Regulatory Considerations in the Approval of Rezafungin (REZZAYO) for the Treatment of Candidemia and Invasive Candidiasis in Adults.

On March 22, 2023, the FDA approved rezafungin (REZZAYO) for the treatment of candidemia and invasive candidiasis in adults with limited or no alternative treatment options. Rezafungin is an echinocandin that supports weekly dosing, enabling outpatient parenteral treatment that potentially avoids the need for a central venous catheter. Approval of rezafungin was based on a single adequate and well-controlled phase 3 study designed with a Day 30 all-cause mortality primary endpoint and 20% noninferiority margin, which demonstrated that rezafungin is noninferior to the comparator echinocandin. Nonclinical studies of rezafungin in non-human primates identified a neurotoxicity safety signal; however, rezafungin's safety profile in the completed clinical studies was similar to other FDA-approved echinocandins. Here we describe the rationale for this approval and important considerations during the review process for a flexible development program intended to expedite the availability of antimicrobial therapies to treat serious infections in patients with limited treatment options.

Application of Population Pharmacokinetic Modeling, Exposure-Response Analysis, and Classification and Regression Tree Analysis to Support Dosage Regimen and Therapeutic Drug Monitoring of Plazomicin in Complicated Urinary Tract Infection Patients with Renal Impairment.

In 2018, the FDA approved plazomicin for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis in adult patients with limited or no alternative treatment options. The objective of this article is to provide the scientific rationales behind the recommended dosage regimen and therapeutic drug monitoring (TDM) of plazomicin in cUTI patients with renal impairment. A previous population pharmacokinetic (PK) model was used to evaluate the dosage regimen in cUTI patients with different degrees of renal impairment. The exposure-response analysis was conducted to identify the relationship between plazomicin exposure and nephrotoxicity incidence in cUTI patients with renal impairment. Classification and regression tree (CART) analysis was utilized to assess the TDM strategy. The receiver operating characteristics curve was plotted to compare two TDM thresholds in cUTI patients with renal impairment. The analyses suggested that dose reduction is necessary for cUTI patients with moderate or severe renal impairment. TDM should be implemented for cUTI patients with mild, moderate, or severe renal impairment to reduce the risk of nephrotoxicity. The trough concentration of 3 µg/mL is a reasonable TDM threshold to reduce the nephrotoxicity incidence while maintaining efficacy in cUTI patients with renal impairment. The application of population PK modeling, exposure-response analysis, and CART analysis allowed for the evaluation of a dosage regimen and TDM strategy for plazomicin in cUTI patients with renal impairment. Our study demonstrates the utility of pharmacometrics and statistical approaches to inform a dosage regimen and TDM strategy for drugs with narrow therapeutic windows.

US Food and Drug Administration (FDA): Benefit-Risk Considerations for Cefiderocol (Fetroja®).

In November 2019, the Food and Drug Administration (FDA) approved cefiderocol for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis caused by susceptible gram-negative bacteria in adults with limited to no alternative treatment options based on a randomized, double-blind, noninferiority cUTI trial (APEKS-cUTI). In a randomized, open-label trial (CREDIBLE-CR) in patients with cUTI, nosocomial pneumonia, bloodstream infections, or sepsis due to carbapenem-resistant gram-negative bacteria, an increase in all-cause mortality was observed in patients treated with cefiderocol as compared to best available therapy. The cause of the increased mortality was not established, but some deaths were attributed to treatment failure. Preliminary data from a randomized, double-blind trial (APEKS-NP) in patients with nosocomial pneumonia due to carbapenem-susceptible gram-negative bacteria showed a similar rate of mortality as compared to meropenem. We describe the uncertainties and challenges in the interpretation of the CREDIBLE-CR trial and some benefit-risk considerations for the use of cefiderocol in clinical practice. Clinical Trials Registration: NCT02321800.

FDA Public Workshop Summary: Advancing Animal Models for Antibacterial Drug Development.

