ro13-9904 and Alcoholism

Infections by Bartonella spp. include a wide spectrum of emerging and re-emerging infectious diseases, such as culture-negative endocarditis.. Description of 3 cases of endocarditis due to Bartonella spp. and review of those previously reported in Spain.. Including these 3 new cases of endocarditis due to Bartonella spp., a total of 6 cases have been reported in Spain. The median age of the patients was 51.6 years and 83.3% were men. There was history of contact with cats in 66.7%, and 50% were alcoholic. Only one patient had prior valvular disease. There were no clinical manifestations typical to any of the Bartonella species. The aortic valve was the one most commonly affected. In all cases, B. henselae was the agent implicated. The diagnosis was made by serology in 5 cases (83.3%). The outcome was favorable in all patients, although 4 of them (66.7%) required valve replacement.. Endocarditis due to Bartonella spp. is present in Spain and is likely to be underestimated. We should suspect this pathogen in patients with negative blood cultures and a history of chronic alcoholism, homeless patients, and those who have had contact with cats or who have been bitten by fleas or lice, as well as patients with endocarditis and positive serology against Chlamydia spp.

Topics: Actinobacillus Infections; Adult; Aged; Aggregatibacter actinomycetemcomitans; Alcoholism; Animals; Anti-Bacterial Agents; Antibodies, Bacterial; Aortic Valve; Bartonella henselae; Bartonella Infections; Blood; Cardiomyopathy, Hypertrophic; Cat-Scratch Disease; Cats; Ceftriaxone; Chlamydia; Ciprofloxacin; Combined Modality Therapy; Disease Susceptibility; Doxycycline; Endocarditis, Bacterial; Endocarditis, Subacute Bacterial; False Negative Reactions; Female; Gentamicins; Heart Valve Prosthesis Implantation; Humans; Male; Middle Aged; Spain; Vancomycin

Alcohol dependence results in long-lasting neuroadaptive changes in meso-corticolimbic system, especially in the nucleus accumbens (NAc), which drives relapse-like ethanol drinking upon abstinence or withdrawal. Within NAc, altered glutamate homeostasis is one of the neuroadaptive changes caused by alcohol dependence. Accumbal glutamate homeostasis is tightly maintained through glutamate transporter 1 (GLT-1) and cystine-glutamate antiporter (xCT). But the role of GLT-1 and xCT in relapse-like ethanol drinking is poorly understood. Here, we used alcohol-preferring (P) rats in relapse-like ethanol drinking paradigm to (a) determine the effect of relapse-like ethanol drinking on gene and protein expression of GLT-1 and xCT in NAc, measured by quantitative polymerase chain reaction (qPCR) and Western blot, respectively; (b) examine if glutamate uptake is affected by relapse-like ethanol drinking in NAc, measured by radioactive glutamate uptake assay; (c) elucidate if upregulation of either/both GLT-1 or/and xCT through ceftriaxone is/are required to attenuate relapse-like ethanol drinking. The GLT-1 or xCT protein expression was suppressed during ceftriaxone treatments through microinjection of GLT-1/xCT anti-sense vivo-morpholinos. We found that relapse-like ethanol drinking did not affect the gene and protein expression of GLT-1 and xCT in NAc. The glutamate uptake was also unaltered. Ceftriaxone (200 mg/kg body weight, i.p.) treatments during the last 5 days of abstinence attenuated relapse-like ethanol drinking. The suppression of GLT-1 or xCT expression prevented the ceftriaxone-induced attenuation of relapse-like ethanol drinking. These findings confirm that upregulation of both GLT-1 and xCT within NAc is crucial for ceftriaxone-mediated attenuation of relapse-like ethanol drinking.

Topics: Alcohol Drinking; Alcoholism; Amino Acid Transport Systems, Acidic; Animals; Ceftriaxone; Ethanol; Excitatory Amino Acid Transporter 2; Glutamic Acid; Nucleus Accumbens; Rats; Recurrence

Topics: Alcoholism; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Ceftriaxone; Diabetes Mellitus; Drainage; Drug Therapy, Combination; Humans; Klebsiella Infections; Klebsiella pneumoniae; Liver Abscess, Pyogenic; Male; Metronidazole; Middle Aged

