In order to predict the in vivo effects of antibiotic therapy, a pharmacokinetic/pharmacodynamic (PK/PD) index is conventionally selected from three indices, including the ratio of the area under the curve to the minimum inhibitory concentration (AUC/MIC), the ratio of the maximum plasma concentration to the MIC (C_max/MIC), and the period of time for which the drug concentration exceeds the MIC (time above MIC), depending on the in vitro characteristics of the antibiotic. Convention dictates that the in vivo efficacy of a concentration-dependent antibiotic is related to its AUC/MIC and/or C_max/MIC, while that of a time-dependent antibiotic is related to its time above MIC. The “PK/PD index map” proposes the optimal PK/PD index for a given antibiotic based on a mathematical simulation model. This model consists of a PK unit, which is a typical 1-compartment model with a gut compartment, and a PD unit, which is an enhanced-death constant-replication model. The association between the two units was created on the basis that the plasma concentration at a given point in time determines the effect at that time. It was observed that the recommended index provided by the PK/PD index map was generally in good agreement with the conventional classification, providing theoretical support for that classification. The PK/PD index map is a practical guide for optimizing antibiotic therapy and also has the potential to determine the most favorable pharmacokinetic profile for a given antibiotic. Consequently, the PK/PD index map may help to establish a rational goal for the DDS research after the selection of a candidate molecule.

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The oral route is considered to be most convenient for administration of drugs to patients. However, solubility limitations to oral drug delivery are frequently encountered in the development of commercial products. In recent years scientific and technological advancements have been made in the research and development of rate-controlled oral drug delivery systems by overcoming physiological adversities. Several prodrug esters have been reported to improve the oral absorption of penicillin, for example pivaloyloxymethyl ester, acetoxymethyl ester, propionyloxymethyl ester and phthalidyl ester. Carrier or delivery systems such as liposomes and microspheres have been developed for the sustained delivery of antibiotics. In this article, we introduce the characteristics of the oral DDS for antimicrobial therapy.

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Inhalation therapy has been usually used for the patients with bronchial asthma or chronic obstructive pulmonary disease. In contrast, it has not been used for respiratory tract infection except for influenza virus infection. There is a demand for antibiotic inhalation therapy, because the development of novel antibiotics is stagnant but the multidrug-resistant bacteria are increasing. Among the pathogens, P. aeruginosa has been a common cause of chronic respiratory infection and hospital-acquired pneumonia (HAP) including ventilator-associated pneumonia (VAP). Although there are several anti-pseudomonal agents, P. aeruginosa is associated with high in-hospital mortality and prolonged length of stay in hospitals. P. aeruginosa infection has been difficult to treat because the bacteria possess numerous mechanisms of antimicrobial resistance. Thus, antibiotics, such as tobramycin, colistin, and aztreonam, have been administered via inhalation to patients with chronic respiratory tract infections or HAP to maximize the drug delivery to the target site of infection and limit the potential for systemic side effects. Recently, several clinical studies reported that administration of amikacin via inhalation is effective in patients with VAP. Our previous study also demonstrated the in vivo effectiveness of arbekacin inhalation therapy in the murine model of VAP caused by P. aeruginosa. The antibiotic inhalation therapy would be the option in the patients with respiratory tract infection.

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According to the autopsy report, the most frequent mycoses in Japan are aspergillosis, then candidiasis, cryptococcosis, followed by mucormycosis. On the other hand, the antifungal drugs that can be used in Japan are amphotericin B (AMPH-B) and liposomal amphotericin B (L-AMB), fluconazole, fosfluconazole, miconazole, itraconazole, voriconazole, micafungin, caspofungin and flucytosine. L-AMB is the first liposomal preparation as a pharmaceutical drug and it is a pioneer as a DDS of antifungal drugs. Although AMPH-B is a highly reliable antifungal agent with a wide antifungal spectrum, the conventional formulation has severe adverse effects such as hypokalemia and renal dysfunction. The main purpose in developing lipid formulations was to reduce side effects while maintaining high antifungal activity as AMPH-B. In fact it is more tolerable than its conventional formulation and it fulfilled the purpose of DDS. Ten years have passed since the start of clinical use, but L-AMB still remains to be recognized as one of the important drugs against fungal diseases in the various guidelines and clinical practice. Development of DDS for antifungal drugs is still less developed. Azoles and echinocandins have few side effects, and it may be one of the reasons that it is difficult to set clear purpose of DDS like L-AMB. Echinocandins exhibit fungicidal action against Candida spp. and are expected to be effective even in neutropenia. However, tissue penetration is poor as compared with azoles that have a fungistatic effect on Candida spp. Therefore, it is desirable to develop DDS for improving pharmacokinetics rather than reducing adverse effects.

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Mucosal tissues are constantly exposed by exogenous materials including various pathogens and thus they invade into our body through mucosal tissues. Mucosal vaccine is an effective strategy against mucosal infectious diseases, and has been already clinically used. Unlike injectable vaccines, mucosal vaccines induce immune responses at mucosal as well as systemic compartments. Because administration of protein vaccine alone to mucosal tissues dose not induce sufficient immune responses, mucosal vaccines require antigen delivery system to deliver the antigen to mucosa-associate lymphoid tissues for the induction of effective immune responses. In this review, we focus on the development of vaccine delivery system for the prospective mucosal vaccine.

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