The U.S. Food and Drug Administration (FDA) hosted a public workshop entitled "Advancing Animal Models for Antibacterial Drug Development" on 5 March 2020. The workshop mainly focused on models of pneumonia caused by Pseudomonas aeruginosa and Acinetobacter baumannii The program included discussions from academic investigators, industry, and U.S. government scientists. The potential use of mouse, rabbit, and pig models for antibacterial drug development was presented and discussed.

Hypoglycemia in patients treated with linezolid.

Hypoglycemia was not previously known to be a linezolid-associated adverse reaction. A case report describing symptomatic hypoglycemia in a linezolid recipient prompted a review of the US Food and Drug Administration Adverse Event Reporting System, which demonstrated a relationship between linezolid and hypoglycemia. A warning with this information was added to the linezolid package insert.

Hypersensitivity reactions associated with fidaxomicin use.

We report hypersensitivity reactions associated with fidaxomicin, an antibacterial drug approved for the treatment of Clostridium difficile-associated diarrhea. These reactions are viewed as significant because of severity and unexpected because fidaxomicin is minimally absorbed. The fidaxomicin labeling was revised to include information about the possibility of hypersensitivity reactions.

Antimicrobial surfaces using covalently bound polyallylamine.

We investigated the antimicrobial properties of the cationic polymer polyallylamine (PA) when covalently bonded to glass. The objective was to obtain a robust attachment, yet still allow extension of the polymer chain into solution to enable interaction with the bacteria. The PA film displayed strong antimicrobial activity against Staphylococcus epidermidis , Staphylococcus aureus , and Pseudomonas aeruginosa , which includes both Gram-positive and Gram-negative bacteria. Glass surfaces were prepared by a straightforward two-step procedure of first functionalizing with epoxide groups using 3-glycidoxypropyltrimethoxy silane (GOPTS) and then exposing to PA so that the PA could bind via reaction of a fraction of its amine groups. The surfaces were characterized using X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy to verify the presence of the polymer on the surface, zeta potential measurements to estimate the surface charge of the films, and atomic force microscopy to determine the extension of the polymer chains into solution. Antimicrobial properties of these coatings were evaluated by spraying aqueous suspensions of bacteria on the functionalized glass slides, incubating them under agar, and counting the number of surviving cell colonies.

Effect of grafted oligopeptides on friction.

Frictional and normal forces in aqueous solution at 25 °C were measured between a glass particle and oligopeptide films grafted from a glass plate. Homopeptide molecules consisting of 11 monomers of either glutamine, leucine, glutamic acid, lysine, or phenylalanine and one heteropolymer were each "grafted from" an oxidized silicon wafer using microwave-assisted solid-phase peptide synthesis. The peptide films were characterized using X-ray photoelectron spectroscopy and secondary ion mass spectrometry. Frictional force measurements showed that the oligopeptides increased the magnitude of friction compared to that on a bare hydrophilic silicon wafer but that the friction was a strong function of the nature of the monomer unit. Overall we find that the friction is lower for more hydrophilic films. For example, the most hydrophobic monomer, leucine, exhibited the highest friction whereas the hydrophilic monomer, polyglutamic acid, exhibited the lowest friction at zero load. When the two surfaces had opposite charges, there was a strong attraction, adhesion, and high friction between the surfaces. Friction for all polymers was lower in phosphate-buffered saline than in pure water, which was attributed to lubrication via hydrated salt ions.

Cefiderocol Dosing for Patients Receiving Continuous Renal Replacement Therapy.

