A novel biomarker for pleural effusion diagnosis: Interleukin‐36γ in pleural fluid

BackgroundNumerous studies have described the critical importance of interleukin (IL) ‐36γ in host defense against lung infections, but it is unknown whether it plays a role in infectious pleural effusion (IPE). This study aimed to examine the levels of IL‐36γ in pleural effusions of different etiologies and evaluate the diagnostic accuracy of IL‐36γ in the differential diagnosis of IPE.MethodsA total of 112 individuals was enrolled in this research. IL‐36γ levels in pleural fluids of all 112 patients were measured by enzyme‐linked immunosorbent assay (ELISA). We also characterized these markers'' diagnostic values across various groups.ResultsPatients with tuberculous pleural effusion (TPE) and parapneumonic effusion (PPE) had exhibited markedly higher IL‐36γ levels in their pleural fluid than the malignant pleural effusion (MPE) and transudative effusion patients. Furthermore, the IL‐36γ concentrations in TPE patients were evidently higher than in uncomplicated parapneumonic effusion (UPPE) patients but significantly lower than in complicated parapneumonic effusion (CPPE)/empyema patients. Pleural fluid IL‐36γ is a useful marker to differentiate TPE from UPPE, at a cut‐off value for 657.5 pg/ml (area under the curve = 0.904, p < 0.0001) with 70.0% sensitivity and 95.7% specificity.ConclusionsThe elevated IL‐36γ in pleural effusion may be used as a novel biomarker for infectious pleural effusion diagnosis, particularly in patients with CPPE/empyema, and is a potentially promising biomarker to differentiate between TPE and UPPE.     

Pharmacokinetics of Liposomal Amphotericin B in Pleural Fluid

We report the penetration of liposomal amphotericin B into the pleural fluid of a patient with pulmonary zygomycosis and empyema. The ratio of area under the concentration-versus-time curve in pleural fluid (AUC_{pleural fluid}) to that in serum (AUC_serum) for liposomal amphotericin B over 24 h was 9.4%, with pleural fluid concentrations of 2.12 to 4.91 μg/ml. Given the relatively low level of intrapleural penetration of liposomal amphotericin B, chest tube drainage may be warranted for successful treatment of zygomycotic empyema.Invasion of the pleural space is a serious complication of fungal pneumonias (9). There is limited information on the penetration of liposomal amphotericin B (LAmB) into the pleural fluid of humans (20). We report herein a detailed pharmacokinetic sampling and analysis of the penetration of LAmB into the pleural fluid of a patient with pulmonary zygomycosis (mucormycosis) and empyema.     

Pleural effusions caused by infection

Diagnostic thoracentesis is imperative when pneumonia is accompanied by an effusion (parapneumonic effusion). Examination of the pleural fluid is the only way to differentiate empyema and complicated parapneumonic effusions from uncomplicated parapneumonic effusions, and this differentiation is vital in deciding whether chest tube drainage is needed. If the aspirated pleural fluid contains pus or bacteria, closed chest tube drainage and antibiotic therapy should be started promptly. The same management approach is indicated if the pleural fluid pH is less than 7.00 or the glucose level is less than 40 mg/ml, since these effusions almost invariably are complicated parapneumonic effusions that do not resolve without fluid drainage. If the pleural fluid pH is greater than 7.20 and glucose level is more than 40 mg/ml, antibiotic therapy alone will suffice. Management of parapneumonic effusions with a pH of 7.00 to 7.20 should be based on serial observations of clinical status and pleural fluid findings.     

