Outcomes in patients with gram-negative sepsis treated with gentamicin.

OBJECTIVE: Recent changes to therapeutic drug monitoring (TDM) of gentamicin have been advocated in Australia. It remains uncertain whether these will have an effect on hard clinical endpoints. The aim of this study was to determine clinical outcomes in patients with gram-negative infections treated with gentamicin. METHODS: Microbiology results of patients with confirmed gram-negative cultures were retrospectively reviewed and those treated with gentamicin included. Medical records were reviewed and patient demographics, diagnosis, renal function, comorbidities, gentamicin doses, duration, monitoring, concomitant antibiotics, antimicrobial sensitivity and clinical and microbiological outcomes recorded. RESULTS: A total of 100 patients were included in the study: 52% were male, median age 64 years (17-97). Total body weight was recorded in 56% (median 74.5 kg, range 35-134 kg). Most patients had two or more important comorbidities. A total of 72% received empiric and 28% directed treatment. The organism was identified on blood culture in 45%, urine culture in 43% and aspiration of liver abscess in 12%; 95% of organisms were sensitive to gentamicin. Baseline renal function was normal in 62%. Mean gentamicin dose was 3.9 ± 0.9 mg/kg and mean duration 2.9 ± 2.5 days. Only 21% had optimal TDM. Clinical outcome was favourable in 90%. There were no cases of preventable serious toxicity. CONCLUSIONS: Despite the modest doses of gentamicin used in an elderly population with comorbidities, as well as the absence of optimal TDM, outcomes were favourable without preventable serious toxicity.

Varied effects of conventional antiepileptics on responding maintained by negative versus positive reinforcement.

We analyzed the effects of four conventional antiepileptic drugs (AEDs) - carbamazepine (CBZ), ethosuximide (ETH), phenytoin (PHT), and valproate (VPA) - on operant behavior maintained by negative or positive reinforcement contingencies. Rats were trained to lever press on a free-operant avoidance schedule or variable-interval (VI) schedule of appetitive reinforcement. Dose-effect functions were separately established on each reinforcement contingency for CBZ (12.5-100 mg/kg), ETH (25-200 mg/kg), PHT (12.5-50 mg/kg), and VPA (50-400 mg/kg). CBZ and PHT reduced responding on free-operant avoidance and VI appetitive reinforcement tasks, with positively reinforced behavior reduced at lower drug dosages than negatively reinforced responding. ETH and VPA reduced responding on the VI appetitive reinforcement task, but did not alter behavior maintained on the free-operant avoidance schedule. Our results suggest that conventional AEDs vary in their effect on operant behavior, depending on the type of reinforcement process maintaining responding.

Possible role for the 5-HT1A receptor in the behavioral effects of REM sleep deprivation on free-operant avoidance responding in rat.

RATIONALE: REM sleep deprivation (REMSD) has been shown to increase rates of free-operant avoidance responding. Depletion of 5-hydroxytryptamine (5-HT, serotonin) levels produces similar effects on responding. OBJECTIVE: We studied whether the pharmacological activation of the 5-HT1A receptor would produce effects on avoidance responding similar to REMSD and depleted 5-HT levels. METHODS: Rats were trained to lever press on a free-operant avoidance task. Dose-effect functions were established for 8-OH-DPAT (a 5-HT1A receptor agonist) (0.1-1.0 mg/kg) and WAY 100635 (a 5-HT1A receptor antagonist) (0.1-1.0 mg/kg). Rats were then exposed to REMSD (48 h) or equivalent control conditions, and then administered 8-OH-DPAT (0.6 mg/kg) and/or WAY 100635 (0.025-0.1 mg/kg). RESULTS: Injections of 8-OH-DPAT increased rates of avoidance responding in a dose-dependent manner, while WAY 100635 did not alter responding. The effect of 8-OH-DPAT was antagonized by pre-injection of WAY 100635. REMSD and injections of 8-OH-DPAT increased rates of avoidance responding and the effects of both manipulations were reversed by pre-injection of WAY 100635. CONCLUSIONS: Activation of the 5-HT1A receptor may be a mechanism by which REMSD increases rates of free-operant avoidance responding.

Identifying specific sensory modalities maintaining the stereotypy of students with multiple profound disabilities.

In Experiment 1, analogue functional analyses were conducted to identify the functions of stereotypy for six students with multiple profound disabilities. Results indicated that stereotypy (a) occurred across conditions, (b) occurred primarily when alone, or (c) occurred during all sessions except in the Control condition. Experiment 2 analyzed stereotypy while masking visual, auditory, or tactile sensory consequences. Results showed that stereotypy was maintained by visual stimulation, tactile stimulation, or was undifferentiated across conditions. In Experiment 3, we showed that stereotypy could be reduced by providing competing sensory stimulation. In Experiment 4, stereotypy that was undifferentiated in Experiment 1 was analyzed using a concurrent operants procedure. Results showed that stereotypy was not multiply determined, but occurred to produce visual sensory stimulation. Our findings are discussed in terms of the sensory and social reinforcers that maintain stereotypy, assessment procedures used to identify those reinforcers, and the interpretation of assessment results.

Differential effects of carbamazepine on negatively versus positively reinforced responding.

To assess its effects on negatively versus positively reinforced operant behavior, carbamazepine (CBZ) or vehicle was acutely administered to rats. Negative reinforcement baselines consisted of a free-operant avoidance task with 5-s shock-shock and 20-s response-shock intervals. Positive reinforcement baselines consisted of responding for food pellets on a variable interval 30-s schedule. Ascending dose-effect functions were established using CBZ for negatively reinforced responding (vehicle, 25, 50, 100 mg/kg ip) and positively reinforced responding (vehicle, 12.5, 25, 50, 100 mg/kg ip). Negatively reinforced responses and avoided shocks were significantly reduced by CBZ injections at 100 mg/kg. Positively reinforced responses and food pellet deliveries were significantly reduced by CBZ injections at 25, 50, and 100 mg/kg. The results show that CBZ has differential, dose-dependent effects on negatively versus positively reinforced responding.