In this report, we describe our scientific approach for including effluent flow rate (QE )-based dosing recommendations of cefiderocol for patients receiving continuous renal replacement therapy (CRRT) in the product labeling. The total clearance (CL) of cefiderocol in patients receiving CRRT was estimated as the sum of patients' nonrenal clearance (CLnonrenal ) and extracorporeal clearance by CRRT (CLCRRT ), based on the following rationale: (a) The renal clearance (CLrenal ) of cefiderocol is assumed to be negligible in patients receiving CRRT, (b) CLnonrenal represents the CRRT patients' own remaining systemic clearance and is estimated from the observed clearance in participants with creatinine clearance (CLcr) < 15 mL/minute without undergoing hemodialysis, and (c) CLCRRT was estimated by the product of unbound (free) fraction of plasma drug concentration (fu ) and QE because the free fraction of low-molecular-weight compounds like cefiderocol (752 Da) can be completely filtered by CRRT, regardless of CRRT modality. Hence, cefiderocol CL in CRRT patients was calculated by the equation of CL = CLnonrenal + fu × QE . Accordingly, the cefiderocol dosing regimens for patients receiving CRRT in clinically relevant ranges of QE were determined with the goal of achieving an average daily area under the concentration-time curve (AUC) observed in patients not receiving CRRT. Subsequently, pharmacokinetic (PK) simulations demonstrated that cefiderocol PK profiles following the QE -based dosing in patients receiving CRRT would be similar to those in patients not receiving CRRT.

Low prevalence of primary HIV resistance in western Massachusetts.

Most studies of primary antiretroviral (ARV) resistance have been conducted in large metropolitan areas with reported rates of 8% to 25%. We collected data on 99 HIV-1-infected antiretroviral-naive patients from several sites in Springfield, MA, who underwent genotypic resistance assay between 2004 and 2008. Only major resistance mutations per International AIDS Society-USA (IAS-USA) drug resistance mutations list were considered. The prevalence of resistance was 5% (5 of 99). Three patients had one nonnucleoside reverse transcriptase inhibitor (NNRTI) mutation: 103N, 103N, and 190A, 1 patient had a protease inhibitor (PI) mutation: 90M; and 1 patient had 3-class resistance with NNRTI: 181C, 190A, PI: 90M, and nucleoside analogue reverse transcriptase inhibitor (NRTI): 41L, 210W. Mean time from HIV diagnosis to resistance testing was shorter in patients with resistance versus those without: 9 (range 0.3-42 months) versus 27 (range 0.1-418 months), P = .11. There was a trend to lower mean CD4 count in those with resistance, 170 versus 318 cells/mm(3), P = .06. No differences were noted in gender, age, HIV risk category, or HIV RNA level. The low prevalence of primary resistance may be explained by differences in demographic and risk factors or may reflect the time from infection to resistance testing. Our findings emphasize the importance of continued resistance surveillance.

Extensive development of flat warts as a cutaneous manifestation of immune reconstitution syndrome.

Cutaneous manifestations of immune recovery in response to highly active antiretroviral therapy may account for up to 54% to 78% of the clinical presentations of the immune reconstitution syndrome (IRS). Genital herpes, varicella-zoster virus infection, genital warts, and molluscum contagiosum represent the majority of these cutaneous manifestations. Inflammation of preexisting cutaneous warts in response to effective antiretroviral therapy has rarely been described. We report the case of sudden extensive development of cutaneous warts, specifically verruca plana confirmed by skin biopsy, observed following antiretroviral therapy-associated immune reconstitution in a patient without a history of warts. The possibility of cutaneous IRS after commencement of antiretroviral therapy should be considered in a patient with unusual skin manifestations.

Delayed transplantation with exogenous neurotrophin administration enhances plasticity of corticofugal projections after spinal cord injury.

Functional deficits following spinal cord injury (SCI) result from a disruption of corticofugal projections at the lesion site. Not only direct regeneration of the severed axons but also anatomical re-organization of spared corticofugal pathways can reestablish connections between the supraspinal and spinal motor centers. We have previously shown that delayed transplantation of fetal spinal cord tissue and neurotrophin administration by two weeks after SCI supported recovery of forelimb function in adult rats. The current study determined whether the same intervention enhances plasticity of corticofugal fibers at the midbrain and spinal cord level. Anterograde tracing of the left corticorubral fibers revealed that the animals with transplants and neurotrophins (BDNF or NT-3) increased the extent of the traced fibers crossing to the right red nucleus (RN), of which the axons are spared by a right cervical overhemisection lesion. More neurons in the left motor cortex were recruited by the treatment to establish connections with the right RN. The right corticorubral projections also increased the density of midline crossing fibers to the axotomized left RN in response to transplants and neurotrophins. Transplants plus NT-3, but not BDNF, significantly increased the amount of spared corticospinal fibers in the left dorsolateral funiculus at the spinal level both rostral and caudal to the lesion. These results suggest that corticofugal projections retain the capacity until at least two weeks after injury to undergo extensive reorganization along the entire neuraxis in response to transplants and neurotrophins. Targeting anatomical plasticity of corticofugal projections may be a promising strategy to enhance functional recovery following incomplete SCI.

