Jiping Wang

BACKGROUND: Polymyxin B is a last-line therapy for multidrug-resistant gram-negative bacteria. There is a dearth of pharmacokinetic data to guide dosing in critically ill patients. METHODS: Twenty-four critically ill patients were enrolled and blood/urine samples were collected over a dosing interval at steady state. Polymyxin B concentrations were measured by liquid chromatography-tandem mass spectrometry. Population pharmacokinetic analysis and Monte Carlo simulations were conducted. RESULTS: Twenty-four patients aged 21-87 years received intravenous polymyxin B (0.45-3.38 mg/kg/day). Two patients were on continuous hemodialysis, and creatinine clearance in the other patients was 10-143 mL/min. Even with very diverse demographics, the total body clearance of polymyxin B when scaled by total body weight (population mean, 0.0276 L/hour/kg) showed remarkably low interindividual variability (32.4% coefficient of variation). Polymyxin B was predominantly nonrenally cleared with median urinary recovery of 4.04%. Polymyxin B total body clearance did not show any relationship with creatinine clearance (r(2) = 0.008), APACHE II score, or age. Median unbound fraction in plasma was 0.42. Monte Carlo simulations revealed the importance of initiating therapeutic regimens with a loading dose. CONCLUSIONS: Our study showed that doses of intravenous polymyxin B are best scaled by total body weight. Importantly, dosage selection of this drug should not be based on renal function.

BACKGROUND: Examination was performed on pathologic material from patients enrolled in the National Surgical Adjuvant Breast Project (NSABP) protocol B-18, in which the clinical effects of preoperative (preop) and postoperative (postop) doxorubicin and cyclophosphamide (AC) were compared. METHODS: Of the total number of 1523 patients, 1234 patients (81%) were in the pathologically evaluable cohort. Six hundred twenty-six patients had been randomized prospectively to receive AC postop and 608 had been randomized to receive AC preop. Preentry diagnosis was made by fine-needle aspiration (FNA) and/or Tru-cut biopsy (TC). AC-induced and other pathologic changes were identified, and their relation to pathologic response and overall survival (OS) and disease-free survival (DFS) was determined. Frequencies of the number of lymph node metastases, their size, stromal reaction, and extracapsular extension (ECE) were compared in the two treatment groups, as was their correlation with OS and DFS. Survival estimates were based on 9 years of follow-up. RESULTS: Approximately 13% of primary breast carcinoma cases exhibited both a clinical complete response (cCR) and a pathologic complete response (absence of invasive tumor [pCR]) to preop AC. An additional 7% of patients exhibited a pCR in the absence of a cCR. A pCR occurred in 38% of those patients determined to have achieved a cCR. Poor nuclear grade of the tumor cells in the pre-entry FNA and/or TC specimens significantly predicted a pCR. Patients with the latter exhibited a better OS and DFS compared with those with a pathologic partial response (presence of sparse invasive tumor [pPR]) or no pathologic response (pNR). Epithelial alterations considered to be induced in tumors by preop AC were comprised of types 1 and 2 giant cells with meganuclei, apocrine metaplasia, and cytoplasmic vacuolation. They had a high degree of specificity (range, 86-99%) but a low sensitivity (range, 7-38%). All were predictive of a pPR and were found to be related adversely to OS and DFS. A fibrous stromal reaction noted in tumors or their putative sites in the preop group was found to have only modest degrees of specificity (63%) and sensitivity (74%). Moderate/marked sclerosis of basement membranes of the ductal and ductular elements of the terminal ductolobular unit (TDLU) was significantly more frequent in nontumor-bearing areas of breasts from patients in the preop treatment group compared with those in the postop treatment group (67% vs. 48%; P < 0.0001). The degrees of change in the TDLU in patients in the postop treatment group were found to be unrelated to age. Lymphatic tumor extension in the primary tumor, as well as a positive lymph node status, were less frequent in the preop treatment group compared with the postop treatment group. The OS and DFS were nearly identical in both treatment groups, being 69% and 55% and 70% and 53% in the preop and postop treatment groups, respectively, at 9 years. A fibrous stromal response to lymph node metastases was found to be significant for DFS but not OS. ECE was similar in both groups (55% vs. 48%; P = 0.12). Only 1% of ECE was found to be related to axillary failure in both treatment arms combined. There was no significant difference with regard to the parameters of survival for patients in the postop treatment group whose lymph nodes contained micrometastases (< 2.0 mm) or mini micrometastases (< 1.0 mm) (the latter detected immunohistochemically with anticytokeratin), and a true-negative lymph node status (not immunohistochemically converted to positive). Conversely, there was no apparent difference with regard to OS in preop treated patients with lymph node micrometastases, mini micrometastases, and macrometastases (P = 0.19). Those with mini micrometastases had a significantly worse OS compared with those with a true-negative lymph node status (P = 0.0007). DFS remained worse for patients in that treatment group with micrometastases and mini micrometastases compared with those with negative lymph nodes, although it was better than that for patients with macrometastases (P = 0.02). CONCLUSIONS: Poor nuclear grade of tumor cells in the preentry FNA or TC specimens in the preop group was predictive of a pCR. AC-induced meganuclear giant cells and apocrine changes and nuclear and histologic grades of the primary tumors also were found to be prognostically significant in patients in the preop treatment group, and the latter two variables were found to be significant for those patients in the postop treatment group. No evidence was found to support the need for axillary lymph node radiation for ECE of lymph node metastases. Extended pathologic or immunohistochemical procedures also appear to be unnecessary for the detection of lymph node mini micrometastases, at least when traditional postop chemotherapy is used. The adverse relation between such small metastases and OS and DFS after preop AC appears to be related to the timing of the chemotherapy administration rather than any pathobiologic reasons.

OBJECTIVES: This study investigated the exposure-response relationships between unbound colistin in plasma and antibacterial activity in mouse thigh and lung infections. METHODS: Dose fractionation studies (subcutaneous colistin sulphate at 1.25-160 mg/kg/day) were conducted in neutropenic mice in which infection (three strains of Pseudomonas aeruginosa and three strains of Acinetobacter baumannii) had been produced by intramuscular thigh injection or aerosol lung delivery. Bacterial burden was measured at 24 h after initiation of colistin treatment. Plasma protein binding was measured by rapid equilibrium dialysis and ultracentrifugation. The inhibitory sigmoid dose-effect model and non-linear least squares regression were employed to determine the relationship between exposure to unbound colistin and efficacy. RESULTS: Plasma binding of colistin was constant over the concentration range ∼2-50 mg/L. The average ± SD percentage bound for all concentrations was 92.9 ± 3.3% by ultracentrifugation and 90.4 ± 1.1% by equilibrium dialysis. In the thigh model, across all six strains the antibacterial effect of colistin was well correlated with fAUC/MIC (R(2) = 0.82-0.94 for P. aeruginosa and R(2) = 0.84-0.95 for A. baumannii). Target values of fAUC/MIC for 2 log10 kill were 7.4-13.7 for P. aeruginosa and 7.4-17.6 for A. baumannii. In the lung model, for only two strains of P. aeruginosa and one strain of A. baumannii was it possible to achieve 2 log10 kill (fAUC/MIC target values 36.8-105), even at the highest colistin dose tolerated by mice. This dose was not able to achieve bacteriostasis for the other two strains of A. baumannii. CONCLUSIONS: Colistin was substantially less effective in lung infection. The pharmacokinetic/pharmacodynamic target values will assist in the design of optimized dosage regimens.