Poloxamer 407/188 Binary Thermosensitive Gel as a Moxidectin Delivery System: In Vitro Release and In Vivo Evaluation.

Moxidectin (MXD) is an antiparasitic drug used extensively in veterinary clinics. In this study, to develop a new formulation of MXD, a thermosensitive gel of MXD (MXD-TG) was prepared based on poloxamer 407/188. Furthermore, the gelation temperature, the stability, in vitro release kinetics and in vivo pharmacokinetics of MXD-TG were evaluated. The results showed that the gelation temperature was approximately 27 °C. MXD-TG was physically stable and can be released continuously for more than 96 h in vitro. The Korsmeyer−Peppas model provided the best fit to the release kinetics, and the release mechanism followed a diffusive erosion style. MXD-TG was released persistently for over 70 days in sheep. Part of pharmacokinetic parameters had a difference in female and male sheep (p < 0.05). It was concluded that MXD-TG had a good stability, and its release followed the characteristics of a diffusive erosion style in vitro and a sustained release pattern in vivo.

Preparation, relative toxicity, chemotherapeutic activity, and pharmacokinetics of liposomal SJA-95: a new polyene macrolide antibiotic.

The research work was designed to compare the relative toxicity, chemotherapeutic activity, and pharmacokinetic parameters of liposomal incorporated SJA-95 with that of free SJA-95, with an objective to reduce toxicity and improve therapeutic activity in vivo. Liposomal-incorporated SJA-95 (Lip SJA-95), prepared using the proliposome method, was found to exhibit a higher LD(50) value in mice, and the relative toxicity was about 2.5 times lower than that of the free drug. Lip SJA-95 treatment in experimental mice model of Candidiasis showed increased survival and reduced fungal loads in various organs. The pharmacokinetic profile of the free and liposomal drug was evaluated by administration of free and Lip SJA-95 intravenously to healthy albino rabbits in a crossover fashion. Lip SJA-95 showed an initial fall in plasma levels and longer half-life. The improved microbial clearance following treatment with Lip SJA-95 could be attributed partly to an increased tissue uptake, which was reflected in a marked increase in volume of distribution (V(d)) and longer half-life (T(1/2)). The present results clearly indicated that Lip SJA-95 treatment led to prolonged survival time, effective microbiological clearance, and reduced toxicity in the mice model of Candidiasis.

A Qualitative Review on the Pharmacokinetics of Antibiotics in Saliva: Implications on Clinical Pharmacokinetic Monitoring in Humans.

We conducted a systematic search to describe the current state of knowledge regarding the utility of saliva for clinical pharmacokinetic monitoring (CPM) of antibiotics. Although the majority of identified studies lacked sufficient pharmacokinetic data needed to assign an appropriate suitability classification, most aminoglycosides, fluoroquinolones, macrolides, penicillins/cephalosporins, and tetracyclines are likely not suitable for CPM in saliva. No clear pattern of correlation was observed between physiochemical properties that favor drug distribution into saliva and the likelihood of the antibiotic being classified as suitable for CPM in saliva (and vice versa). Insufficient data were available to determine if pathophysiological conditions affected salivary distribution of antibiotics. Additional confirmatory data are required for drugs (especially in patients) that are deemed likely suitable for CPM in saliva because only a few studies were available and many focused only on healthy subjects. All studies identified had relatively small sample sizes and exhibited large variability. Very few studies reported salivary collection parameters (e.g., salivary flow, pH) that could potentially have some impact on drug distribution into saliva. The available data are heavily weighted on healthy subjects, and insufficient data were available to determine if pathophysiology had effects on saliva drug distribution. Some studies also lacked assay sensitivity for detecting antibiotics in saliva. Overall, this review can be useful to clinicians who desire an overview on the suitability of saliva for conducting CPM of specific antibiotics, or for researchers who wish to fill the identified knowledge gaps to move the science of salivary CPM further.

Mechanisms of action of systemic antibiotics used in periodontal treatment and mechanisms of bacterial resistance to these drugs.

Antibiotics are important adjuncts in the treatment of infectious diseases, including periodontitis. The most severe criticisms to the indiscriminate use of these drugs are their side effects and, especially, the development of bacterial resistance. The knowledge of the biological mechanisms involved with the antibiotic usage would help the medical and dental communities to overcome these two problems. Therefore, the aim of this manuscript was to review the mechanisms of action of the antibiotics most commonly used in the periodontal treatment (i.e. penicillin, tetracycline, macrolide and metronidazole) and the main mechanisms of bacterial resistance to these drugs. Antimicrobial resistance can be classified into three groups: intrinsic, mutational and acquired. Penicillin, tetracycline and erythromycin are broad-spectrum drugs, effective against gram-positive and gram-negative microorganisms. Bacterial resistance to penicillin may occur due to diminished permeability of the bacterial cell to the antibiotic; alteration of the penicillin-binding proteins, or production of ß-lactamases. However, a very small proportion of the subgingival microbiota is resistant to penicillins. Bacteria become resistant to tetracyclines or macrolides by limiting their access to the cell, by altering the ribosome in order to prevent effective binding of the drug, or by producing tetracycline/macrolide-inactivating enzymes. Periodontal pathogens may become resistant to these drugs. Finally, metronidazole can be considered a prodrug in the sense that it requires metabolic activation by strict anaerobe microorganisms. Acquired resistance to this drug has rarely been reported. Due to these low rates of resistance and to its high activity against the gram-negative anaerobic bacterial species, metronidazole is a promising drug for treating periodontal infections.

