Impact of airborne particle size, acoustic airflow and breathing pattern on delivery of nebulized antibiotic into the maxillary sinuses using a realistic human nasal replica.

PURPOSE: Improvement of clinical outcome in patients with sinuses disorders involves targeting delivery of nebulized drug into the maxillary sinuses. We investigated the impact of nebulization conditions (with and without 100 Hz acoustic airflow), particle size (9.9 µm, 2.8 µm, 550 nm and 230 nm) and breathing pattern (nasal vs. no nasal breathing) on enhancement of aerosol delivery into the sinuses using a realistic nasal replica developed by our team. METHODS: After segmentation of the airways by means of high-resolution computed tomography scans, a well-characterized nasal replica was created using a rapid prototyping technology. A total of 168 intrasinus aerosol depositions were performed with changes of aerosol particle size and breathing patterns under different nebulization conditions using gentamicin as a marker. RESULTS: The results demonstrate that the fraction of aerosol deposited in the maxillary sinuses is enhanced by use of submicrometric aerosols, e.g. 8.155 ± 1.476 mg/L of gentamicin in the left maxillary sinus for the 2.8 µm particles vs. 2.056 ± 0.0474 for the 550 nm particles. Utilization of 100-Hz acoustic airflow nebulization also produced a 2- to 3-fold increase in drug deposition in the maxillary sinuses (e.g. 8.155 ± 1.476 vs. 3.990 ± 1.690 for the 2.8 µm particles). CONCLUSIONS: Our study clearly shows that optimum deposition was achieved using submicrometric particles and 100-Hz acoustic airflow nebulization with no nasal breathing. It is hoped that our new respiratory nasal replica will greatly facilitate the development of more effective delivery systems in the future.

Detection of carbapenemase-producing bacteria by using an ultra-performance liquid chromatography-tandem mass spectrometry method.

The emergence of carbapenemase-producing bacteria poses a new challenge in the management of antibiotic therapies for patients. This report describes a new method using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) for rapid detection of carbapenemase activity in enterobacteria, Pseudomonas aeruginosa, and Acinetobacter baumannii. In a panel of 78 isolates, including 41 carbapenemase-producing strains, the ULPC-MS/MS assay showed 100% agreement with molecular characterization, whereas six carbapenemase-producing isolates were not detected by the modified Hodge test.

Outbreak of multidrug-resistant Klebsiella pneumoniae carrying qnrB1 and blaCTX-M15 in a French intensive care unit.

BACKGROUND: The prevalence of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae is increasing globally and is a major clinical concern. Between June 2008 and September 2009, 4% of patients in an intensive care unit (ICU) were found to be colonized or infected by strains of Klebsiella pneumoniae multiresistant to ceftazidime, ciprofloxacin, and tobramycin; an investigation was initiated and isolates were characterized by molecular typing and resistance patterns. METHODS: Antibiotic susceptibilities were determined by Vitek2®, Etest®, and agar dilution. Gene encoding beta-lactamases and plasmid-mediated quinolone resistance PMQR determinants (qnr, aac(6')-Ib) were characterized by PCR, sequencing, and transfer assays. DiversiLab® fingerprints were used to study the relatedness of isolates. RESULTS: Fourteen isolates co-expressing blaCTX-M15, qnrB1, and aac(6')-Ib-cr were identified. Genotypic analysis of these isolates identified 12 clonally related strains recovered from 10 patients. The increased prevalence of blaCTX-M15-qnrB1-aac(6')-Ib-cr-producing K. pneumoniae coincided with the presence in the ICU of a patient originally from Nigeria. This patient was infected by a strain not clonally related to the others but harbouring qnrB1 and aac(6')-Ib-cr genes, a finding not hitherto observed in France. We suspected transmission of resistance plasmids followed by rapid dissemination of the multiresistant K. pneumoniae clone by cross-transmission. CONCLUSION: This study highlights the importance of microbiological screening for multidrug-resistant strains in ICUs, particularly among patients from regions in which multidrug-resistant bacteria are known to exist.