Association between inflammatory mediators and the fibrinolysis system in infectious pleural effusions

The response of the fibrinolytic system to inflammatory mediators in empyema and complicated parapneumonic pleural effusions is still uncertain. We prospectively analysed 100 patients with pleural effusion: 25 with empyema or complicated parapneumonic effusion, 22 with tuberculous effusion, 28 with malignant effusion and 25 with transudate effusion. Inflammatory mediators, tumour necrosis factor-alpha (TNF-alpha), interleukin-8 (IL-8) and polymorphonuclear elastase, were measured in serum and pleural fluid. Fibrinolytic system parameters, plasminogen, tissue-type plasminogen activator (t-PA) and urokinase PA, PA inhibitor type 1 (PAI 1) and PAI type 2 concentrations and PAI 1 activity, were quantified in plasma and pleural fluid. The Wilcoxon signed-rank test was used to compare plasma and pleural values and to compare pleural values according to the aetiology of the effusion. The Pearson correlation coefficient was used to assess the relationship between fibrinolytic and inflammatory markers in pleural fluid. Significant differences were found between pleural and plasma fibrinolytic system levels. Pleural fluid exudates had higher fibrinolytic levels than transudates. Among exudates, tuberculous, empyema and complicated parapneumonic effusions demonstrated higher pleural PAI levels than malignant effusions, whereas t-PA was lowest in empyema and complicated parapneumonic pleural effusions. PAI concentrations correlated with TNF-alpha, IL-8 and polymorphonuclear elastase when all exudative effusions were analysed, but the association was not maintained in empyema and complicated parapneumonic effusions. A negative association found between t-PA and both IL-8 and polymorphonuclear elastase in exudative effusions was strongest in empyema and complicated parapneumonic effusions. Blockage of fibrin clearance in empyema and complicated parapneumonic effusions was associated with both enhanced levels of PAIs and decreased levels of t-PA.     

Pleural effusions in right-sided endocarditis: characteristics and pathophysiology.

The incidence, characteristics, and pathogenesis of pleural effusions in patients with right-sided endocarditis (RSE) are poorly defined. We have recently observed four patients with a history of intravenous drug abuse and bacteremia due to Staphylococcus aureus who had pleural effusions during an episode of RSE. We report the pleural fluid characteristics of five effusions in these four patients and attempt to define the pathogenesis of each. We found that (1) an exudative, sterile, serosanguineous, or bloody effusion is common in RSE, (2) empyema occurred in only one patient, and (3) transudative effusions due to CHF were not observed. Possible mechanisms of pleural fluid formation in RSE include parapneumonic effusion, septic pulmonary emboli with or without infarction, and empyema. Congestive heart failure does not appear to be a common cause of pleural effusion in pure right-sided endocarditis.     

An Open,Randomized, Single-Center,Crossover Pharmacokinetic Study of Meropenem after Intraperitoneal and Intravenous Administration in Patients Receiving Automated Peritoneal Dialysis

The objective of this study was to determine the pharmacokinetic profile of meropenem in automated peritoneal dialysis (APD) patients. In 6 patients without peritonitis, a single dose of 0.5 g of meropenem was applied intraperitoneally (i.p.) or intravenously (i.v.) and concentrations in serum and dialysate were measured at specified intervals over 24 h with high-performance liquid chromatography-mass spectrometry. The mean maximum concentrations of meropenem in serum (C_max) were 27.2 mg/liter (standard deviation [SD], ±6.9) and 10.1 mg/liter (SD, ±2.5) and in dialysate were 3.6 mg/liter (SD, ±2.3) and 185.8 mg/liter (SD, ±18.7) after i.v. and i.p. administrations, respectively. The mean areas under the curve from 0 to 24 (AUC_0–24) of meropenem in serum were 173.5 mg · h/liter (SD, ±29.7) and 141.4 mg · h/liter (SD, ±37.5) (P = 0.046) and in dialysate were 42.6 mg · h/liter (SD, ±20.0) and 623.4 mg · h/liter (SD, ±84.1) (P = 0.028) after i.v. and i.p. administrations, respectively. The ratios for dialysate exposure over plasma exposure after i.v. and i.p. treatments were 0.2 (SD, ±0.1) and 4.6 (SD, ±0.9), respectively (P = 0.031). A mean target value of 40% T>MIC (time for which the free meropenem concentration exceeds the MIC) for clinically relevant pathogens with EUCAST susceptibility breakpoints of 2 mg/liter was reached in serum after i.p. and i.v. administrations and in dialysate after i.p. but not after i.v. administration. The present data indicate that low i.p. exposure limits the i.v. use of meropenem for PD-associated peritonitis. In contrast, i.p. administration not only results in superior concentrations in dialysate but also might be used to treat systemic infections.     

