5-(2-Pyrimidinyl)-imidazo[1,2-a]pyridines are antibacterial agents targeting the ATPase domains of DNA gyrase and topoisomerase IV.

Dual inhibitors of bacterial gyrB and parE based on a 5-(2-pyrimidinyl)-imidazo[1,2-a]pyridine template exhibited MICs (microg/mL) of 0.06-64 (Sau), 0.25-64 (MRSA), 0.06-64 (Spy), 0.06-64 (Spn), and 0.03-64 (FQR Spn). Selected examples were efficacious in mouse sepsis and lung infection models at <50mg/kg (PO dosing).

In vitro and in vivo activities of PD 0305970 and PD 0326448, new bacterial gyrase/topoisomerase inhibitors with potent antibacterial activities versus multidrug-resistant gram-positive and fastidious organism groups.

PD 0305970 and PD 0326448 are new bacterial gyrase and topoisomerase inhibitors (quinazoline-2,4-diones) that possess outstanding in vitro and in vivo activities against a wide spectrum of bacterial species including quinolone- and multidrug-resistant gram-positive and fastidious organism groups. The respective MICs (microg/ml) for PD 0305970 capable of inhibiting>or=90% of bacterial strains tested ranged from 0.125 to 0.5 versus staphylococci, 0.03 to 0.06 versus streptococci, 0.25 to 2 versus enterococci, and 0.25 to 0.5 versus Moraxella catarrhalis, Haemophilus influenzae, Listeria monocytogenes, Legionella pneumophila, and Neisseria spp. PD 0326448 MIC90s were generally twofold higher versus these same organism groups. Comparative quinolone MIC90 values were 4- to 512-fold higher than those of PD 0305970. In testing for frequency of resistance, PD 0305970 and levofloxacin showed low levels of development of spontaneous resistant mutants versus both Staphylococcus aureus and Streptococcus pneumoniae. Unlike quinolones, which target primarily gyrA and parC, analysis of resistant mutants in S. pneumoniae indicates that the likely targets of PD 0305970 are gyrB and parE. PD 0305970 demonstrated rapid bactericidal activity by in vitro time-kill testing versus streptococci. This bactericidal activity carried over to in vivo testing, where PD 0305970 and PD 0326448 displayed outstanding Streptococcus pyogenes 50% protective doses (PD50s) (oral dosing) of 0.7 and 3.6 mg/kg, respectively (ciprofloxacin and levofloxacin PD50s were>100 and 17.7 mg/kg, respectively). PD 0305970 was also potent in a pneumococcal pneumonia mouse infection model (PD50=3.2 mg/kg) and was 22-fold more potent than levofloxacin.

3-aminoquinazolinediones as a new class of antibacterial agents demonstrating excellent antibacterial activity against wild-type and multidrug resistant organisms.

The 3-aminoquinzolinediones represent a new series of antibacterial agents structurally related to the fluoroquinolones. They are inhibitors of bacterial gyrase and topoisomerase IV and demonstrate clinically useful antibacterial activity against fastidious Gram-negative and Gram-positive organisms, including multidrug- and fluoroquinolone-resistant organisms. These agents also demonstrate in vivo efficacy in murine systemic infection models.

Energy requirements of non-ambulatory, tube-fed adult patients with cerebral palsy and chronic hypothermia.

OBJECTIVES: We investigated the energy requirements of non-ambulatory patients with severe neurodevelopmental disabilities and chronic hypothermia. METHODS: Six adult patients with a permanent ostomy for tube feeding were studied. Otic temperature was taken before the indirect calorimetry measurements. Prescribed tube-feeding intake and nutrient prescription changes were evaluated for 4 y for each patient. Monthly body weights and periodic anthropometric body fat assessments were measured for assessment of the need for weight gain, loss, or maintenance. The prescribed caloric intake was compared with the measured energy expenditure when normothermic, the Harris-Benedict equations, and the Arlington Developmental Center equation for non-ambulatory adult patients with severe neurodevelopmental disabilities (estimated resting energy expenditure [kcal/d] = [22.3 x fat-free mass [kg]] - [9.4 x age [y]] + 557). RESULTS: Mean energy expenditure was 783 +/- 81 kcal/d or 29.0 +/- 10.9 kcal. kg(-1)d(-1) when normothermic versus 606 +/- 11 kcal/d or 19.5 +/- 8.5 kcal. kg(-1)d(-1) (P < 0.05) when hypothermic (36.9 degrees C +/- 0.4 versus 35.5 degrees C +/- 0.4; P < 0.02), respectively. Prescribed caloric intakes to achieve weight gain, maintenance and loss were 138 +/- 13%, 105 +/- 15%, and 74 +/- 11% of the measured energy expenditure when normothermic (P < 0.001); 107 +/- 19%, 86 +/- 18%, and 56 +/- 3% of the Harris-Benedict equations (P < 0.02); or 130 +/- 23%, 100 +/- 19%, and 75 +/- 11% of the Arlington Developmental Center equation (P < 0.02). CONCLUSIONS: Measured energy expenditure when the patient is normothermic significantly overestimated actual caloric needs. The energy intake necessary to achieve desired weight changes are restrictive when compared with the basal energy expenditure, Arlington Developmental Center equation, or measured energy expenditure when normothermic.

