Quarterly Round-up of Notable Articles (January 2025–February 2025)

1. Are Contemporary Antifungal Doses Sufficient for Critically Ill Patients? Outcomes from an International, Multicenter Pharmacokinetic (PK) Study for Screening Antifungal Exposure in Intensive Care Units (SAFE-ICU) Study. Existing PK data on antifungals in critically ill patients mostly come from small, single-center studies with limited generalizability and insufficient guidance for dosing recommendations. While large multicenter studies like the DALI study[1] provided valuable insights into antibacterial PK, antifungal data remained sparse. To address this gap, the SAFE-ICU study[2] was designed to collect comprehensive antifungal PK data across multiple ICUs. Its primary goal was to assess whether the current dosing of triazoles, echinocandins, and polyenes achieves therapeutic levels for optimal outcomes. The secondary objectives included examining the relationship between antifungal exposure and patient characteristics and determining if reaching target plasma levels improves clinical outcomes. A total of 350 patients from 30 ICUs across 12 countries were recruited, with 11 excluded due to exclusion criteria, consent withdrawal, or missing data. Among the 339 remaining patients, 349 antifungal courses were administered, with 10 patients receiving multiple treatments. Antifungal therapy was primarily for treatment (80.8%), with fluconazole being the most prescribed (40.7%). The most common indication was intra-abdominal infection (30.7%), while fungemia was present in 15.7% of cases. Fungi were identified in 54% of treatment and 7.7% of prophylaxis patients, with Candida albicans (51.7%) being the most prevalent. Minimum inhibitory concentration (MIC) data were available for 26% of cases. Clinical cure was achieved in 69% of treated patients, but by day 30, 39.2% of patients receiving antifungals had died, with 88% in the treatment and 12% in the prophylaxis groups. Target attainment could not be assessed in 46 (7.9%) courses due to insufficient sampling. Prophylaxis patients had higher target attainment, with most exceeding 80%. In contrast, treatment patients showed lower rates, particularly for voriconazole (57.1%), posaconazole (63.2%), micafungin (64.1%), and amphotericin B (41.7%). Results: This international study is the first large-scale investigation into antifungal PK/pharmacodynamics (PD) target attainment in ICUs. Over 25% of patients failed to reach target antifungal exposures early in treatment, with voriconazole, posaconazole, micafungin, and amphotericin B having the lowest attainment (≥35%). The current dosing regimens may be inadequate for critically ill patients, emphasizing the need for improved dosing strategies. Lower target attainment was linked to infections outside the bloodstream, abdomen, and urinary tract. Vasopressor/inotrope use was associated with improved attainment, while higher SOFA scores correlated with clinical failure and 30-day mortality. Previous research also reported lower antifungal exposures in ICU patients, with significant variability across drugs. Standard doses often fail to account for PK differences in critically ill patients, reinforcing the need for therapeutic drug monitoring (TDM). For azoles, fluconazole frequently failed to reach targets, though weight- and renal-based adjustments may help. Voriconazole showed better target attainment in prophylaxis than treatment, despite higher doses in the latter. Posaconazole and isavuconazole also had suboptimal attainment, with limited ICU data. Among echinocandins, Continuous renal replacement therapy(CRRT) was linked to higher mortality, likely due to patient severity rather than drug effects. Standard anidulafungin, caspofungin, and micafungin dosing often resulted in inadequate target attainment, suggesting a need for dose adjustments. Liposomal amphotericin B showed the highest variability, requiring further study. Overall, standard antifungal doses may suffice for pathogens with low MICs, but are often inadequate for those with higher MICs. Clinicians should identify pathogens and MICs to guide dosing, but MIC data were available in only 26% of cases. Future studies should focus on broader MIC data collection. Higher-than-standard doses may benefit patients at risk of underexposure, but could also increase toxicity