Population Pharmacokinetics of Emtricitabine in HIV-1-Infected Adult Patients

The aims of this study were to describe emtricitabine concentration-time courses in a large population of HIV-1-infected adults, to evaluate the influence of renal function on emtricitabine disposition, and to assess current dosing adjustment recommendations. Emtricitabine blood plasma concentrations were determined from samples collected from 161 adult patients during therapeutic drug monitoring and measured by liquid chromatography coupled to tandem mass spectrometry. The data were analyzed by a population approach. Emtricitabine pharmacokinetics was best described by a two-compartment model in which the absorption and distribution rate constants were assumed to be equal. Typical population parameter estimates (interindividual variability) were apparent elimination and intercompartmental clearances of 15.1 liters/h (17.4%) and 5.75 liters/h, respectively, and apparent central and peripheral volumes of distribution of 42.3 liters and 55.4 liters, respectively. The apparent elimination clearance was significantly related to creatinine clearance (CL_CR), reflecting renal function. For 200 mg once a day (QD), the median area under the concentration-time curve over 24 h (AUC_0-24) was 12.5 mg · h/liter for patients with normal renal function (CL_CR, >80 ml/min), 14.7 mg · h/liter for patients with mild renal impairment (CL_CR, 79 to 50 ml/min), and 17.9 mg · h/liter for patients with moderate renal impairment (CL_CR, 49 to 30 ml/min). Simulations of the recommended dosing schemes for the oral solid form of emtricitabine (i.e., 200 mg per 48 h according to renal function) led to lower emtricitabine exposures for patients with moderate renal impairment (median AUC_0-48, 17.2 mg · h/liter) than for patients with normal renal function (median AUC_0-48, 25.6 mg · h/liter). Administering 18 ml of emtricitabine oral solution (10 mg/ml) QD to patients with moderate renal impairment should yield emtricitabine exposures similar to those in patients with normal renal function.     

144例老年胸腔积液病因分析

目的探讨老年胸腔积液的病因,了解老年良、恶性胸腔积液特点。方法对144例老年胸腔积液的临床资料进行回顾性分析。结果恶性胸腔积液,结核性胸膜炎,感染性胸腔积液（肺炎旁胸腔积液和脓胸）为老年胸腔积液主要病因;恶性胸腔积液中肺癌为主要病因。恶性胸腔积液患者的血清和胸水癌胚抗原水平显著高于良性胸腔积液患者（P〈0．005,P〈O．oo0。结论老年胸腔积液多为恶性,常合并其他慢诬疾病,易误诊或漏诊,应尽早作正确诊断。     

Pharmacokinetics of First-Line Tuberculosis Drugs in Tanzanian Patients

East Africa has a high tuberculosis (TB) incidence and mortality, yet there are very limited data on exposure to TB drugs in patients from this region. We therefore determined the pharmacokinetic characteristics of first-line TB drugs in Tanzanian patients using intensive pharmacokinetic sampling. In 20 adult TB patients, plasma concentrations were determined just before and at 1, 2, 3, 4, 6, 8, 10, and 24 h after observed drug intake with food to estimate the areas under the curve from 0 to 24 h (AUC_0–24) and peak plasma concentrations (C_max) of isoniazid, rifampin, pyrazinamide, and ethambutol. Acetylator status for isoniazid was assessed phenotypically using the isoniazid elimination half-life and the acetylisoniazid/isoniazid metabolic ratio at 3 h postdose. The geometric mean AUC_0–24s were as follows: isoniazid, 11.0 h · mg/liter; rifampin, 39.9 h · mg/liter; pyrazinamide, 344 h · mg/liter; and ethambutol, 20.2 h · mg/liter. The C_max was below the reference range for isoniazid in 10/19 patients and for rifampin in 7/20 patients. In none of the patients were the C_maxs for pyrazinamide and ethambutol below the reference range. Elimination half-life and metabolic ratio of isoniazid gave discordant phenotyping results in only 2/19 patients. A substantial proportion of patients had an isoniazid and/or rifampin C_max below the reference range. Intake of TB drugs with food may partly explain these low drug levels, but such a drug intake reflects common practice. The finding of low TB drug concentrations is concerning because low concentrations have been associated with worse treatment outcome in several other studies.     

