7181927/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9447980/