Stability of dobutamine in continuous ambulatory delivery devices.

WHAT IS KNOWN AND OBJECTIVE: Continuous infusion of dobutamine plays an important role in the management of patients with end-stage heart failure. Home infusion of dobutamine using a continuous ambulatory delivery device (CADD) facilitates the management of patients in their home, avoiding complications associated with long-term hospitalization. However, the stability of dobutamine in CADD is currently unknown. Therefore, this study investigated the physicochemical stability of dobutamine in CADDs at three different temperatures over various time points. METHODS: Six CADDs (three containing dobutamine 10 mg/mL in 0.9% sodium chloride and three containing dobutamine 10 mg/mL in 5% glucose) were prepared and stored at 4°C for 7 days, followed by 12 hours at 35°C and then for another 12 hours at 25°C. An aliquot (n = 3) was withdrawn aseptically at 0, 24, 48, 72, 96, 120, 144 and 168 hours when stored at 4°C, and at 0, 6 and 12 hours when stored at the other two temperatures. Each sample was analysed for dobutamine concentration using a stability-indicating high-performance liquid chromatography. All the samples were also evaluated for change in pH, colour and for particle content. RESULTS AND DISCUSSION: No evidence of particle formation, colour or pH change was observed throughout the study period. Dobutamine, when admixed with 0.9% sodium chloride or 5% glucose, was found to be chemically stable for at least 168 hours at 4°C and for another 12 hours at 35°C and for another 12 hours at 25°C. WHAT IS NEW AND CONCLUSIONS: Our findings will allow health professionals to provide a weekly supply of dobutamine-containing CADDs to patients for home infusions. Continuous infusion over a 24-hour period using one CADD per day will also decrease the number of exchanges required and thus reduce the risk of catheter-related bloodstream infections.

Retrospective audit of antimicrobial prescribing practices for acute exacerbations of chronic obstructive pulmonary diseases in a large regional hospital.

WHAT IS KNOWN AND OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is associated with significant morbidity and mortality, and frequent exacerbations are associated with an increased risk of death, deterioration in lung function and reduced quality of life. Current Australian guidelines developed by the Lung Foundation of Australia (the COPD-X Plan) recommends the use of a short course of corticosteroids and oral antibiotics (amoxycillin or doxycycline) as part of the treatment of an AECOPD; however, it was noted that clinical practice at the study hospital had deviated from these guidelines. To evaluate the antibiotic prescribing practices in acute exacerbations of chronic obstructive pulmonary disease (AECOPD) patients, and to compare the differences in clinical outcomes (primarily mean length of stay and the rate of unplanned readmissions) between patients who received broad- vs. narrow-spectrum antibiotics in a large regional hospital. METHODS: Retrospective audit of medical records for patients admitted with uncomplicated AECOPD during January-September, 2014 in a 224 acute bed regional hospital in Victoria, Australia. RESULTS AND DISCUSSION: Fifty-nine per cent of patients received broad-spectrum antibiotics (ceftriaxone), whereas only 10% of prescriptions were concordant with current Australian guideline recommendations. Patients receiving a broad-spectrum regimen were more likely to be older (74·9 vs. 69·9 years; P = 0·009), have a higher COPD severity score (i.e. BAP-65 score, 1·55 vs. 1·06; P = 0·002) and a higher CRP (59·2 vs. 25·5 mg/L; P = 0·003) on admission. The mean LOS was not significantly different between those who received ceftriaxone and those who did not (5·09 vs. 4·55 days; P = 0·47). There was no significant difference between the groups in rates of readmissions. WHAT IS NEW AND CONCLUSION: The antibiotic prescribing patterns for AECOPD in rural and regional Australian hospitals have not previously been examined in the current literature. In the study hospital, the majority of patients received broad-spectrum antibiotics in the initial treatment of AECOPD. No differences in hospital length of stay, or rate of readmission for AECOPD were observed between those who received broad- and narrow-spectrum antibiotics.

Efficacy and safety of low-dose colistin in the treatment for infections caused by multidrug-resistant gram-negative bacteria.