Moxifloxacin's Limited Efficacy in the Hollow-Fiber Model of Mycobacterium abscessus Disease

Current regimens used to treat pulmonary Mycobacterium abscessus disease have limited efficacy. There is an urgent need for new drugs and optimized combinations and doses. We performed hollow-fiber-system studies in which M. abscessus was exposed to moxifloxacin lung concentration-time profiles similar to human doses of between 0 and 800 mg/day. The minimum bactericidal concentration and MIC were 8 and 2 mg/liter, respectively, in our M. abscessus strain, suggesting bactericidal activity. Measurement of the moxifloxacin concentrations in each hollow-fiber system revealed an elimination rate constant (k_el) of 0.11 ± 0.05 h⁻¹ (mean ± standard deviation) (half-life of 9.8 h). Inhibitory sigmoid maximal effect (E_max) modeling revealed that the highest E_max was 3.15 ± 1.84 log₁₀ CFU/ml on day 3, and the exposure mediating 50% of E_max (EC₅₀) was a 0- to 24-h area under the concentration time curve (AUC_0–24)-to-MIC ratio of 41.99 ± 31.78 (r² = 0.99). The EC₈₀ was an AUC_0–24/MIC ratio of 102.11. However, no moxifloxacin concentration killed the bacteria to burdens below the starting inoculum. There was regrowth beyond day 3 in all doses, with replacement by a resistant subpopulation that had an MIC of >32 mg/liter by the end of the experiment. A quadratic function best described the relationship between the AUC_0–24/MIC ratio and the moxifloxacin-resistant subpopulation. Monte Carlo simulations of 10,000 patients revealed that the 400- to 800-mg/day doses would achieve or exceed the EC₈₀ in ≤12.5% of patients. The moxifloxacin susceptibility breakpoint was 0.25 mg/liter, which means that almost all M. abscessus clinical strains are moxifloxacin resistant by these criteria. While moxifloxacin''s efficacy against M. abscessus was poor, formal combination therapy studies with moxifloxacin are still recommended.     

Pharmacokinetics of Second-Line Antituberculosis Drugs after Multiple Administrations in Healthy Volunteers

Therapeutic drug monitoring (TDM) of second-line antituberculosis drugs would allow for optimal individualized dosage adjustments and improve drug safety and therapeutic outcomes. To evaluate the pharmacokinetic (PK) characteristics of clinically relevant, multidrug treatment regimens and to improve the feasibility of TDM, we conducted an open-label, multiple-dosing study with 16 healthy subjects who were divided into two groups. Cycloserine (250 mg), p-aminosalicylic acid (PAS) (5.28 g), and prothionamide (250 mg) twice daily and pyrazinamide (1,500 mg) once daily were administered to both groups. Additionally, levofloxacin (750 mg) and streptomycin (1 g) once daily were administered to group 1 and moxifloxacin (400 mg) and kanamycin (1 g) once daily were administered to group 2. Blood samples for PK analysis were collected up to 24 h following the 5 days of drug administration. The PK parameters, including the maximum plasma concentration (C_max) and the area under the plasma concentration-time curve during a dosing interval at steady state (AUC_τ), were evaluated. The correlations between the PK parameters and the concentrations at each time point were analyzed. The mean C_max and AUC_τ, respectively, for each drug were as follows: cycloserine, 24.9 mg/liter and 242.3 mg · h/liter; PAS, 65.9 mg/liter and 326.5 mg · h/liter; prothionamide, 5.3 mg/liter and 22.1 mg · h/liter; levofloxacin, 6.6 mg/liter and 64.4 mg · h/liter; moxifloxacin, 4.7 mg/liter and 54.2 mg · h/liter; streptomycin, 42.0 mg/liter and 196.7 mg · h/liter; kanamycin, 34.5 mg/liter and 153.5 mg · h/liter. The results indicated that sampling at 1, 2.5, and 6 h postdosing is needed for TDM when all seven drugs are administered concomitantly. This study indicates that PK characteristics must be considered when prescribing optimal treatments for patients. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT02128308","term_id":"NCT02128308"}}NCT02128308.)     

