Long-acting injectable cabotegravir is more effective than daily oral PrEP at preventing HIV transmission due to improved adherence, but requires bi-monthly large-volume intramuscular injections. Subcutaneous (SC) contraceptive implants can be formulated with antiretrovirals for extended-duration HIV PrEP. Islatravir (ISL) is a first-in-class, investigational antiretroviral with pharmacologic properties well-suited for implant delivery. We performed preclinical studies for the development of a reservoir-style, poly(ε-caprolactone) ISL-eluting implant by conducting a single-dose SC ISL dose-ranging pharmacokinetic (PK) study of 0.1, 0.3, and 1 mg/kg in adult Wistar rats. Non-compartmental analysis was conducted, and dose proportionality assessed for ISL plasma and intracellular islatravir-triphosphate (ISL-tp). Population PK models estimated ISL’s unit impulse response to deconvolve ISL-implant in vivo absorption rate (mg/day) and cumulative mass (mg) from published rat plasma PK (n = 10). Drug release was interpreted using four kinetic models. Dose proportionality was affirmed for ISL and ISL-tp. A first-order, two-compartment model fitted the SC ISL bolus data. Mean (SD) absorption rate from 0 to 154 days was 0.072 ± 0.024 mg/day, and cumulative mass at 154 days was 8.67 ± 3.22 mg. ISL absorption was well-described by zero-order (r² = 0.95) and Ritger–Peppas (r² = 0.98). Our zero-order ISL-release poly(ε-caprolactone) implant is projected to achieve clinical PK above ISL-tp’s PrEP efficacy threshold. Continued development for HIV PrEP applications is warranted.

Foremost in the design of new β-lactamase inhibitors (BLIs) are the boronic acid transition state inhibitors (BATSIs). Two highly potent BATSIs being developed are S02030 and MB076 strategically designed to be active against cephalosporinases and carbapenemases, especially KPC. When combined with cefepime, S02030 and MB076 demonstrated potent antimicrobial activity against laboratory and clinical strains of Enterobacterales expressing a variety of class A and class C β-lactamases, including bla _KPC-2 and bla _KPC-3 . Static time-kill assays revealed the bactericidal activity of cefepime in combination with S02030 and MB076 against a multidrug-resistant KPC-producing K. pneumoniae (KPC- Kpn -1), in which a ≥ 3-log ₁₀ decrease in the bacterial density was observed by 6 h. In vivo efficacy of MB076 in combination with cefepime was evaluated in a lung infection model where male C57BL/6 mice were infected intranasally with KPC- Kpn -1. Cefepime alone administered at 2 h post infection resulted in a 1.07 log ₁₀ CFU reduction at 24 h, while cefepime in combination with MB076 resulted in an enhanced reduction of 2.70 log ₁₀ CFU ( P < 0.0001) compared to the no treatment control group. In a survival analysis where mice were infected via the tail vein with KPC- Kpn -1 , all mice treated with placebo or cefepime alone (100 mg/kg) died, whereas those treated with a 1:4 molar ratio of cefepime-MB076 survived. Our data demonstrate bactericidal activity and in vivo efficacy of cefepime-MB076 comparable to ceftazidime-avibactam and support the continued development of this combination as a new treatment option for infections caused by class A carbapenemase producing Enterobacterales, particularly KPC- Kpn .

Bacteriophages are a promising strategy for treating multidrug-resistant bacterial infections, yet clinical translation is hindered by the lack of frameworks linking in vitro phage biology to in vivo efficacy. We developed an in vitro–in vivo extrapolation (IVIVE) framework integrating physiologically based pharmacokinetics (PBPK) with an in vitro-derived pharmacodynamic (PD) model to predict phage amplification and bacterial killing. Phage PD was characterized using static concentration–time kill assays across bacterial inocula and PSA07 concentrations, while a PBPK model simulated phage disposition in plasma and lung. The framework predicted infection-driven phage amplification, resulting in a ~40-fold increase in lung exposure and a 3-log₁₀ reduction in bacterial burden within 24 h, and retained predictive performance during external validation. Sensitivity analyses identified adsorption rate constant and burst size as key determinants of efficacy, demonstrating that phage quality, rather than dose escalation, drives therapeutic success and supports rational phage selection and dose optimization.