risks, particularly for drugs like voriconazole. Proper loading doses are crucial for early adequate exposure, yet often insufficient, especially for echinocandins. The significant PK variability observed highlights the need for routine TDM in critically ill patients. Comment: Tailor-made antimicrobial regimens are essential for optimizing treatment outcomes, as opposed to a one-size-fits-all approach that overlooks critical organism and patient-specific factors. Effective dosing requires a thorough understanding of MICs, drug penetration into sheltered infection sites, PK/PD, and the accessibility of TDM. By integrating these factors, personalized regimens can enhance efficacy, reduce resistance, and minimize toxicity, ensuring better patient care. 2. Oral Regimens for Rifampin-Resistant, Fluoroquinolone-Susceptible Tuberculosis (endTB trial). Rifampin-resistant tuberculosis is a major global health concern, with 410,000 new cases annually, but only 40% are diagnosed and treated, with a 65% success rate. Traditional treatments lasted 18–24 months and had severe side effects. Trials such as endTB,[3] STREAM 2,[4] and TB-PRACTECAL[5] evaluated 6–9-month, all-oral regimens featuring newer and repurposed drugs in an effort to identify safer and shorter treatment alternatives. The endTB trial, a multinational Phase 3 study, evaluated five 9-month regimens for fluoroquinolone-susceptible, rifampin-resistant TB, aiming to improve patient care. The trial excluded individuals who, at baseline, were pregnant, had elevated liver enzymes, uncorrectable electrolyte imbalances, or a QTcF of 450 ms or higher. It also excluded those with resistance to or prior use (30+ days) of bedaquiline, delamanid, clofazimine, or linezolid, as well as those who had received at least 15 days of second-line tuberculosis treatment during their current infection. The experimental regimens were administered over the course of 39 weeks (9 months) and contained 4–5 of the following drugs: bedaquiline (B), delamanid (D), clofazimine (C), linezolid (L), levofloxacin (Lfx), moxifloxacin (M), and pyrazinamide (Z). The regimen combinations were BLMZ, BCLLfxZ, BDLLfxZ, DCLLfxZ, and DCMZ. In the standard-therapy group, favorable outcomes were observed in 80.7% of the modified intention-to-treat population and 95.9% of the per-protocol population. Four experimental regimens (BCLLfxZ, BLMZ, BDLLfxZ, and DCMZ) were found to be noninferior to standard therapy, while DCLLfxZ was not. Unfavorable outcomes due to positive culture occurred in 4.1% of participants overall, with higher rates in the DCMZ (7.5%) and DCLLfxZ (10.2%) groups. Recurrence was rare, occurring in only 3 (0.4%) participants. Treatment effects remained consistent across secondary analyses, with some variations based on country, prior drug exposure, cavitation, HIV status, and body mass index. Over time, the overall outcomes improved, and the BCLLfxZ group showed a longer time to unfavorable outcomes compared to standard therapy. In terms of safety, severe adverse events (Grade 3 or higher) affected 54.8% to 61.4% of participants, with 62.7% in the standard-therapy group. Serious adverse events occurred in 13.1% to 16.7% across groups. By week 73, 15 (2%) participants had died, increasing to 18 (2.4%) by week 104, with no deaths linked to trial drugs. Investigators classified 34.7% of severe and 31% of serious adverse events as drug related. Hepatotoxicity was the most common (6.3%–18.3%), followed by hematologic toxicity (7.4%–10.5%) and peripheral neuropathy (2.4%–7.1%). QTc prolongation occurred only in the DCMZ (4.2%) and BCLLfxZ (3.3%) groups. Comment: The study supports three new all-oral, shorter regimens (BLMZ, BCLLfxZ, and BDLLfxZ) for fluoroquinolone-susceptible, rifampin-resistant tuberculosis. These regimens, endorsed by the WHO in August 2024, can be used in nearly all patients, including children and pregnant individuals. However, bedaquiline-sparing regimens (DCMZ and DCLLfxZ) showed less favorable outcomes, warranting further research. Unfortunately, with fluoroquinolone resistance in India reaching 33%,[6] the applicability of these findings is limited. Genotypic and phenotypic susceptibility testing is essential before programmatic rollout to ensure effective treatment and prevent further resistance. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.