Optimizing the Initial Amikacin Dosage in Adults

We report on the pharmacokinetics (PK) and pharmacodynamics (PD) of high-dose (>15 mg/kg of body weight per day) amikacin. A mean (standard deviation [SD]) maximum drug concentration in the serum (C_max) and 24-h area under the concentration-time curve (AUC₂₄) of 101 (49.4) mg/liter and 600 (387) mg · h/liter, respectively, were observed (n = 73) with 28.0 (8.47) mg/kg/day doses. An initial amikacin dose of 2,500 mg in adults weighing 40 kg to 200 kg with therapeutic drug monitoring to adjust the maintenance dose will optimize its PK and PD.     

Repeated-Dose Pharmacokinetics of an Oral Solution of Itraconazole in Infants and Children

The safety, tolerability, and pharmacokinetics of an oral solution of itraconazole and its active metabolite hydroxyitraconazole were investigated in an open multicenter study of 26 infants and children aged 6 months to 12 years with documented mucosal fungal infections or at risk for the development of invasive fungal disease. The most frequent underlying illness was acute lymphoblastic leukemia, except in the patients aged 6 months to 2 years, of whom six were liver transplant recipients. The patients were treated with itraconazole at a dosage of 5 mg/kg of body weight once daily for 2 weeks. Blood samples were taken after the first dose, during treatment, and up to 8 days after the last itraconazole dose. On day 1, the mean peak concentrations in plasma after the first and last doses (C_max) and areas under the concentration-time curve from 0 to 24 h (AUC_0–24) for itraconazole and hydroxyitraconazole were lower in the children aged 6 months to 2 years than in children aged 2 to 12 years but were comparable on day 14. The mean AUC_0–24-based accumulation factors of itraconazole and hydroxyitraconazole from day 1 to 14 ranged from 3.3 to 8.6 and 2.3 to 11.4, respectively. After 14 days of treatment, C_max, AUC_0–24, and the half-life, respectively, were (mean ± standard deviation) 571 ± 416 ng/ml, 6,930 ± 5,830 ng · h/ml, and 47 ± 55 h in the children aged 6 months to 2 years; 534 ± 431 ng/ml, 7,330 ± 5,420 ng · h/ml, and 30.6 ± 25.3 h in the children aged 2 to 5 years; and 631 ± 358 ng/ml, 8,770 ± 5,050 ng · h/ml, and 28.3 ± 9.6 h in the children aged 5 to 12 years. There was a tendency to have more frequent low minimum concentrations of the drugs in plasma for both itraconazole and hydroxyitraconazole for the children aged 6 months to 2 years. The oral bioavailability of the solubilizer hydroxypropyl-β-cyclodextrin was less than 1% in the majority of the patients. In conclusion, an itraconazole oral solution given at 5 mg/kg/day provides potentially therapeutic concentrations in plasma, which are, however, substantially lower than those attained in adult cancer patients, and is well tolerated and safe in infants and children.     

Rapid Drug Tolerance and Dramatic Sterilizing Effect of Moxifloxacin Monotherapy in a Novel Hollow-Fiber Model of Intracellular Mycobacterium kansasii Disease