Adverse Events Associated with Fosfomycin Use: Review of the Literature and Analyses of the FDA Adverse Event Reporting System Database.

INTRODUCTION: The growing problem of antibacterial resistance resulted in an increased interest in fosfomycin, especially its parenteral formulation. We reviewed fosfomycin safety profile using the Food and Drug Administration Adverse Event (AE) Reporting System (FAERS) and published literature. METHODS: We conducted a FAERS search and disproportionality analysis of all fosfomycin-associated AEs. We also conducted a FAERS search for AEs implicating fosfomycin as the primary suspect and a search of reports of fosfomycin-associated bone marrow toxicity. We then review the literature for publications reporting AEs associated with fosfomycin by conducting PubMed searches. RESULTS: The disproportionality analysis of all FAERS reports of fosfomycin-associated AEs produced a higher than expected frequency of agranulocytosis, liver injury, severe skin reactions, and pseudomembranous colitis. Subsequent search for AEs where fosfomycin was the primary suspect and the literature review did not suggest a higher association of fosfomycin with these AEs. The search of bone marrow toxicity reports did not demonstrate an association between aplastic anemia and fosfomycin. The literature review selected 23 trials of parenteral administration of fosfomycin in 1242 patients including 8 comparative and 15 non-comparative trials. For oral fosfomycin, only prospective comparative trials (n = 28) in 2743 patients were included. The most frequent AEs associated with parenteral fosfomycin included rash, peripheral phlebitis, hypokalemia, and gastrointestinal disorders. Serious AEs such as aplastic anemia, anaphylaxis, and liver toxicities were reported infrequently. Gastrointestinal disorders were the most common AEs associated with oral fosfomycin. CONCLUSION: The identified AEs were consistent with the safety profile of fosfomycin. No new safety signals related to either parenteral or oral fosfomycin were identified.

Use of HIV resistance testing after prolonged treatment interruption.

BACKGROUND: HIV-1 genotypic resistance testing is not routinely recommended for patients who have been off antiretroviral therapy (ART) for longer than 4 weeks. We assessed the results and use of resistance testing in patients off ART. METHODS: All HIV resistance genotypes from November 2003 through April 2008 were reviewed from one large teaching hospital and two private HIV practices. Inclusion criterion was having a genotypic resistance test after an ART interruption of at least 2 months. Medical records were reviewed using a standardized data collection sheet. RESULTS: Sixty-two of 304 treatment-experienced patients with HIV genotypes met the inclusion criteria. Prior cumulative ART class exposure included nucleoside reverse transcriptase inhibitors in 54 patients, nonnucleoside reverse transcriptase inhibitors in 32 patients, and protease inhibitors in 30 patients. Resistance testing was performed at a mean of 12 months (range, 2.5-48 months) after ART interruption. The mean time between ART interruption and resistance testing did not differ for patients with mutations and those without mutations detected. Seventeen of 62 (27.4%) patients were found to have resistance mutations. Eleven patients were found to have mutations to nonnucleoside reverse transcriptase inhibitors, four patients had mutations to nucleoside reverse transcriptase inhibitors, and two patients had protease inhibitor-associated mutations. No patient had multiclass resistance. Among the 17 patients with mutations after treatment interruption, 15 had mutations that were either not present on a prior genotype (n = 2) or did not have a prior genotype (n = 13). CONCLUSIONS: HIV genotypic resistance assays may identify mutations even when performed after a prolonged treatment interruption and may offer clinically significant information. Current guidelines that discourage resistance testing after treatment interruptions of longer than 4 weeks should be re-evaluated.