Over the last decades, numerous papers have appeared-and still are appearing-that describe concentrations in tissues in an effort to predict the efficacy of an antimicrobial agent based on these concentrations and MICs for microorganisms. A common method is to use measurements of concentrations in tissue homogenates, comparing these with values derived from the corresponding blood samples and on that basis draw conclusions with respect to the potential clinical use of the drug. This approach is not justifiable for a number of reasons that includes both pharmacokinetic as well as pharmacodynamic causes. This way of presenting data with the derived conclusions is often misleading and may ultimately be harmful in patient care.

/pdf/tissue-concentrations-do-we-ever-learn-2uhpi3blsd.pdf

Tissue concentrations: do we ever learn?

https://repositorio-aberto.up.pt/bitstream/10216/67103/2/56957.pdf

The atypical pneumonias: clinical diagnosis and importance.

Gram-positive organisms, particularly staphylococci and streptococci, are responsible for the majority of bone and joint infections. Treatment of these infections can be difficult, usually involving a prolonged course of antibiotics, often with surgical intervention. The selection of antibiotics depends on sensitivity profile, patient tolerance and long-term goals, e.g. cure or suppression, but there are few randomized con- trolled trials in patients comparing efficacy of different antibiotics. Different degrees of bone penetration and clinical outcome for specific antibiotics, e.g. the β-lactams, clindamycin and quinolones, have been described, although the methodology in these studies is not standardized and findings cannot always be applied directly to patients. The effect of attaining minimum serum bactericidal concentrations in patients has also been studied but this is no longer routinely recommended in clinical practice. Comparative clinical trials are few but have demonstrated efficacy of oral fluoroquinolones in combination with either rifampicin or fusidic acid for selected Gram-positive infections. In the past decade, increasingly resistant organisms, e.g. methicillin- resistant Staphylococcus aureus and vancomycin-resistant enterococci have been recognized as causes of orthopaedic infection. Individual case reports describe successful treatment using the newer antibiotics, e.g. linezolid and quinupristin/dalfopristin, but results of clinical trials are awaited.

/pdf/antibiotic-treatment-of-gram-positive-bone-and-joint-4vl2p090e5.pdf

Antibiotic treatment of gram-positive bone and joint infections.

In spite of the development and wide use of antibiotics, pneumonia is still the leading cause of infection-related mortality worldwide (101), and antibiotic resistance in the major pathogens of pneumonia has become more frequent during the past several decades. In order to defeat and prevent antibiotic resistance, antibiotics need to be used based on pharmacokinetics (PK) and pharmacodynamics (PD) (6, 10, 35). With regard to the PK/PD of antibiotics, considerable effort has been devoted to directly measure the concentrations of antibiotics at infection sites, because the distributions of antibiotics may be different among a variety of tissues. However, even beyond the fact that these measurements are carried out in normal tissues, the techniques used for the measurement are variable in accuracy and reproducibility and the interpretation of their results is hindered by many confounding factors (74, 75). For pulmonary infections, concentrations of antibiotics in epithelial lining fluid (ELF) for extracellular pathogens and in alveolar macrophage (AM) cells for intracellular pathogens are thought to reflect antibiotic activity in pneumonia. Antibiotics whose concentrations are high at these extravascular sites, such as macrolides and fluoroquinolones, tend to be promoted for treatment of pulmonary infection over antibiotics like betalactams and aminoglycosides, even though clinical trials do not show differences in clinical outcome or even bacteriological response. In fact, it is less clear why the ratios of ELF to plasma concentrations are diverse between antibiotics and even between members of the same antibiotic class. The measured ELF-to-plasma concentration ratios may differ based on physicochemical characteristics intrinsic to the molecules. And also, as the ELF concentration of antibiotics is commonly measured by bronchoalveolar lavage (BAL), technical factors or errors in the method of measurement may create these differences. It is believed that these factors need to be clarified before the concept of ELF concentration should be connected to antibiotic outcomes such as bacterial eradication or clinical response. In the current review, data from published human studies were extracted and analyzed to interpret ELF concentrations of antibiotics measured by BAL, considering possible confounding factors.