WHAT IS KNOWN AND OBJECTIVE: Infections due to multidrug-resistant gram-negative bacteria (MDR-GNB) are a significant burden to the healthcare system globally. Colistin is the drug of choice for MDR-GNB and recent studies recommend high doses. This study investigated the safety of low-dose colistin and the relationship of minimum inhibitory concentration (MIC) of colistin with bacterial cure in the treatment for MDR-GNB infections. METHODS: Computerized dispensing records identified all patients who received colistin during January 2010 and December 2011. Patients who were aged < 12 years old, who received colistin for < 72 h or had moderate to severe renal impairment were excluded. Medical records of the remaining patients were reviewed for the necessary data to determine the bacterial cure and nephrotoxicity of colistin. Multivariate logistic regression analysis was used to determine the predictors of bacterial cure. RESULTS: A total of 125 evaluable patients received colistin during the study period. Ninety-four of 125 (75·2%) patients achieved bacterial cure. No statistically significant differences were observed between patients who achieved and failed to achieve bacterial cure with regards to age, gender, site of infection, mg/kg dose or duration of colistin use. The average MIC in the bacterial cure group was significantly lower than the MIC in the bacterial failure group (P = 0·002). Similarly, 30-day mortality from the last dose of colistin was significantly lower in the bacterial cure group (P = 0·002). Nephrotoxicity occurred in 12·8% of patients and was not associated with the dose of colistin or concomitant use of nephrotoxic medications. MIC of <1 µg/mL was the only significant independent predictor of bacterial cure in the multivariate logistic regression analysis (P = 0·015), whereas infection caused by MDR Klebsiella pneumonia was an independent risk factor for bacterial failure (P = 0·049). WHAT IS NEW AND CONCLUSION: Low-dose colistin is an effective option in the treatment for infections caused by MDR-GNB with a low incidence of nephrotoxicity. Patients who achieved bacterial cure had significantly lower MIC values of colistin against MDR-GNB than those who failed to achieve it. Colistin dose should be based on the MIC data of a given patient or local antimicrobial sensitivity data to maximize its efficacy.

Using formative evaluation to improve uptake of a web-based tool to support antimicrobial stewardship.

WHAT IS KNOWN AND OBJECTIVE: Web-based decision support tools have rationalized prescribing of antimicrobials in healthcare settings. Clinicians' acceptance of decision support tools is one of the important factors that determine successful implementation of such tools. This study evaluated the impact of a formative evaluation on the uptake of a web-based antibiotic computerized decision support system (CDSS) by clinicians at a university teaching hospital. METHODS: Semi-structured qualitative interviews were conducted with junior and senior doctors and pharmacists. Interviews were transcribed verbatim and reviewed to identify barriers surrounding clinicians' use of the antibiotic CDSS. Recommendations were made to the development team of the studied system regarding system modifications and the implementation strategy. An automated log of the clinicians' use of antibiotic CDSS was generated before and after the formative evaluation. RESULTS: Interviews of 42 clinicians identified several barriers related to contents and implementation strategy of the antibiotic CDSS. Important differences were observed between senior and junior doctors about various aspects of the antibiotic restriction strategy and applicability of antibiotic CDSS in specialized clinical areas. Recommendations from the formative evaluation study resulted in significant modifications to the contents and implementation strategy of the antibiotic CDSS. A significant increase in uptake of the antibiotic CDSS by clinicians was observed following the formative evaluation. WHAT IS NEW AND CONCLUSION: The formative evaluation approach during the implementation period of the studied antibiotic CDSS increased clinicians' uptake of the system. Formative evaluation may be recommended as a routine strategy to implement future CDSS and related clinical computing applications in hospital settings.

Hypopigmented mycosis fungoides in a 10-year-old boy.

Cutaneous T-cell lymphoma (CTCL) presenting with hypopigmented lesions is an uncommon clinical variant of the disease, usually described in dark-skinned patients. We report a case of hypopigmented CTCL in a 10-year-old boy. The disease has responded favorably to narrowband UVB therapy. This case illustrates the importance of clinical suspicion for mycosis fungoides in patients with widespread hypopigmentation.

Correlation of spontaneous and induced premature atrial complexes initiating atrial fibrillation in humans: electrophysiologic parameters for guiding therapy.