Impact of acoustic airflow nebulization on intrasinus drug deposition of a human plastinated nasal cast: new insights into the mechanisms involved.

PURPOSE: The impact of 100 Hz (Hertz) acoustic frequency airflow on sinus drug deposition of aerosols was investigated using a human plastinated nasal cast. The influence of drug concentration and endonasal anatomical features on the sinus deposition enhanced by the 100 Hz acoustic airflow was also examined. METHODS: Plastinated models were anatomically, geometrically and aerodynamically validated (endoscopy, CT scans, acoustic rhinometry and rhinomanometry). Using the gentamicin as a marker, 286 experiments of aerosol deposition were performed. Changes of airborne particles metrology produced under different nebulization conditions (100 Hz acoustic airflow and gentamicin concentration) were also examined. RESULTS: Aerodynamic and geometric investigations highlighted a global behaviour of plastinated models in perfect accordance with a nasal decongested healthy subject. The results of intrasinus drug deposition clearly demonstrated that the aerosols can penetrate into the maxillary sinuses. The 100 Hz acoustic airflow led to increase the deposition of drug into the maxillary sinuses by a factor 2-3 depending on the nebulization conditions. A differential intrasinus deposition of active substance depending on maxillary ostium anatomical features and drug concentration was emphasized. CONCLUSION: The existence of a specific transport mechanism of penetration of nebulized particles delivered with acoustic airflow was proposed.

De-escalation as part of a global strategy of empiric antibiotherapy management. A retrospective study in a medico-surgical intensive care unit.

INTRODUCTION: Most data on de-escalation of empirical antimicrobial therapy has focused on ventilator-associated pneumonia. In this retrospective monocentric study, we evaluated de-escalation as part of a global strategy of empiric antibiotherapy management irrespective of the location and the severity of the infection. The goal of this trial was to assess the application of a de-escalation strategy and the impact in terms of re-escalation, recurrent infection and to identify variables associated with de-escalation. METHODS: All consecutive patients treated with empiric antibiotic therapy and hospitalized in the intensive care unit for at least 72 hours within a period of 16 months were included. We compared the characteristics and outcome of patients who have experienced de-escalation therapy with those who have not. RESULTS: A total of 116 patients were studied corresponding to 133 infections. Antibiotic therapy was de-escalated in 60 cases (45%). De-escalation, primarily accomplished by a reduction in the number of antibiotics used, was observed in 52% of severe sepsis or septic shock patients. Adequate empiric antibiotic and use of aminoglycoside were independently linked with de-escalation. De-escalation therapy was associated with a significant reduction of recurrent infection (19% vs 5% P = 0.01). Mortality was not changed by de-escalation. CONCLUSIONS: As part of a global management of empiric antibiotherapy in an intensive care unit, de-escalation might be safe and feasible in a large proportion of patients.

Prospective determination of serum ceftazidime concentrations in intensive care units.

INTRODUCTION: The purpose of this study was to assess the value of a serum assay for ceftazidime (CAZ) in patients in the intensive care unit (ICU) of the Saint-Etienne University Teaching Hospital and in other ICUs in the region to optimize therapy. MATERIAL AND METHODS: Between November 1, 2005, and February 29, 2008, for patients hospitalized in ICUs not on dialysis and undergoing continuous CAZ infusion, serum assay of the antibiotic was performed 36 to 48 hours after the start of treatment using a single serum sample. The target serum CAZ concentration was 40 +/- 10 mg/L with a concentration/minimum inhibitory concentration ratio of 5 or greater x minimum inhibitory concentration of CAZ when a strain was isolated. RESULTS: Serum CAZ concentration was determined in 92 patients (28 females, 64 males) receiving CAZ by continuous infusion. The mean age was 66 years (range, 19-89 years) and the mean weight was 73 kg (range, 33-122 kg). The CAZ dose was between 1 g and 6 g/24 hours. The mean serum CAZ concentration was 46.9 mg/L (range, 7.4-162.3 mg/L). Serum CAZ concentrations were as follows: 30 to 50 mg/L in 35.9% of patients, less than 30 mg/L in 36.9%, and greater than 50 mg/L in 27.2%. Infection was documented in 51 patients, with 42 strains of Pseudomonas aeruginosa being detected. The serum concentration/minimum inhibitory concentration ratio was 5 or greater for 84.3%. Antibiotic dosage was adjusted based on the CAZ assay results. CONCLUSION: Our study suggests that CAZ measurement is needed in ICUs to achieve adequate CAZ concentrations to avoid treatment toxicity and to achieve efficacy as rapidly as possible, particularly in strains having limited susceptibility to antibiotics.

