Cationic Polyelectrolyte Nanocapsules of Moxifloxacin for Microbial Keratitis Therapy: Development, Characterization, and Pharmacodynamic Study.

Microbial keratitis (MK) is a vision-threatening disease and the fourth leading cause of blindness worldwide. In this work, we aim to develop moxifloxacin (MXN)-loaded chitosan-based cationic mucoadhesive polyelectrolyte nanocapsules (PENs) for the effective treatment of MK. PENs were formulated by polyelectrolyte complex coacervation method and characterized for their particle size, surface charge, morphology, mucoadhesive property, in-vitro and ex-vivo release, ocular tolerance, and antimicrobial efficacy studies. The pharmacodynamic study was conducted on rabbit eye model of induced keratitis and it is compared with marketed formulation (MF). Developed PENs showed the size range from 230.7 ± 0.64 to 249.0 ± 0.49 nm and positive surface charge, spherical shape along with appropriate physico-chemical parameters. Both in-vitro and ex-vivo examination concludes that PENs having more efficiency in sustained release of MXN compared to MF. Ocular irritation studies demonstrated that no corneal damage or ocular irritation. The in-vivo study proved that the anti-bacterial efficacy of PENs was improved when compared with MF. These results suggested that PENs are a feasible choice for MK therapy because of their ability to enhance ocular retention of loaded MXN through interaction with the corneal surface of the mucous membrane.

Is Moxifloxacin a Treatment Option for Pancreatic Infections? A Pharmacometric Analysis of Serum and Pancreatic Juice.

Postoperative local infection is a major complication after pancreatic surgery. The aim of this prospective clinical trial was to assess the potential of moxifloxacin (MXF) to treat pancreatic infections from a pharmacokinetic (PK)/pharmacodynamic (PD) perspective. The PK of MXF in serum and pancreatic juice, via an inserted tube in the pancreatic duct, was determined in 19 patients up to day 7 after pancreatoduodenectomy. PK data in both specimens was analyzed with NONMEM 7.3. Intraoperative swipes were performed for microbiological examination. PK/PD target attainment was assessed in both matrices using unbound area under the plasma concentration-time curve/minimum inhibitory concentration (MIC) targets of ≥30 and ≥100, for gram-positive and gram-negative pathogens, respectively. A 2-compartment population PK model in which the measurements in pancreatic juice were assigned to a scaled peripheral compartment best described the PK in both specimens simultaneously. Median (10th-90th percentile) area under the plasma concentration-time curve values after the third dose were 28.9 mg · h/L (18.6-42.0) in serum and 55.8 mg · h/L (23.7-81.4) in pancreatic juice. Target attainment rate for the intraoperatively isolated bacterial strains was ≥0.88 after the third MXF dose. For gram-negatives, high probability of target attainment ≥0.84 was observed in serum for MIC ≤ 0.125 mg/L and in pancreatic juice for MIC ≤ 0.25 mg/L. For gram-positives, the probability of target attainment was 0.84-1 in serum for MIC ≤ 0.5 mg/L and in pancreatic juice for MIC ≤ 1 mg/L. In conclusion, penetration of MXF into pancreatic juice was substantial. The PK/PD analysis indicated that treatment of pancreatic infections by isolates with MIC ≤ 0.25 mg/L (gram-negative) and ≤1 mg/L (gram-positive) should be evaluated in further studies.

Limited Sampling Strategies Using Linear Regression and the Bayesian Approach for Therapeutic Drug Monitoring of Moxifloxacin in Tuberculosis Patients.

Therapeutic drug monitoring (TDM) of moxifloxacin is recommended to improve the response to tuberculosis treatment and reduce acquired drug resistance. Limited sampling strategies (LSSs) are able to reduce the burden of TDM by using a small number of appropriately timed samples to estimate the parameter of interest, the area under the concentration-time curve. This study aimed to develop LSSs for moxifloxacin alone (MFX) and together with rifampin (MFX+RIF) in tuberculosis (TB) patients. Population pharmacokinetic (popPK) models were developed for MFX (n = 77) and MFX+RIF (n = 24). In addition, LSSs using Bayesian approach and multiple linear regression were developed. Jackknife analysis was used for internal validation of the popPK models and multiple linear regression LSSs. Clinically feasible LSSs (one to three samples, 6-h timespan postdose, and 1-h interval) were tested. Moxifloxacin exposure was slightly underestimated in the one-compartment models of MFX (mean -5.1%, standard error [SE] 0.8%) and MFX+RIF (mean -10%, SE 2.5%). The Bayesian LSSs for MFX and MFX+RIF (both 0 and 6 h) slightly underestimated drug exposure (MFX mean -4.8%, SE 1.3%; MFX+RIF mean -5.5%, SE 3.1%). The multiple linear regression LSS for MFX (0 and 4 h) and MFX+RIF (1 and 6 h), showed mean overestimations of 0.2% (SE 1.3%) and 0.9% (SE 2.1%), respectively. LSSs were successfully developed using the Bayesian approach (MFX and MFX+RIF; 0 and 6 h) and multiple linear regression (MFX, 0 and 4 h; MFX+RIF, 1 and 6 h). These LSSs can be implemented in clinical practice to facilitate TDM of moxifloxacin in TB patients.