INTRODUCTION: The low frequency of spontaneous premature atrial contractions (PACs) may be an impediment to mapping and ablation of atrial fibrillation (AF). It has been shown that PACs following external or internal cardioversion of AF can initiate AF. If this method could reproducibly induce PACs from the same location as spontaneous PACs, it would be clinically significant. High-resolution noncontact mapping can map a single beat, should help identify the sites of spontaneously occurring PACs and PACs induced following cardioversion of spontaneous or induced AF, and could help correlate the trigger sites for AF induction. METHODS AND RESULTS: Twelve patients (8 men and 4 women; mean age 49+/-10 years) with spontaneous PACs were included in the study. In all patients, AF was induced and subsequently cardioverted to assess and map isolated PACs or PACs that induced AF. Using the EnSite 3000 noncontact mapping system, mapping was performed of spontaneously occurring isolated PACs and PACs that induced AF and PACs (both with and without AF) that occurred on at least two different occasions following cardioversion. The locations of the spontaneous and the induced PACs were similar; 97% of induced PACs came from the same locations as those of spontaneous PACs (P = 0.5). Radiofrequency lesions guided by this mapping technique were delivered at 14 pulmonary vein sites. Following a single ablation attempt during a mean follow-up of 19+/-4 weeks, 42% of the patients were in sinus rhythm and drug-free, whereas an additional 24% of patients could be maintained in sinus rhythm on drugs that had failed before. CONCLUSION: There is a high degree of correlation between spontaneous and induced PACs as the trigger sites for AF initiation. Cardioversion of spontaneous or induced AF could be used as an electrophysiologic parameter for guiding therapy.

Enhancement of fractionated-dose irradiation by retinoic acid plus interferon.

PURPOSE: To evaluate the relative cytotoxicity of fractionated-dose radiation in the presence and absence of 13-cis-retinoic acid (RA) plus alpha-2a-interferon (IFN), as a function of overall treatment time. METHODS AND MATERIALS: Studies were performed with the human squamous cell carcinoma line FaDu, in vitro. Attached exponential phase cells were treated with RA + IFN for 8-10 h and then exposed to single graded doses of radiation, or 1 to 6 doses of radiation at 2 Gy per dose, or to 5 doses of radiation at 2 Gy/dose with a time interval of 4-24 h between treatments. Following irradiation, the cells were incubated with drugs present throughout colony formation, and the fraction of survivors in the presence and absence of the combined drugs was calculated. RESULTS: For single graded-dose irradiation, the surviving fraction ratio at 2 Gy in the absence vs. presence of drugs was 1.27 +/- 0.19 in 3 repeat experiments. Following administration of 6 doses of radiation at 2 Gy/fraction with a 5-h time interval between treatments and, after correcting for cell proliferation between treatments, the surviving fractions differed by a factor of 3.25, again indicating an average difference in survival of 1.26 after each of the 6 2-Gy/fractions. Treatment with 5 2-Gy doses of irradiation with 24 vs. 4 h elapsing between doses, resulted in a 3-fold greater decrease in survival in the presence of drugs vs. no drug. The relatively greater cell kill due to 24 vs. 4 h between treatments was due to drug inhibition of cell proliferation between the more prolonged treatments. CONCLUSIONS: The results of this study indicate that retinoic acid plus interferon both sensitizes and inhibits cell proliferation during treatment. These results suggest that this combination of radiation and drugs, when used concurrently, may be effective for inhibiting tumor cell proliferation or accelerated repopulation during clinical fractionated radiotherapy.

The reproducibility and relationship between single and fractionated dose estimates of the surviving fraction at 2 Gy.

PURPOSE: To evaluate the reproducibility and relationship between the surviving fraction at 2 Gy obtained from single-graded dose and multifraction survival curve assays. METHODS AND MATERIALS: Single-graded dose and multifraction survival curve assays were concurrently performed in five human cell lines. For the multifraction studies, five to six doses at 2 Gy per fraction were administered with a time interval of 5.5 h between fractions. All surviving fraction data was corrected for multiplicity and cell proliferation during treatment. Replicate experiments were performed for each cell line. RESULTS: The precision of the Sf2 estimates obtained from multifraction studies was approximately three times greater than was obtained in the single-dose studies. For the single-dose studies, the average difference between the Sf2s obtained in the initial vs. repeat experiment was 0.11; for the fractionated-dose studies the difference was significantly reduced to 0.032. A rank-order correlation was not obtained between the 2 Gy Sfs in the initial and repeat single-dose assays; in the multifraction studies, the correlation was significant (p < 0.05). The rank-order correlation between the single- and fractionated-dose Sf2 assays was significant only when the two sets of assays were pooled; however, the coefficient of correlation remained low (R(2) = 0.50). CONCLUSIONS: The precision of the estimates of the surviving fraction at 2 Gy, obtained from multifraction assays, was substantially greater than was obtained in single dose-survival curve assays.

Energy status parameters, hypoxia fraction and radiocurability across tumor types.