Mycobacterium kansasii is the second most common mycobacterial cause of lung disease. Standard treatment consists of rifampin, isoniazid, and ethambutol for at least 12 months after negative sputum. Thus, shorter-duration therapies are needed. Moxifloxacin has good MICs for M. kansasii. However, good preclinical models to identify optimal doses currently are lacking. We developed a novel hollow fiber system model of intracellular M. kansasii infection. We indexed the efficacy of the standard combination regimen, which was a kill rate of −0.08 ± 0.05 log₁₀ CFU/ml/day (r² = 0.99). We next performed moxifloxacin dose-effect and dose-scheduling studies at a half-life of 11.1 ± 6.47 h. Some systems also were treated with the efflux pump inhibitor reserpine. The highest moxifloxacin exposure, as well as lower exposures plus reserpine, sterilized the cultures by day 7. This suggests that efflux pump-mediated tolerance at low ratios of the area under the concentration-time curve from 0 to 24 h (AUC_0–24) to MICs is an early bacterial defense mechanism but is overcome by higher exposures. The highest rate of moxifloxacin monotherapy sterilization was −0.82 ± 0.15 log₁₀ CFU/ml/day (r² = 0.97). The moxifloxacin exposure associated with 80% of maximal kill (EC₈₀) was an AUC_0–24/MIC of 317 (the non-protein-bound moxifloxacin AUC_0–24/MIC was 158.5). We performed Monte Carlo simulations of 10,000 patients in order to identify the moxifloxacin dose that would achieve or exceed the EC₈₀. The simulations revealed an optimal moxifloxacin dose of 800 mg a day. The MIC susceptibility breakpoint at this dose was 0.25 mg/liter. Thus, moxifloxacin, at high enough doses, is suitable to study in patients for the potential to add rapid sterilization to the standard regimen.     

Disposition and Elimination of Meropenem in Cerebrospinal Fluid of Hydrocephalic Patients with External Ventriculostomy

The broad antibacterial spectrum and the low incidence of seizures in meropenem-treated patients qualifies meropenem for therapy of bacterial meningitis. The present study evaluates concentrations in ventricular cerebrospinal fluid (CSF) in the absence of pronounced meningeal inflammation. Patients with occlusive hydrocephalus caused by cerebrovascular diseases, who had undergone external ventriculostomy (n = 10, age range 48 to 75 years), received 2 g of meropenem intravenously over 30 min. Serum and CSF were drawn repeatedly and analyzed by liquid chromatography-mass spectroscopy. Pharmacokinetics were determined by noncompartmental analysis. Maximum concentrations in serum were 84.7 ± 23.7 μg/ml. A CSF maximum (C_maxCSF) of 0.63 ± 0.50 μg/ml (mean ± standard deviation) was observed 4.1 ± 2.6 h after the end of the infusion. C_maxCSF and the area under the curve for CSF (AUC_CSF) depended on the AUC for serum (AUC_S), the CSF-to-serum albumin ratio, and the CSF leukocyte count. Elimination from CSF was considerably slower than from serum (half-life at β phase [t_1/2β] of 7.36 ± 2.89 h in CSF versus t_1/2β of 1.69 ± 0.60 h in serum). The AUC_CSF/AUC_S ratio for meropenem, as a measure of overall CSF penetration, was 0.047 ± 0.022. The AUC_CSF/AUC_S ratio for meropenem was similar to that for other β-lactam antibiotics with a low binding to serum proteins. The concentration maxima of meropenem in ventricular CSF observed in this study are high enough to kill fully susceptible pathogens. They may not be sufficient to kill bacteria with a reduced sensitivity to carbapenems, although clinical success has been reported for patients with meningitis caused by penicillin-resistant pneumococci and Pseudomonas aeruginosa.     

Association between Vancomycin Trough Concentration and Area under the Concentration-Time Curve in Neonates

