Accumulation and activity of cethromycin (ABT-773) within human polymorphonuclear leucocytes

Antimicrobial therapy of infections with Staphylococcus aureus can pose a challenge due to slow response to therapy and recurrence of infection. These treatment difficulties can partly be explained by intracellular survival of staphylococci, which is why the intracellular activity of antistaphylococcal compounds has received increased attention within recent years. The intracellular activity of plectasin, an antimicrobial peptide, against S. aureus was determined both in vitro and in vivo. In vitro studies using THP-1 monocytes showed that some intracellular antibacterial activity of plectasin was maintained (maximal relative efficacy [E max ], 1.0-to 1.3-log reduction in CFU) even though efficacy was inferior to that of extracellular killing (E max , >4.5-log CFU reduction). Animal studies included a novel use of the mouse peritonitis model, exploiting extra-and intracellular differentiation assays, and assessment of the correlations between activity and pharmacokinetic (PK) parameters. The intracellular activity of plectasin was in accordance with the in vitro studies, with an E max of a 1.1-log CFU reduction. The parameter most important for activity was fC peak /MIC, where fC peak is the free peak concentration. These findings stress the importance of performing studies of extra-and intracellular activity since these features cannot be predicted from traditional MIC and killing kinetic studies. Application of both the THP-1 and the mouse peritonitis models showed that the in vitro results were similar to findings in the in vivo model with respect to demonstration of intracellular activity. Therefore the in vitro model was a good screening model for intracellular activity. However, animal models should be applied if further information on activity, PK/pharmacodynamic parameters, and optimal dosing regimens is required.

Section: Discussionmentioning

confidence: 90%

mentioning

confidence: 99%

Plectasin Shows Intracellular Activity against Staphylococcus aureus in Human THP-1 Monocytes and in a Mouse Peritonitis Model

Brinch

Sandberg

Baudoux

et al. 2009

“…Actually, the strain studied here has been widely used for the evaluation of the in vitro activities of new antibiotics in broth (61) as well as in phagocytes (24). The choice of a unique, well-characterized strain was actually essential for addressing the question of antibiotic intracellular activity per se and avoiding the blurring of the results because of other factors that can modulate the intracellular response to antibiotics, such as virulence and variations in the expression of resistance mechanisms.…”

mentioning

confidence: 99%

Pharmacodynamic Evaluation of the Intracellular Activities of Antibiotics against Staphylococcus aureus in a Model of THP-1 Macrophages

Barcia-Macay

Seral

Mingeot‐Leclercq

et al. 2006

232

341

Staphylococcus aureus, which often causes chronic or relapsing diseases (68), is reported to persist as an opportunistic intracellular organism both in vitro and in vivo (8,10,18,30,31,34,39). Antibiotic treatments should therefore be optimized not only toward the extracellular forms of S. aureus but also toward the intracellular forms of S. aureus to avoid creating a niche where bacteria may persist, cause cell alterations, and possibly, be selected for resistance if they are exposed to subtherapeutic concentrations (1). A large body of literature on the activities of antibiotics against intracellular S. aureus in various cellular models is available (see references 54, 66, 67, and 70 for reviews). Yet, many of these studies yield contradictory results, and we still lack a clear understanding of which parameters are truly critical for the expression of antibiotic activity in the intracellular milieu (11). In a previous study, we measured the activities of selected antibiotics characterized by a fair to high level of cellular accumulation against intracellular S. aureus in a model of unstimulated murine J774 macrophages (57). We observed that cellular accumulation was only partially and nonconsistently predictive of activity. In a subsequent pilot study, performed with human THP-1 macrophages, we also noted that ␤-lactams, which notoriously do not accumulate in cells, actually showed significant activity against intracellular S. aureus when their extracellular concentration was brought to a sufficiently high but still clinically meaningful level (36). This triggered us to broaden and systematize our approach. For this purpose, we selected typical representatives of seven classes of antibiotics with known activities against S. aureus and included in commonly used guidelines for the handling of staphylococcal infections. We concentrated our effort on THP-1 macrophages because these cells present many of the characteristics of human monocytes while forming a homogeneous and reproducible population (6). THP-1 macrophages have been successfully used in various studies aimed at characterizing the interactions between S. aureus and macrophages in a clinical context (19,28,49) and to analyze the potential relationship between the accumulation of antibiotics in cells and intracellular activity (48). In contrast to many other models, however, we explored a large array of extracellular concentrations (including the range observed in the serum of patients receiving conventional doses) and used incubation times up to 24 h. Our purpose, indeed, was to analyze the pharmacodynamic parameters governing the activities of these antibiotics against intra-* Corresponding author. Mailing address:

“…We did not directly measure intracellular antimicrobial activity in AC, and the presence of the drug does not confirm antimicrobial activity. However, intracellular cethromycin has been reported to accumulate and to retain its antimicrobial activity within polymorphonuclear cells (13). A larger dose would also yield C max ELF concentrations that would likely exceed the MIC 90 for H. influenzae; however, the determination of the duration above MIC 90 and other pharmacodynamic parameters requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

Steady-State Plasma and Intrapulmonary Pharmacokinetics and Pharmacodynamics of Cethromycin

Conte

Golden²,

Kipps³

et al. 2004

The objective of this study was to determine the steady-state plasma and intrapulmonary pharmacokinetic parameters of orally administered cethromycin in healthy volunteers. The study design included administering 150 or 300 mg of cethromycin once daily to 25 or 35 healthy adult subjects, respectively, for a total of five doses. Standardized and timed bronchoalveolar lavage (BAL) was performed after the last dose. Blood was obtained for drug assay prior to the first and last dose, at multiple time points following the last dose, and at the time of BAL. Cethromycin was measured in plasma, BAL, and alveolar cell (AC) by using a combined high-performance liquid chromatography-mass spectrometric technique. Plasma, epithelial lining fluid (ELF), and AC pharmacokinetics were derived by noncompartmental methods. C max /90% minimum inhibitory concentration (MIC 90 ) ratios, area under the concentration-time curve (AUC)/MIC 90 ratios, intrapulmonary drug exposure ratios, and percent time above MIC 90 during the dosing interval (%T > MIC 90 ) were calculated for recently reported respiratory pathogens. The kinetics were nonlinear, i.e., not proportional to dose. In the 150-mg-dose group, the C max (mean ؎ standard deviations), AUC 0-24 , and half-life for plasma were 0.181 ؎ 0.084 g/ml, 0.902 ؎ 0.469 g · h/ml, and 4.85 ؎ 1.10 h, respectively; for ELF the values were 0.9 ؎ 0.2 g/ml, 11.4 g · h/ml, and 6.43 h, respectively; for AC the values were 12.7 ؎ 6.4 g/ml, 160.8 g · h/ml, and 10.0 h, respectively. In the 300-mg-dose group, the C max (mean ؎ standard deviations), AUC 0-24 , and half-life for plasma were 0.500 ؎ 0.168 g/ml, 3.067 ؎ 1.205 g · h/ml, and 4.94 ؎ 0.66 h, respectively; for ELF the values were 2.7 ؎ 2.0 g/ml, 24.15 g · h/ml, and 5.26 h, respectively; for AC the values were 55.4 ؎ 38.7 g/ml, 636.2 g · h/ml, and 11.6 h, respectively. We concluded that the C max /MIC 90 ratios, AUC/MIC 90 ratios, %T > MIC 90 values, and extended plasma and intrapulmonary half-lives provide a pharmacokinetic rationale for once-daily administration and are favorable for the treatment of cethromycin-susceptible pulmonary infections.Cethromycin is an investigational ketolide antibiotic that is active against common respiratory pathogens, such as Streptococcus pneumoniae, Mycoplasma pneumoniae, Chlamydia pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, group A streptococci, and Streptococcus viridans (14,15,17,18,29). Cethromycin is also active, in vitro and in a murine model, against Mycobacterium avium infection (10), and related macrolides are active against other mycobacteria (12, 21). Doses of cethromycin ranging from 100 to 1,200 mg have been administered to humans in phase I clinical studies. The plasma elimination half-life (t 1/2 ) ranges from 3.6 to 6.7 h (R. S. Pradhan, L. E. Gustavson, D. D. Londo, Y. Shang, J. Zhang, and M. Paris, Abstr. 40th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 2138, 2000). The maximum concentration of drug in serum (C max ), area under the concentration-time curve from 0 to 24...