Mechanisms of action of systemic antibiotics used in periodontal treatment and mechanisms of bacterial resistance to these drugs

Antibiotics are important adjuncts in the treatment of infectious diseases, including periodontitis. The most severe criticisms to the indiscriminate use of these drugs are their side effects and, especially, the development of bacterial resistance. The knowledge of the biological mechanisms involved with the antibiotic usage would help the medical and dental communities to overcome these two problems. Therefore, the aim of this manuscript was to review the mechanisms of action of the antibiotics most commonly used in the periodontal treatment (i.e. penicillin, tetracycline, macrolide and metronidazole) and the main mechanisms of bacterial resistance to these drugs. Antimicrobial resistance can be classified into three groups: intrinsic, mutational and acquired. Penicillin, tetracycline and erythromycin are broad-spectrum drugs, effective against gram-positive and gram-negative microorganisms. Bacterial resistance to penicillin may occur due to diminished permeability of the bacterial cell to the antibiotic; alteration of the penicillin-binding proteins, or production of β-lactamases. However, a very small proportion of the subgingival microbiota is resistant to penicillins. Bacteria become resistant to tetracyclines or macrolides by limiting their access to the cell, by altering the ribosome in order to prevent effective binding of the drug, or by producing tetracycline/macrolide-inactivating enzymes. Periodontal pathogens may become resistant to these drugs. Finally, metronidazole can be considered a prodrug in the sense that it requires metabolic activation by strict anaerobe microorganisms. Acquired resistance to this drug has rarely been reported. Due to these low rates of resistance and to its high activity against the gram-negative anaerobic bacterial species, metronidazole is a promising drug for treating periodontal infections.

Pharmacodynamic activity of telithromycin against macrolide-susceptible and macrolide-resistant Streptococcus pneumoniae simulating clinically achievable free serum and epithelial lining fluid concentrations.

BACKGROUND: The association between macrolide resistance mechanisms and ketolide bacteriological eradication of Streptococcus pneumoniae remains poorly studied. The present study, using an in vitro model, assessed telithromycin pharmacodynamic activity against macrolide-susceptible and macrolide-resistant S. pneumoniae simulating clinically achievable free serum and epithelial lining fluid (ELF) concentrations. MATERIALS AND METHODS: Two macrolide-susceptible [PCR-negative for both mef(A) and erm(B)] and six macrolide-resistant [five mef(A)-positive/erm(B)-negative displaying various degrees of macrolide resistance and one mef(A)-negative/erm(B)-positive] S. pneumoniae were tested. Telithromycin was modelled simulating a dosage of 800 mg by mouth once daily [free serum: maximum concentration (C(max)) 0.7 mg/L, t(1/2) 10 h; and free ELF: C(max) 6.0 mg/L, t(1/2) 10 h]. Starting inocula were 1 x 10(6) cfu/mL in Mueller-Hinton broth with 2% lysed horse blood. Sampling at 0, 2, 4, 6, 12, 24 and 48 h assessed the extent of bacterial killing (decrease in log(10) cfu/mL versus initial inoculum). RESULTS: Telithromycin free serum concentrations achieved in the model were: C(max) 0.9+/-0.08 mg/L, AUC(0-24) 6.4+/-1.5 mg.h/L and t(1/2) of 10.6+/-1.6 h. Telithromycin free ELF concentrations achieved in the model were: C(max) 6.6+/-0.8 mg/L, AUC(0-24) 45.5+/-5.5 mg.h/L and t(1/2) of 10.5+/-1.7 h. At 2 h, free serum telithromycin concentrations achieved a 1.0-1.9 log(10) reduction in inoculum compared with a 3.0-3.3 log(10) reduction with free ELF versus macrolide-susceptible and macrolide-resistant S. pneumoniae. Free telithromycin serum and ELF concentrations simulating C(max)/MIC > or =14.1 and area under the curve to MIC (AUC(0-24)/MIC) > or =100 [time above the MIC (t > MIC) of 100%], were bactericidal (> or =3 log(10) killing) at 4, 6, 12, 24 and 48 h versus macrolide-susceptible and macrolide-resistant S. pneumoniae. CONCLUSION: Telithromycin serum and ELF concentrations rapidly eradicated macrolide-susceptible and macrolide-resistant S. pneumoniae regardless of resistance phenotype. Achieving C(max)/MIC > or =14.1 and AUC(0-24)/MIC > or =100 resulted in bactericidal activity at 4 h with no regrowth over 48 h.