National treatment guidelines for invasive methicillin-resistant Staphylococcus aureus (MRSA) infections recommend targeting a vancomycin 24-h area under the concentration-time curve (AUC_0–24)-to-MIC ratio of >400. The range of vancomycin trough concentrations that best predicts an AUC_0–24 of >400 in neonates is not known. This understanding would help clarify target trough concentrations in neonates when treating MRSA. A retrospective chart review from a level III neonatal intensive care unit was performed to identify neonates treated with vancomycin over a 5-year period. Vancomycin concentrations and clinical covariates were utilized to develop a one-compartment population pharmacokinetic model and examine the relationships between trough and AUC_0–24 in the study neonates. Monte Carlo simulations were performed to examine the effect of dose, postmenstrual age (PMA), and serum creatinine level on trough and AUC_0–24 achievement. A total of 1,702 vancomycin concentrations from 249 neonates were available for analysis. The median (interquartile range) PMA was 39 weeks (32 to 42 weeks) and weight was 2.9 kg (1.6 to 3.7 kg). Vancomycin clearance was predicted by weight, PMA, and serum creatinine level. At a trough of 10 mg/liter, 89% of the study neonates had an AUC_0–24 of >400. Monte Carlo simulations demonstrated that troughs ranging from 7 to 11 mg/liter were highly predictive of an AUC_0–24 of >400 across a range of PMA, serum creatinine levels, and vancomycin doses. However, a trough of ≥10 mg/liter was not readily achieved in most simulated subgroups using routine starting doses. Higher starting doses frequently resulted in troughs of >20 mg/liter. A vancomycin trough of ∼10 mg/liter is likely adequate for most neonates with invasive MRSA infections based on considerations of the AUC_0–24. Due to pharmacokinetic and clinical heterogeneity in neonates, consistently achieving this target vancomycin exposure with routine starting doses is difficult. More robust clinical dosing support tools are needed to help clinicians with dose individualization.     

Phase I,Open-Label,Safety and Pharmacokinetic Study To Assess Bronchopulmonary Disposition of Intravenous Eravacycline in Healthy Men and Women

This study evaluated the pulmonary disposition of eravacycline in 20 healthy adult volunteers receiving 1.0 mg of eravacycline/kg intravenously every 12 h for a total of seven doses over 4 days. Plasma samples were collected at 0, 1, 2, 4, 6, and 12 h on day 4, with each subject randomized to undergo a single bronchoalveolar lavage (BAL) at 2, 4, 6, or 12 h. Drug concentrations in plasma, BAL fluid, and alveolar macrophages (AM) were determined by liquid chromatography-tandem mass spectrometry, and the urea correction method was used to calculate epithelial lining fluid (ELF) concentrations. Pharmacokinetic parameters were estimated by noncompartmental methods. Penetration for ELF and AM was calculated by using a ratio of the area under the concentration time curve (AUC_0–12) for each respective parameter against free drug AUC (fAUC_0–12) in plasma. The total AUC_0–12 in plasma was 4.56 ± 0.94 μg·h/ml with a mean fAUC_0–12 of 0.77 ± 0.14 μg·h/ml. The eravacycline concentrations in ELF and AM at 2, 4, 6, and 12 h were means ± the standard deviations (μg/ml) of 0.70 ± 0.30, 0.57 ± 0.20, 0.34 ± 0.16, and 0.25 ± 0.13 with a penetration ratio of 6.44 and 8.25 ± 4.55, 5.15 ± 1.25, 1.77 ± 0.64, and 1.42 ± 1.45 with a penetration ratio of 51.63, respectively. The eravacycline concentrations in the ELF and AM achieved greater levels than plasma by 6- and 50-fold, respectively, supporting further study of eravacycline for patients with respiratory infections.     

Effect of Coadministered Fat on the Tolerability,Safety, and Pharmacokinetic Properties of Dihydroartemisinin-Piperaquine in Papua New Guinean Children with Uncomplicated Malaria

Coadministration of dihydroartemisinin-piperaquine (DHA-PQ) with fat may improve bioavailability and antimalarial efficacy, but it might also increase toxicity. There have been no studies of these potential effects in the pediatric age group. The tolerability, safety, efficacy, and pharmacokinetics of DHA-PQ administered with or without 8.5 g fat were investigated in 30 Papua New Guinean children aged 5 to 10 years diagnosed with uncomplicated falciparum malaria. Three daily 2.5:11.5-mg-base/kg doses were given with water (n = 14, group A) or milk (n = 16, group B), with regular clinical/laboratory assessment and blood sampling over 42 days. Plasma PQ was assayed by high-performance liquid chromatography with UV detection, and DHA was assayed using liquid chromatography-mass spectrometry. Compartmental pharmacokinetic models for PQ and DHA were developed using a population-based approach. DHA-PQ was generally well tolerated, and initial fever and parasite clearance were prompt. There were no differences in the areas under the concentration-time curve (AUC_0–∞) for PQ (median, 41,906 versus 36,752 μg · h/liter in groups A and B, respectively; P = 0.24) or DHA (4,047 versus 4,190 μg · h/liter; P = 0.67). There were also no significant between-group differences in prolongation of the corrected electrocardiographic QT interval (QT_c) initially during follow-up, but the QT_c tended to be higher in group B children at 24 h (mean ± standard deviation [SD], 15 ± 10 versus 6 ± 15 ms^0.5 in group A, P = 0.067) and 168 h (10 ± 18 versus 1 ± 23 ms^0.5, P = 0.24) when plasma PQ concentrations were relatively low. A small amount of fat does not change the bioavailability of DHA-PQ in children, but a delayed persistent effect on ventricular repolarization cannot be excluded.     