Under full nutrient in vitro conditions, the cellular adenylate energy charge of six different rodent and human tumor cell types was identical, i.e., 0.94 +/- 0.01, suggesting the potential utility of this parameter as a cell (and tissue) independent marker of nutrient deprivation and hypoxia, across tumor types. The adenylate energy charge values of tumors, arising from these cells, was reduced and variable ranging from 0.72 to 0.91 for the various tumor types. However, neither the tumor adenylate energy charge, NTP/Pi, nor PCr/Pi ratios correlated with the radiobiologic hypoxic cell fractions across tumor types. The reduced adenylate energy charge in vivo suggests varying degrees of nutrient deprivation in the different tumor types, however, factors other than or in addition to hypoxia likely contribute to tumor energy status.

Influence of experimental factors on intrinsic radiosensitivity assays at low doses of radiation: cell multiplicity.

Evaluation of the probability of biological phenomena per cell by colony formation, requires knowledge not only of the number of cells at risk but also of their microdistribution. In the present study, the influence of cellular multiplicity (number of cells per potential colony-forming unit) on the determination of radiation sensitivity is evaluated for a range of multiplicity distributions. Cell surviving fraction was calculated using no multiplicity correction, an average multiplicity correction or the fractional distribution of multiplicities of the control and irradiated population. The results obtained show that: (a) multiplicity corrections are required when the number of cells per potential colony-forming unit is greater than 1.00 either immediately after plating or at the time of irradiation; (b) both the control and irradiated populations must be corrected for multiplicity; (c) multiplicity errors are most pronounced in the low-dose range, e.g. in the survival range with 2 Gy; and (d) the error introduced by using an average vs fractional distribution of multiplicities increases with the multiplicity dispersion. Seemingly small errors due to uncorrected multiplicity effects lead to markedly different predicted isoeffect doses when amplified through multiple (e.g. 30) fractions.

Multivariate determinants of radiocurability. I: Prediction of single fraction tumor control doses.

PURPOSE: The relationship between various laboratory determinants of radiocurability considered alone and in combination, and the observed 50% tumor control dose, has been examined in rodent and xenografted human tumors. METHODS AND MATERIALS: The single fraction 50% tumor control dose (TCD50) under normal and clamp hypoxic conditions, 50% tumor cell transplant dose (Td50), and in vitro estimated tumor cell radiosensitivity parameters, were determined in each of six tumor types (four isografted murine and two xenografted human tumors). Subcutaneous transplant sites and identical or similar tumor generations were used for both the Td50 and TCD50 studies. Radiosensitivity parameters were obtained using the clonogenic assay, after allowing cells to enter the active growth phase to recover from trypsin induced alterations of cell radiosensitivity. Both control and irradiated cells were multiplicity corrected. RESULTS: No single parameter (InTd50, hypoxic fraction, or intrinsic radiosensitivity) correlated with the observed tumor control doses under aerobic or hypoxic conditions. However, when considered in combination, clonogenic fraction (estimated by Td50(-1)), and intrinsic radiosensitivity, predicted the rank-order of tumor control doses with a significant degree of accuracy, and tumor hypoxia influenced the value of the control dose. All parameters were demonstrated to be significant determinants of radiocurability, with substantial tumor to tumor variation in the relative importance of each. For the six tumor types, the combined laboratory determinants predicted 50% tumor control doses which differed from the observed TCD50s by an average of approximately 9 Gy under hypoxic conditions. CONCLUSION: The results obtained demonstrate: (a) the necessity of simultaneously considering all determinants of radiocurability if the role of a single determinant is to be assessed; (b) laboratory determinants may accurately predict tumor radiocurability.

Energy status in the murine FSaII and MCaIV tumors under aerobic and hypoxic conditions: an in-vivo and in-vitro analysis.

The relationship between energy status and hypoxia was examined in two murine tumors with substantially different hypoxic cell fractions in situ and in cells derived from these tumors in vitro. Parameters of tumor energy status were NTP/Pi and PCr/Pi obtained by 31P-NMR spectroscopy and adenylate energy charge and energy status obtained by high-pressure liquid chromatographic analysis of tumor extracts. Adenylate energy charge and rates of high-energy phosphate degradation were determined on cells obtained from both tumor types (MCaIV and FSaII) under identical nutrient and oxygen conditions, that is, air and nitrogen for various durations (0-6 hr). No consistent or substantial differences were noted in the various parameters of tumor energy status obtained by nuclear magnetic resonance analysis or analysis of tumor extracts, even though the MCaIV contains a substantially larger hypoxic fraction (49% vs 12%). Under in vitro conditions, the two cell lines exhibited different responses to oxygen deprivation, the MCaIV being substantially more refractory to energy changes secondary to hypoxia. Noting with caution that this study is based on only two tumor types, our results suggest that differences in cellular capacity for energy maintenance preclude quantitative inferences regarding tumor oxygen status from energy status between tumor types.