Can systemically administered antibiotics be detected in wound tissues and surfaces under negative pressure wound therapy?

In this study, we evaluated a new aspect of negative pressure wound therapy (NPWT) as an analytical tool for pharmacokinetic studies. Twenty-one patients with soft tissue defects scheduled to receive NPWT were included in this study. Concomitant to NPWT, all patients received intravenous moxifloxacin (MX). At different time intervals, blood plasma levels of MX were sampled and compared with synchronous concentrations of MX in the exudate obtained from the NPWT drainage system. Serial measurements were performed upon initiation of the therapy as well as in the steady state (after 5 days). At steady state, wound tissue was obtained intraoperatively. High-performance liquid-chromatography (HPLC) was used for analysis. At 1 hour post-administration, the exudate/plasma levels (mg/L) were 1.92/3.07; at 12 hours, 0.80/1.14; at 24 hours, 0.26/0.43; and at 120 hours (steady state), 0.42/0.47. There was a correlation between exudate and plasma levels reaching approximately 0.75. Until now, methods for pharmacokinetic studies concerning interstitial fluid are difficult to apply in the clinical context. The presented method showed limitations, but we believe that, after methodological improvements, measurements of substances in the interstitial fluid by means of NPWT are feasible.

Nanoparticle Formulation of Moxifloxacin and Intramuscular Route of Delivery Improve Antibiotic Pharmacokinetics and Treatment of Pneumonic Tularemia in a Mouse Model.

Francisella tularensis causes a serious and often fatal infection, tularemia. We compared the efficacy of moxifloxacin formulated as free drug vs disulfide snap-top mesoporous silica nanoparticles (MSNs) in a mouse model of pneumonic tularemia. We found that MSN-formulated moxifloxacin was more effective than free drug and that the intramuscular and subcutaneous routes were markedly more effective than the intravenous route. Measurement of tissue silica levels and fluorescent flow cytometry assessment of colocalization of MSNs with infected cells revealed that the enhanced efficacy of MSNs and the intramuscular route of delivery was not due to better delivery of MSNs to infected tissues or cells. However, moxifloxacin blood levels demonstrated that the nanoparticle formulation and intramuscular route provided the longest half-life and longest time above the minimal inhibitory concentration. Thus, improved pharmacokinetics are responsible for the greater efficacy of nanoparticle formulation and intramuscular delivery compared with free drug and intravenous delivery.

Multiparameter Responses to Tedizolid Monotherapy and Moxifloxacin Combination Therapy Models of Children With Intracellular Tuberculosis.

Background: Children are often neglected during early development of antituberculosis agents, and most receive treatment after it is first tested in adults. However, very young children have tuberculosis that differs in many respects from adult cavitary pneumonia and could have different toxicity profiles to drugs. Linezolid is effective against intracellular tuberculosis, a common manifestation in young children. However, linezolid has considerable toxicity due to inhibition of mitochondrial enzymes. Tedizolid could be a replacement if it shows equal efficacy and reduced toxicity. Methods: We performed tedizolid dose-effect studies in the hollow fiber system model of intracellular tuberculosis. We measured linezolid concentrations, colony-forming units (CFU), time-to-positivity, and monocyte viability and performed RNA sequencing on infected cells collected from repetitive sampling of each system. We also compared efficacy of tedizolid vs linezolid and vs tedizolid-moxifloxacin combination. Results: There was no downregulation of mitochondrial enzyme genes, with a tedizolid 0-24 hour area under the concentration-time curve (AUC0-24) of up to 90 mg*h/L. Instead, high exposures led to increased mitochondrial gene expression and monocyte survival. The AUC0-24 to minimum inhibitory concentration ratio associated with 80% of maximal bacterial kill (EC80) was 184 by CFU/mL (r2 = 0.96) and 189 by time-to-positivity (r2 = 0.99). Tedizolid EC80 killed 4.0 log10 CFU/mL higher than linezolid EC80. The tedizolid-moxifloxacin combination had a bacterial burden elimination rate constant of 0.27 ± 0.05 per day. Conclusions: Tedizolid demonstrated better efficacy than linezolid, without the mitochondrial toxicity gene or cytotoxicity signatures encountered with linezolid. Tedizolid-moxifloxacin combination had a high bacterial elimination rate.