The changing pathogens of complicated parapneumonic effusions or empyemas in a medical intensive care unit

Objectives To assess the incidence, pathogens, and outcome of complicated parapneumonic effusions or empyemas in a medical intensive care unit (MICU) patients with pleural effusions. Design and setting Prospective study of febrile MICU patients with pleural effusion carried out in a tertiary care hospital between April 2001 and September 2003. Patients The study included 175 patients with a temperature above 38° for more than 8 h with evidence of pleural effusion confirmed by chest radiography and ultrasound. Intervention Routine thoracentesis and effusion cultures. Results The prevalence of complicated parapneumonic effusions or thoracic empyemas in febrile MICU patients with pleural effusions was 45% (78/175). A total of 78 micro-organisms were isolated from the pleural fluid of 58 patients (positive microbiological culture 74%) including aerobic Gram-negative (n = 45), aerobic Gram-positive (n = 23), anaerobic (n = 5), Myobacterium tuberculosis (n = 3), and Candida (n = 2). The infection-related mortality rate of complicated parapneumonic effusions or empyemic patients in the MICU was 41% (32/78). Conclusion The development of complicated parapneumonic effusions or thoracic empyemas in MICU patients is a high-mortality disease. The increasing incidence of aerobic Gram-negative pathogens in empyema has become a more urgent problem. Electronic supplementary material The electronic reference of this article is . The online full-text version of this article includes electronic supplementary material. This material is available to authorised users and can be accessed by means of the ESM button beneath the abstract or in the structured full-text article. To cite or link to this article you can use the above reference.     

Emtricitabine Seminal Plasma and Blood Plasma Population Pharmacokinetics in HIV-Infected Men in the EVARIST ANRS-EP 49 Study

We aimed to describe blood plasma (BP) and seminal plasma (SP) pharmacokinetics of emtricitabine (FTC) in HIV-1-infected men, assess its penetration in the male genital tract, and evaluate its impact on seminal plasma HIV load (spVL) detection. Men from the EVARIST ANRS EP49 study receiving combined antiretroviral therapy with FTC and with suppressed BP viral load were included in the study. A total of 236 and 209 FTC BP and SP concentrations, respectively, were available. A population pharmacokinetic model was developed with Monolix 4.1.4. The impact of FTC seminal exposure on spVL detection was explored by receiver operating characteristic (ROC) curves and mixed-effects logistic regressions. FTC BP pharmacokinetics was described by a two-compartment model. The addition of an effect compartment with different input and output constants best described FTC SP pharmacokinetics. No covariates were found to explain the variability in SP. FTC exposures (area under the concentration-time curve from 0 to 24 h [AUC_0–24]) were higher in SP than in BP (median AUC_0–24, 38.04 and 12.95 mg · liter⁻¹ · h, respectively). The median (range) SP-to-BP AUC_0–24 ratio was 2.91 (0.84 to 10.08). Less than 1% of FTC AUC_0–24 ratios were lower than 1. The impact of FTC SP AUC_0–24 or FTC SP-to-BP AUC_0–24 ratio on spVL detection was not significant (P = 0.943 or 0.893, respectively). This is the first population model describing FTC pharmacokinetics simultaneously in both BP and SP. FTC distributes well in the male genital tract with higher FTC concentrations in SP than in BP. FTC seminal plasma exposures were considered efficient in the majority of men.