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Background and Importance Appropriate antibiotic dosage is crucial for improving outcomes in critically ill patients facing pneumonia.Aim and Objectives Our research aimed to evaluate the development of the steady-state concentration (Css) of clarithromycin (CLAR) in this specific patient population with different routes of administration, to identify the influencing factors, and to examine the relationship between clinical outcomes and Css.Material and Methods This study was conducted as a single-centre prospective observational study in the ICU of a pulmonology department between 2 February 2025 and 30 September 2025. The study target group included all adult patients (n=65) treated primarily with empirical CLAR (500mg two times a day, n=63 cases; corrected to kidney function, n=2 cases) due to pneumonia. Blood sample collection was performed on day 3 of the CLAR administration, when 4 samples were taken as follows: at steady-state before drug administration and 1, 2, and 3 hours after intravenous (IV), oral (PO), and nasogastric (NG) drug administration. Determination of CLAR serum concentrations was determined by LC-MS/MS using a CLAR European Pharmacopoeia Reference Standard by Merck. The study received ethics approval (DE RKEB/IKEB: 7094-2025).Results CLAR serum levels followed the expected pharmacokinetics for all three routes of administration. The CLAR Css was 4.3-fold higher for PO (n=30) than for IV (n=20) administration and 2.99-fold higher for NG (n=15) administration (6.13 vs 1.41 μg/ml and 6.13 vs 2.05 μg/ml, p<0.05). Severe reduction of CrCl (59-10 ml/min) increased serum levels for all administration routes. CLAR serum levels increased proportionally with increasing albumin serum levels (as the faster clearance of the free fraction resulted in lower serum levels, especially for IV) and with the increasing CCI (Charles Comorbidity Index). No significant difference in length of stay (LOS) and in survival was found between IV and PO administration (80 and 84%); however, the probability of survival was significantly lower (50%) in the case of NG administration.Conclusion and Relevance PO administration presented the highest Css levels. CrCl, albumin levels, and CCI were found to be influencing factors of Css. PO and IV administration resulted in similar clinical outcomes; however, the lower survival rate associated with higher Css values in the case of NG administration requires further investigation.Conflict of Interest No conflict of interest