Interpretation of antibiotic concentration ratios measured in epithelial lining fluid

The exposure-response relationship of anti-infective agents at the site of infection is currently being re-examined. Epithelial lining fluid (ELF) has been suggested as the site (compartment) of antimicrobial activity against lung infections caused by extracellular pathogens. There have been an extensive number of studies conducted during the past 20 years to determine drug penetration into ELF and to compare plasma and ELF concentrations of anti-infective agents. The majority of these studies estimated ELF drug concentrations by the method of urea dilution and involved either healthy adult subjects or patients undergoing diagnostic bronchoscopy. Antibacterial agents such as macrolides, ketolides, newer fluoroquinolones and oxazolidinones have ELF to plasma concentration ratios of >1. In comparison, β-lactams, aminoglycosides and glycopeptides have ELF to plasma concentration ratios of ≤1. Potential explanations (e.g. drug transporters, overestimation of the ELF volume, lysis of cells) for why these differences in ELF penetration occur among antibacterial classes need further investigation. The relationship between ELF concentrations and clinical outcomes has been under-studied. In vitro pharmacodynamic models, using simulated ELF and plasma concentrations, have been used to examine the eradication rates of resistant and susceptible pathogens and to explain why selected anti-infective agents (e.g. those with ELF to plasma concentration ratios of >1) are less likely to be associated with clinical treatment failures. Population pharmacokinetic modelling and Monte Carlo simulations have recently been used and permit ELF and plasma concentrations to be evaluated with regard to achievement of target attainment rates. These mathematical modelling techniques have also allowed further examination of drug doses and differences in the time courses of ELF and plasma concentrations as potential explanations for clinical and microbiological effects seen in clinical trials. Further studies are warranted in patients with lower respiratory tract infections to confirm and explore the relationships between ELF concentrations, clinical and microbiological outcomes, and pharmacodynamic parameters.

/pdf/penetration-of-anti-infective-agents-into-pulmonary-2s10dv01br.pdf

Penetration of anti-infective agents into pulmonary epithelial lining fluid: focus on antibacterial agents.

Telithromycin (HMR 3647) is the first member of a new family of antimicrobials, the ketolides, developed specifically for the treatment of community-acquired respiratory tract infections. Telithromycin has proven in vitro activity against both common and atypical respiratory tract pathogens. The penetration of telithromycin into bronchopulmonary tissues and subsequent elimination from these sites were evaluated in four groups (groups A, B, C, and D) of six healthy male subjects who received telithromycin at 800 mg once daily for 5 days. Subjects in groups A, B, C, and D underwent fiberoptic bronchoscopy and bronchoalveolar lavage 2, 8, 24, and 48 h after receipt of the last dose, respectively. The concentration of telithromycin in the alveolar macrophages, epithelial lining fluid (ELF), and plasma was determined by the agar diffusion method with Bacillus subtilis ATCC 6633 as the test organism. The concentration of telithromycin in alveolar macrophages markedly exceeded that in plasma, reaching up to 146 times the concentration in plasma 8 h after dosing (median concentration, 81 mg/liter). Telithromycin was retained in alveolar macrophages 24 h after dosing (median concentration, 23 mg/liter), and it was still quantifiable 48 h after dosing (median concentration, 2.15 mg/liter). Telithromycin median concentrations in ELF also markedly exceeded concentrations in plasma (median concentration in ELF, 3.7 mg/liter 8 h after dosing). Telithromycin achieves high and sustained concentrations in ELF and in alveolar macrophages, while it maintains adequate levels in plasma, providing an ideal pharmacokinetic profile for effective treatment of community-acquired respiratory tract infections caused by either common or atypical, including intracellular, respiratory tract pathogens.

Bronchopulmonary Disposition of the Ketolide Telithromycin (HMR 3647)

We compared the efficacies of quinupristin-dalfopristin (Q-D; 30 mg/kg of body weight every 8 h) and vancomycin (60 mg/kg twice daily), alone or in combination with rifampin (10 mg/kg twice daily), in a rabbit model of methicillin-resistant Staphylococcus aureus knee prosthesis infection. In contrast to vancomycin, Q-D significantly reduced the mean log10 CFU per gram of bone versus that for the controls. The combination of rifampin with either Q-D or vancomycin was significantly more effective than monotherapy.

Combination of Quinupristin-Dalfopristin (Synercid) and Rifampin Is Highly Synergistic in Experimental Staphylococcus aureus Joint Prosthesis Infection

Francoise Lemaitre

Papers

Bronchopulmonary Disposition of the Ketolide Telithromycin (HMR 3647)

Combination of Quinupristin-Dalfopristin (Synercid) and Rifampin Is Highly Synergistic in Experimental Staphylococcus aureus Joint Prosthesis Infection