Pharmacokinetic and Pharmacodynamic Profiling of Minocycline for Injection following a Single Infusion in Critically Ill Adults in a Phase IV Open-Label Multicenter Study (ACUMIN)

Abstract

Intravenous (IV) minocycline is increasingly used to treat infections caused by multi-drug resistant (MDR)-Acinetobacter baumannii. Despite being approved nearly 50 years ago, published information on its pharmacokinetic (PK) prolife is limited. This multi-center study examined the PK and probability of pharmacokinetic-pharmacodynamic (PK-PD) target attainment profile of IV minocycline in critically ill patients, with suspected or documented infection with Gram-negative bacteria. The PK study population included 55 patients who received a single 200 mg IV dose of minocycline. Plasma PK samples were collected pre-dose and 1, 4, 12, 24, 36, and 48 hours after initiation of minocycline. Total and unbound minocycline concentrations were determined at each timepoint. Probabilities of achieving the PK-PD targets associated with stasis and 1-log killing (fAUC:MIC of 12 and 18, respectively) were evaluated. A two-compartment population PK model with zero-order IV input and first-order elimination, which estimated a constant fraction unbound (fub) for minocycline, best characterized the total and unbound plasma minocycline concentration-time data. The only two covariates retained in the final PK model were body surface area [associated with central volume of distribution] and albumin (associated with fub). In the PK-PD target attainment analyses, minocycline 200 mg IV Q12H was predicted to result in a suboptimal PK-PD profile for patients with A. baumannii infections with MIC values ≥ 1 mg/L. These findings cast uncertainty on the appropriateness of the current minocycline FDA susceptibility breakpoints and suggest that clinicians should strongly consider only combination antibiotic therapy with IV minocycline for all patients with serious Acinetobacter sp. infections.

Contemporary Perspective on the Treatment of Acinetobacter baumannii Infections: Insights from the Society of Infectious Diseases Pharmacists

“…Unfortunately, the accurate determination of minocycline MICs against A. baumannii is challenging; disk-diffusion and E-test methods may overcall resistance [ 44 ]. The ACUMIN study, a 2021 PK/PD investigation evaluating minocycline in critically ill patients, described the lack of target attainment with minocycline dosed 200 mg IV q12 h against CRAB isolates with MICs > 1 mg/L [ 45 ]. These data emphasize the need for clinicians to consider requesting broth microdilution to confirm minocycline susceptibility if alternative agents are unavailable, and prioritize use only in cases where MICs are less than 1 mg/L.…”

Treatment of patients with serious infections due to carbapenem‐resistant Acinetobacter baumannii: How viable are the current options?

“…In a PK study of critically ill patients receiving minocycline 200 mg IV q12 h, critical ƒ AUC:MIC targets in plasma associated with stasis ( f AUC/MIC of 12) was achieved for isolates with MICs ≤1 mg/L and 1‐log killing ( f AUC/MIC of 18) was only achieved at MICs ≤0.5 mg/L. Like tigecycline, PTA varied as a function of the patients’ baseline albumin 85 …”

Secondary mechanisms of injury and viable pathophysiological targets in intracerebral hemorrhage

“…However, increased risk of hypoglycemia in non-diabetic patients can induce cerebral damage. 36 , 49 The intravenous formulation of glibenclamide (BIIB093) facilitates rapid supra-therapeutic levels and stable maintenance of desired plasma levels of the drug. 42 …”

“…The overall conclusions from both PK models suggest that current intravenous dosing of minocycline used in the intensive care unit might provide only suboptimal dosing and microbiological efficacy, and the higher intravenous minocycline doses used in critically ill patients with infections will require a detailed risk versus benefit assessment for toxicities related to potential kidney damage. 49 …”