Continuous infusion of ceftazidime in critically ill patients undergoing continuous venovenous haemodiafiltration: pharmacokinetic evaluation and dose recommendation.

INTRODUCTION: In seriously infected patients with acute renal failure and who require continuous renal replacement therapy, data on continuous infusion of ceftazidime are lacking. Here we analyzed the pharmacokinetics of ceftazidime administered by continuous infusion in critically ill patients during continuous venovenous haemodiafiltration (CVVHDF) in order to identify the optimal dosage in this setting. METHOD: Seven critically ill patients were prospectively enrolled in the study. CVVHDF was performed using a 0.6 m2 AN69 high-flux membrane and with blood, dialysate and ultrafiltration flow rates of 150 ml/min, 1 l/hour and 1.5 l/hour, respectively. Based on a predicted haemodiafiltration clearance of 32.5 ml/min, all patients received a 2 g loading dose of ceftazidime, followed by a 3 g/day continuous infusion for 72 hours. Serum samples were collected at 0, 3, 15 and 30 minutes and at 1, 2, 4, 6, 8, 12, 24, 36, 48 and 72 hours; dialysate/ultrafiltrate samples were taken at 2, 8, 12, 24, 36 and 48 hours. Ceftazidime concentrations in serum and dialysate/ultrafiltrate were measured using high-performance liquid chromatography. RESULTS: The mean (+/- standard deviation) elimination half-life, volume of distribution, area under the concentration-time curve from time 0 to 72 hours, and total clearance of ceftazidime were 4 +/- 1 hours, 19 +/- 6 l, 2514 +/- 212 mg/h per l, and 62 +/- 5 ml/min, respectively. The mean serum ceftazidime steady-state concentration was 33.5 mg/l (range 28.8-36.3 mg/l). CVVHDF effectively removed continuously infused ceftazidime, with a sieving coefficient and haemodiafiltration clearance of 0.81 +/- 0.11 and 33.6 +/- 4 mg/l, respectively. CONCLUSION: We conclude that a dosing regimen of 3 g/day ceftazidime, by continuous infusion, following a 2 g loading dose, results in serum concentrations more than four times the minimum inhibitory concentration for all susceptible pathogens, and we recommend this regimen in critically ill patients undergoing CVVHDF.

Specific identification of Staphylococcus aureus by Staphychrom II, a rapid chromogenic staphylocoagulase test.

We compared the performance of Staphychrom II (International Microbio, Signes, France), a rapid (2-h) chromogenic staphylocoagulase test that uses human prothrombin and protease inhibitors, with those of the reference tube coagulase test (TCT) and the latex agglutination test (LAT) Slidex Staph Plus for the rapid identification of S. aureus. Prospective evaluation with 293 fresh clinical isolates yielded sensitivities, specificities, and predictive and negative predictive values of 98.1, 100, 100, and 95.1%, respectively, for the Staphychrom II test; 98.6, 98.7, 99.6, and 96.3%, respectively, for LAT; and 97.6, 98.7, 99.5, and 93.9%, respectively, for TCT. The perfect specificity of the Staphychrom II test was confirmed by testing 193 collection strains selected because of their potential testing pitfalls. The Staphychrom II test was positive for 90% of the 215 S. aureus strains tested after only 1 h of incubation. The Staphychrom II test was as sensitive as the reference TCT and was 100% specific.