Pulmonary Pharmacology & Therapeutics (2001) 14, 21–27 doi:10.1006/pupt.2000.0270, available online at http://www.idealibrary.com on PULMONARY PHARMACOLOGY & THERAPEUTICS Review Problems and Perspectives in the Treatment of Respiratory Infections Caused by Atypical Pathogens Luigi Allegra, Francesco Blasi Institute of Respiratory Diseases, University of Milan, IRCCS Ospedale Maggiore di Milano, Italy In order to exert their antibacterial activity, antibiotics exhibits a peculiar behaviour: it has a very long half- life of about 50 h accompanied by very low serum must reach the infectious focus. Infection may develop in the interstitial spaces of tissues or inside the cells. levels and extremely high tissue and intracellular levels, particularly in PMNs, alveolar macrophages and The physicochemical properties of drugs are the main factors conditioning their distribution in body tissues fibroblasts, from which it is slowly released. The C/E ratio in alveolar macrophages is about 300 after 48 h, and their penetration into cells. For the treatment of respiratory infections antibiotics must reach adequate but values may increase to >1000 3–4 days following administration, because of the extremely low serum concentrations in lung parenchyma, bronchial tissues, bronchial secretions, and cells. The behaviour of all levels (Ζ0.01 g/ml). 12–16 Correlation between intracellular accumulation and classes of antibiotics in the respiratory tract has been thoroughly investigated. 1 A recently developed micro- antimicrobial activity has been submitted to careful analysis. The presence of large amounts of antibiotics lavage technique, performed via fibreoptic bron- choscopy, allows the sampling of alveolar epithelial within cells does not always ensure higher antibacterial activity. Cell penetration of macrolides correlates with lining fluid and alveolar macrophages in order to determine antibiotic concentrations following sys- extracellular concentration and antimicrobial activity correlates with intracellular accumulation in ex- temic administration in humans. 2 Information re- garding the pharmacokinetic behaviour of antibiotics perimental models. Fluoroquinolones, which ac- cumulate in cells to a lesser extent than macrolides, in the respiratory tract has been of great importance in anticipating and assessing their clinical efficacy in nevertheless show an excellent antimicrobial activity, while clindamycin, which shows a C/E ratio somewhat respiratory infections. Clindamycin, rifampicin, tetracyclines, macrolides superior to fluoroquinolones, displays low activity against intracellular Staphylococcus aureus. 5 Evidently and fluoroquinolones accumulate in phagocytes. 3,4 Macrolides show the greatest capacity for intracellular the nature of the parasite, its growth rate, the different experimental conditions and the mechanism of action accumulation, localizing within the cytosol and ly- sosomes. In polymorphonuclear neutrophils (PMN), of the antibiotic can greatly influence the outcome of experiments performed in vitro and in animal models. the cellular/extracellular (C/E) ratio varies from 2 to 14 for erythromycin and josamycin and reach the Atypical pneumonia is a clinical syndrome without a precise definition, first described by Reimann in highest values for dirithromycin, clarithromycin and azithromycin. 5–10 In alveolar macrophages the C/E 1938, 17 who realised that some patients with pneu- monia had clinical picture and natural history that ratio of dirithromycin is about 80, that of cla- rithromycin can range according to the time of sample differ from that seen in patients with pneumococcal infection. The syndrome includes a subacute onset collection from about 40 to >100. 10,11 Azithromycin with low–moderate grade fever, dry cough, prominent constitutional symptoms, absent or moderate leuko- Author for correspondence: Francesco Blasi, MD, PhD, Istituto cytosis, with a more extensive radiographic in- di Tisiologia e Malattie dell’Apparato Respiratorio, Universita ` volvement than physical examination would suggest. degli Studi di Milano, Pad. Litta, IRCCS Ospedale Maggiore di The term ‘atypical pathogens’ indicates a number of Milano, via F. Sforza, 35 I-20122 Milano, Italy. Fax: +39 02 55190332. E-mail: francesco.blasi@unimi.it microorganisms that can cause so called ‘atypical 1094–5539/01/010021+07 $35.00/0  2001 Academic Press 21