Effect of upper extremity posturing on measured resting energy expenditure of nonambulatory tube-fed adult patients with severe neurodevelopmental disabilities.

PURPOSE: To ascertain the effect of upper extremity posturing on measured resting energy expenditure (MEE) for patients with severe neurodevelopmental disabilities. METHODS: Twenty-four nonambulatory adult patients with severe neurodevelopmental disabilities referred for evaluation of enteral tube feeding and who had a steady-state MEE performed were studied. Steady-state indirect calorimetry measurements were done through a canopy system. Patients were stratified according to the topography of their neuromotor impairment and motor function as having either fixed upper extremity contractures (Fixed UE) or with preservation of limited functional and nonfunctional upper extremity movement (Preserved UE). RESULTS: Despite a similar age, weight, height, and gender distribution between groups, those patients with Fixed UE (n = 13) had a significantly lower MEE than those with Preserved UE (n = 11): 893 +/- 91 versus 1144 +/- 262 kcal/d (p < .01), respectively. The Harris-Benedict equations' predicted energy expenditures were similar to MEE for patients with Preserved UE (1212 +/- 156 versus 1144 +/- 262 kcal/d, respectively, p = N.S.). Patients with Fixed UE had a significantly lower MEE than predicted by the Harris-Benedict equations (893 +/- 91 versus 1128 +/- 123 kcal/d, respectively, p < .01) CONCLUSIONS: Patients with fixed upper extremity contractures have a significantly lower MEE than those with preserved upper extremity movement. MEE for nonambulatory tube-fed adult patients with severe neurodevelopmental disabilities and fixed upper extremity contractures is significantly lower than predicted by the Harris-Benedict equations.

Validation of a new method for estimating resting energy expenditure of non-ambulatory tube-fed patients with severe neurodevelopmental disabilities.

OBJECTIVE: We assessed the bias and precision of the Arlington Developmental Center (ADC) equations derived from our previous study and the Harris-Benedict equations for estimating resting energy expenditure in non-ambulatory, tube-fed patients with severe neurodevelopmental disabilities. METHODS: Fifteen non-ambulatory patients with neurodevelopmental disabilities referred to the nutrition consult service for evaluation of enteral tube feeding via a permanent ostomy who had a steady-state resting energy expenditure measurement performed by indirect calorimetry were included in the study. The predicted energy expenditure values were compared with the measured resting energy expenditure values and evaluated for bias and precision. RESULTS: Both ADC equations were more precise (95% confidence interval [CI]: 9-22% and 10-18% error, respectively) for the total population than the Harris-Benedict equations (95% CI: 17-40% error). The ADC-2 equation was precise (95% CI: 7-15% error) and unbiased (95% CI: -5 to 139 kcal/d) in contrast to the Harris-Benedict equations (95% CI: 23-54% error; bias, +230 to 365 kcal/d) for patients with cerebral palsy and fixed upper extremity contractures. The Harris-Benedict equations were precise and unbiased (95% CI: 3-14% error; bias, -182 to 39 kcal/d) for patients with cerebral palsy with preservation of upper body movement, whereas the ADC equations were biased toward underprediction and associated with greater error (95% CI: -367 to -73 kcal/d and 7-26% error; 95% CI: -379 to -109 kcal/d and 9-27% error, respectively). CONCLUSIONS: The ADC-2 equation was unbiased and more precise in non-ambulatory adult patients with severe neurodevelopmental disabilities and fixed upper extremity contractures, whereas the Harris-Benedict equations were more precise and unbiased for those with preservation of limited functional and non-functional upper extremity movement.

Topiramate and weight loss in patients with neurodevelopmental disabilities.

STUDY OBJECTIVE: To characterize weight changes in patients with neurodevelopmental disabilities who received topiramate. DESIGN: Retrospective, observational study. SETTING: State-supported developmental center. PATIENTS: Fifteen patients with neurodevelopmental disabilities who received topiramate therapy MEASUREMENTS AND MAIN RESULTS: Monthly weights for 1 year after the start of topiramate therapy were recorded. Mean body weight at drug initiation differed significantly compared with the nadir weight during the next 12 months (52.2+/-7.5 vs 49.9+/-7.2 kg, p<0.02). Twelve patients who were receiving ad libitum oral diets demonstrated a significant decrease in body weight (52.1+/-7.5 vs 49.0+/-7.3 kg, p<0.01), whereas the three patients who received enteral nutrition through enterostomy did not experience significant weight loss. CONCLUSION: Weight loss is common in patients with neurodevelopmental disabilities who receive topiramate. Since patients who received oral diets lost weight whereas those receiving enteral nutrition did not, decreased nutrient intake is the likely cause of weight loss.