Optimizing Aminoglycoside Therapy for Nosocomial Pneumonia Caused by Gram-Negative Bacteria

Abstract

Nosocomial pneumonia is a notable cause of morbidity and mortality and leads to increases in lengths of hospital stays and institutional expenditures. Aminoglycosides are used to treat patients with these infections, but few data on the doses and schedules required to achieve optimal therapeutic outcomes exist. We analyzed aminoglycoside treatment data for 78 patients with nosocomial pneumonia to determine if optimization of aminoglycoside pharmacodynamic parameters results in a more rapid therapeutic response (defined by outcome and days to leukocyte count resolution and temperature resolution). Cox proportional hazards, Classification and Regression Tree (CART), and logistic regression analyses were applied to the data. By all analyses, the first measured maximum concentration of drug in serum (C max)/MIC predicted days to temperature resolution and the second measured C max/MIC predicted days to leukocyte count resolution. For days to temperature resolution and leukocyte count resolution, CART analyses produced breakpoints, with an 89% success rate at 7 days of therapy for aC max/MIC of >4.7 and an 86% success rate at 7 days of therapy for a C max/MIC of >4.5, respectively. Logistic regression analyses predicted a 90% probability of temperature resolution and leukocyte count resolution by day 7 if aC max/MIC of ≥10 is achieved within the first 48 h of aminoglycoside therapy. Aggressive aminoglycoside dosing immediately followed by individualized pharmacokinetic monitoring would ensure that C max/MIC targets are achieved early in therapy. This would increase the probability of a rapid therapeutic response for pneumonia caused by gram-negative bacteria and potentially decreasing durations of parenteral antibiotic therapy, lengths of hospitalization, and institutional expenditures, a situation in which both the patient and the institution benefit.

Optimizing outcomes with antimicrobial therapy through pharmacodynamic profiling

“…With a C max : MIC ratio of Ն10, the potential for clinical response to aminoglycosides was maximized at more than 88%. Kashuba et al 15 showed that the first time an aminoglycoside was given to patients with nosocomial pneumonia, the probability of resolution of white blood cells and temperature by day 7 was Ն90% when the C max : MIC ratio was Ն10. 15 This means that if patients are dosed appropriately to obtain very high peak drug concentrations, the probability of a good outcome is maximized.…”

Appropriate Antibiotic Dosage Levels in the Treatment of Severe Sepsis and Septic Shock

“…In a retrospective study, C max /MIC between 8 and 10 was the major determinant for optimal antibacterial activity and clinical response (Table 1) [39]. Also, target Cmax/MIC ratio achieved in the early therapy increased the probability of a rapid therapeutic response for GNB pneumonia [40]. Because of this PD characteristic and a significant PAE, a single daily administration is the optimal solution to increase aminoglycoside antibacterial activity [24•].…”

Beatmungsassoziierte Pneumonien

“…Im Gegensatz dazu korreliert die Höhe der ᭤Spitzenspiegel von Aminoglykosiden mit dem klinischen Erfolg [97,137].Außerdem haben Aminoglykoside einen ausgeprägten postantibiotischen Effekt, sodass die Talspiegel ohne Beeinträchtigung der Wirksamkeit unterhalb der MHK liegen können. Die Nephrotoxizität der Aminoglykoside beruht auf einer Aufnahme in Epithelzellen des proximalen Tubulussystems, die bei Serumkonzentrationen von ca.…”

“…Obwohl pharmakokinetische Untersuchungen wichtig sind, müssen sie vorsichtig interpretiert werden: Zum einen berücksichtigen viele Spiegelmessungen nicht die heute gebräuchliche Einmalgabe von Aminoglykosiden und den postantibiotischen Effekt, zum anderen spiegeln Gewebekonzentrationen von Ciprofloxacin aufgrund seiner intrazellulären Anreicherung nicht direkt die Wirksamkeit gegen Pseudomonas wider. Die Wirksamkeit von Aminoglykosiden bei gramnegativen Pneumonieerregern ist klinisch belegt [97,137], allerdings treten sie aufgrund der Toxizitätsrisiken zunehmend in den Hintergrund.…”