Jonathan Rosen

Fosfomycin/Tobramycin for Inhalation in Patients with Cystic Fibrosis with Pseudomonas Airway Infection

RATIONALE Fosfomycin/tobramycin for inhalation (FTI), a unique, broad-spectrum antibiotic combination, may have therapeutic potential for patients with cystic fibrosis (CF). OBJECTIVES To evaluate safety and efficacy of FTI (160/40 mg or 80/20 mg), administered twice daily for 28 days versus placebo, in patients greater than or equal to 18 years of age, with CF, chronic Pseudomonas aeruginosa (PA) airway infection, and FEV(1) greater than or equal to 25% and less than or equal to 75% predicted. METHODS This double-blind, placebo-controlled, multicenter study assessed whether FTI/placebo maintained FEV(1) % predicted improvements achieved following a 28-day, open-label, run-in course of aztreonam for inhalation solution (AZLI). MEASUREMENTS AND MAIN RESULTS A total of 119 patients were randomized to FTI (160/40 mg: n = 41; 80/20 mg: n = 38) or placebo (n = 40). Mean age was 32 years and mean FEV(1) was 49% predicted at screening. Relative improvements in FEV(1) % predicted achieved by the AZLI run-in were maintained in FTI groups compared with placebo (160/40 mg vs. placebo: 6.2% treatment difference favoring FTI, P = 0.002 [primary endpoint]; 80/20 mg vs. placebo: 7.5% treatment difference favoring FTI, P < 0.001). The treatment effect on mean PA sputum density was statistically significant for the FTI 80/20 mg group versus placebo (-1.04 log(10) PA colony-forming units/g sputum difference, favoring FTI; P = 0.01). Adverse events, primarily cough, were consistent with CF disease. Respiratory events, including dyspnea and wheezing, were less common with FTI 80/20 mg than FTI 160/40 mg. No clinically significant differences between groups were reported for laboratory values. CONCLUSIONS FTI maintained the substantial improvements in FEV(1) % predicted achieved during the AZLI run-in and was well tolerated. FTI is a promising antipseudomonal therapy for patients with CF.

Acute eosinophilic pneumonia associated with shock

OBJECTIVE To describe an unusual case of acute eosinophilic pneumonia (AEP) associated with hemodynamic instability. DESIGN Case report, clinical. SETTINGS Tertiary care intensive care unit (ICU). PATIENT A single patient admitted to the ICU. INTERVENTIONS Intravenous corticosteroids. MEASUREMENTS AND MAIN RESULTS Resolution of distributive shock and respiratory failure. CONCLUSIONS AEP with respiratory failure was first reported in 1989 as a distinct clinical entity. Patients with this variant of eosinophilic lung disease develop acute hypoxemic respiratory failure with a rapid response to treatment with corticosteroids, The characteristic feature of this syndrome is a predominance of eosinophils found in bronchoalveolar lavage fluid and lung biopsy. Despite the increasing number of reported cases, to our knowledge, distributive shock has not been reported as a feature of AEP. We report a unique case of AEP associated with shock and review the pertinent literature.

Pharmacokinetics and pharmacodynamics of extended-infusion piperacillin/tazobactam in adult patients with cystic fibrosis-related acute pulmonary exacerbations

OBJECTIVES Given the high frequency of acute pulmonary exacerbations due to Pseudomonas aeruginosa in patients with cystic fibrosis (CF), piperacillin/tazobactam is commonly used in empirical regimens. While extended-infusion piperacillin/tazobactam has been employed as one strategy to optimize this agents pharmacodynamics, this approach has not been well characterized in patients with CF. The objectives of this study were to characterize the pharmacokinetics and pharmacodynamics of extended-infusion piperacillin/tazobactam in adult patients with CF and derive optimized piperacillin/tazobactam dosing recommendations. METHODS Six serum samples were collected from nine adult patients with CF hospitalized for acute pulmonary exacerbations who received 3/0.375 g of piperacillin/tazobactam intravenously for 4 h every 8 h. Population pharmacokinetic models were fitted to the data utilizing first-order, Michaelis-Menten (MM) and parallel first-order/MM clearance. Monte Carlo simulations were performed to determine the probability of target attainment (PTA) for regimens where free piperacillin concentrations were above the MIC for at least 50% of the dosing interval. RESULTS The model incorporating MM clearance best described the data. Results of our simulation revealed that piperacillin/tazobactam dosed at 3-4 g for 30 min every 6-8 h led to <90% PTA against MIC values >4 mg/L. More intensive prolonged infusion regimens than are commonly used in practice, such as continuous infusions or 3 h infusions every 6 h, were needed to maximize the PTA for MICs ≥ 8 mg/L. CONCLUSIONS Intensive prolonged infusion regimens are the best option to ensure optimal exposures against most susceptible isolates in adult patients with CF.

Pharmacokinetics and Pharmacodynamics of Once-Daily Administration of Intravenous Tobramycin in Adult Patients with Cystic Fibrosis Hospitalized for an Acute Pulmonary Exacerbation

ABSTRACT The serum pharmacokinetic profile of intravenous (i.v.) tobramycin administration was characterized for a sample of nine adult patients with cystic fibrosis (CF) who were hospitalized for an acute pulmonary exacerbation. Current recommended i.v. tobramycin dosing protocols are predicted through modeling and simulation to be suboptimal. Empirical tobramycin regimens of ≥15 mg/kg of body weight administered i.v. once daily should be evaluated for adult patients with CF to optimize outcomes.

Effect of a face mask on respiratory water loss during sleep in cold conditions

The purpose of this study was to test the hypothesis that a heat-and-moisture-retaining mask would result in a significant decrease in respiratory water loss among healthy subjects sleeping in a cold environment. The study was done in a backyard near a tertiary-care center during winter nights with ambient temperatures of less than 0 degrees C. Subjects were 10 healthy volunteers, 8 males and 2 females, aged 23-40 years, with a mean of 30.9 years. In a crossover design study, subjects slept alone in mountaineering tents on two nights (8 h each night) using sleeping bags and ground insulation. On one night, they wore heat-and-moisture-retaining masks designed for cold weather exercise. On the other night, they wore no mask. Subjects were weighed before and after each session to obtain an estimate of respiratory water loss. Comparisons were made of weight loss with and without the mask. We found the use of the masks resulted in decreased weight loss in all but one subject. The mean reduction in weight loss was 0.13 kg (SD +/- 0.18 kg). Using a one-tailed t-test, this difference was found to be significant (p < .05). We conclude that the use of a simple and inexpensive face mask can result in a meaningful decrease in overnight respiratory water loss while sleeping in a cold environment.

Atypical presentation of pulmonary embolism

Today we have discussed an interesting patient with an atypical presentation of pulmonary embolism. We have outlined a suggested algorithm to aid in the diagnosis and management of this disease. References 8 through 24 in the reference section are suggested readings that offer further insight into the diagnosis and management of this entity.