Pharmacokinetic and pharmacodynamic implications in inhalable antimicrobial therapy

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Abstract

Inhaled antimicrobials provide a promising alternative to the systemically delivered drugs for the treatment of acute and chronic lung infections. The delivery of antimicrobials via inhalation route decreases the systemic exposure while increasing the local concentration in the lungs, enabling the use of antimicrobials with severe systemic side effects. The inhalation route of administration has several challenges in pharmacokinetic (PK) and pharmacodynamic (PD) assessments. This review discusses various issues that need to be considered during study, data analysis, and interpretation of PK and PD of inhaled antimicrobials. Advancements overcoming the challenges are also discussed.

Introduction

The inhalation route of drug administration is vital and preferable in case of targeted drug delivery in lungs, especially in diseases such as cystic fibrosis (CF), non-CF bronchiectasis, tuberculosis (TB), and pneumonia [1], [2], [3], [4], [5]. The inhalation route of antibiotic administration carries many advantages over the oral or parenteral route. These advantages include local targeted delivery of the drugs to the lungs resulting in significant reduction in adverse/toxic effects associated with parenteral/oral delivery [6]. Second, direct drug delivery to the lungs may reduce the dose of administered drug as a part of effective dosage regimen. This route may provide advantage to kill the microbes at a significantly lower dose compared to high doses administered by parenteral/oral route. Targeted antimicrobial delivery may reduce the chances of resistance development because longer treatments using antimicrobial agents may potentiate the resistance mechanism in bacterial pathogens especially in case of CF patients. Additional advantages include faster onset of action, no drug inactivation before reaching the lungs (e.g., first pass metabolism), and suitability for home treatment [7]. Therefore, the inhaled route of drug administration is considered an effective option to deliver antimicrobials to lungs [8].

Lung diseases such as cystic fibrosis (CF), non-CF bronchiectasis, experimental tuberculosis, and pneumonia caused by microbial infections are tough to treat via conventional oral or intravenous route of antibiotic administration and inhalation antimicrobial therapy may be employed for improved therapeutic outcome. CF is a chronic lung infection where morphological changes, including dilation and hypertrophy of bronchial gland, leads to viscid mucus plugging in the airways and bacterial infections [9], [10]. The prevalent species responsible for infection includes Pseudomonas aeruginosa and several other occasional opportunistic bacterial species such as Burkholderia cepacia, Stenotrophomonas maltophilia, Staphylococcus aureus, and Achromobacter xylosoxidans [11]. Another major lung disease, tuberculosis, is caused due to infection with different strains of Mycobacterium mainly Mycobacterium tuberculosis [3]. These bacterial strains possess many virulent factors and a set of immune-evasive properties leading to recurrent and difficult to eradicate infections [12]. The primary treatment of CF includes prophylactic, on-demand, and maintenance treatment therapies with antimicrobials, including levofloxacin, ciprofloxacin, tobramycin, gentamicin, amikacin, and colistin [13], [14]. Similarly, TB is treated with combination of drugs, including rifampin, pyrazinamide, isoniazid, and levofloxacin [15], [16], [17].

Safety and efficacy studies of inhalation antimicrobials conducted so far have shown favorable results. The aerosol inhalation of kanamycin, an aminoglycoside, was found to be safe in 200 bronchopulmonary suppurative tuberculosis patients [18]. Kanamycin, clofazimine, gentamicin, ofloxacin, streptomycin, and neomycin were found to be safe and effective in smaller clinical studies [19], [20], [21]. Addition of aerosol aminoglycosides to the conventional TB treatment in patients with persistent smear-positive pulmonary tuberculosis turned the TB sputum bacterial culture negative [20].

In order to better understand the therapeutic outcome and appropriate dosing regimen design, the study of pharmacokinetics (PK) and pharmacodynamics (PD) is vital. PK describes the time course of drug in the body while PD relates drug concentration with efficacy measures. The PK and PD is linked using PK/PD modeling and different dosing regimen are simulated to arrive at the best dosing regimen of antimicrobials [22], [23]. PK and PD studies have been studied in several clinical and preclinical studies; however, many challenges exist in methodology and current practices. This review aims at highlighting the PK and PD issues in reference to inhalation antimicrobial therapy.

Section snippets

Pharmacokinetic implications of inhaled antimicrobial therapy

Clinical pharmacokinetic studies in healthy volunteers and diseased population suggest that inhalable antimicrobials are well tolerated and safe for a given dosage regimen [19], [24], [25], [26], [27]. Most of the inhaled drugs are delivered to the lungs, while a part of the dose is swallowed and absorbed from intestinal tract. In general, inhaled antimicrobials are rapidly absorbed, and expectedly, the systemic maximum peak concentration (Cmax) and area under the curve (AUC) remain lower in

Susceptibility testing of lung infections

Susceptibility testing of bacteria by determining the MIC of bacteria in the sputum is usually the first step in drug and dose selection in antimicrobial therapy; however, the MIC of bacteria present in the sputum may not represent the true bacterial population present at the site of infection [74], [75]. As discussed earlier, the sputum consists of phlegm from bronchioles and bacterial population and microbes residing in alveolar spaces may not get sampled during expectoration [71]. In

Conclusions

Inhalation antimicrobial therapy is very promising in targeting local lung drug delivery and reducing the systemic side effects associated with the high-dose administration of these agents by oral/parenteral route. However, several challenges exist in PK and PD assessment of inhaled antimicrobials. Some of these challenges are unique to inhalation therapy while some challenges originate from the existing practices in antimicrobial therapy. Most importantly, we do not have good methods available

Acknowledgments

Authors are thankful to Patricia Khan, College of Pharmacy, University of Florida, for her help in figure preparation.

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