Alcoholism and psychiatric disorders like depression and anxiety are often comorbid. Although the mechanisms underlying this comorbidity are unclear, emerging evidence suggests that maladaptation of the glial glutamate transporter GLT-1 may play a role. Findings from animal and human studies have linked aversive states, including those related to drugs of abuse and depression, to aberrant activity in the lateral habenula (LHb). The relationship between GLT-1 maladaptation, LHb activity, and abnormal behaviors related to alcohol withdrawal, however, remains unknown. Here we show that dihydrokainic acid (DHK), a GLT-1 blocker, potentiated glutamatergic transmission to LHb neurons in slices from ethanol naïve rats; this potentiation, though, was not observed in slices from rats withdrawn from repeated in vivo ethanol administration, suggesting reduced GLT-1 function. Furthermore, GLT-1 protein expression was reduced in the LHb of withdrawn rats. This reduction was restored by systemic administration of ceftriaxone, a β-lactam antibiotic known to increase GLT-1 expression. Systemic ceftriaxone treatment also normalized the hyperactivity of LHb neurons in slices from withdrawn rats, which was reversed by bath-applied DHK. Finally, systemic administration of ceftriaxone alleviated depression- and anxiety-like behaviors, which was fully blocked by intra-LHb administrations of DHK, suggesting that GLT-1's function in the LHb is critical. These findings highlight the significant role of LHb astrocytic GLT-1 in the hyperactivity of LHb neurons, and in depressive- and anxiety-like behaviors during ethanol withdrawal. Thus, GLT-1 in the LHb could serve as a therapeutic target for psychiatric disorders comorbid with ethanol withdrawal.

Topics: Alcoholism; Amino Acid Transport System X-AG; Animals; Antidepressive Agents; Anxiety; Ceftriaxone; Central Nervous System Depressants; Depression; Ethanol; Excitatory Amino Acid Agonists; Excitatory Postsynaptic Potentials; Habenula; In Vitro Techniques; Kainic Acid; Male; Maze Learning; Nerve Tissue Proteins; Quinoxalines; Rats; Rats, Sprague-Dawley; Sodium Channel Blockers; Substance Withdrawal Syndrome; Swimming; Tetrodotoxin

Topics: Alcohol Drinking; Alcoholism; Amino Acid Transport Systems, Acidic; Animals; Anti-Bacterial Agents; Body Weight; Ceftriaxone; Central Nervous System Depressants; Drinking; Ethanol; Excitatory Amino Acid Transporter 2; Male; Nucleus Accumbens; Rats; Rats, Sprague-Dawley; Self Administration; Up-Regulation

Increased glutamatergic neurotransmission appears to mediate the reinforcing properties of drugs of abuse, including ethanol (EtOH). We have shown that administration of ceftriaxone (CEF), a β-lactam antibiotic, reduced EtOH intake and increased glutamate transporter 1 (GLT-1) expression in mesocorticolimbic regions of male and female alcohol-preferring (P) rats. In the present study, we tested whether CEF administration would reduce nicotine (NIC) and/or EtOH intake by adult female P rats. P rats were randomly assigned to 4 groups: (a) 5% sucrose (SUC) or 10% SUC [SUC], (b) 5% SUC+0.07mg/ml NIC and 10% SUC+0.14mg/ml NIC [NIC-SUC], 15% EtOH and 30% EtOH [EtOH] and (d) 15% EtOH+0.07mg/ml NIC and 30% EtOH+0.14mg/ml NIC [NIC-EtOH]. After achieving stable intakes (4weeks), the rats were administered 7 consecutive, daily i.p. injections of either saline or 200mg/kg CEF. The effects of CEF on intake were significant but differed across the reinforcers; such that ml/kg/day SUC was reduced by ∼30%, mg/kg/day NIC was reduced by ∼70% in the NIC-SUC group and ∼40% in the EtOH-NIC group, whereas g/kg/day EtOH was reduced by ∼40% in both the EtOH and EtOH-NIC group. The effects of CEF on GLT-1 expression were also studied. We found that CEF significantly increased GLT-1 expression in the prefrontal cortex and the nucleus accumbens of the NIC and NIC-EtOH rats as compared to NIC and NIC-EtOH saline-treated rats. These findings provide further support for GLT-1-associated mechanisms in EtOH and/or NIC abuse. The present results along with previous reports of CEF's efficacy in reducing cocaine self-administration in rats suggest that modulation of GLT-1 expression and/or activity is an important pharmacological target for treating polysubstance abuse and dependence.

Topics: Alcohol Drinking; Alcoholism; Animals; Anti-Bacterial Agents; Behavior, Animal; Ceftriaxone; Ethanol; Excitatory Amino Acid Transporter 2; Female; Nicotine; Nucleus Accumbens; Prefrontal Cortex; Rats; Self Administration; Sucrose; Tobacco Use Disorder

Alteration of glutamatergic-neurotransmission is a hallmark of alcohol dependence. We have previously reported that chronic ethanol-drinking downregulated glutamate transporter 1 (GLT-1) in nucleus accumbens (NAc) in male P rats in a manner that was reversed by ceftriaxone treatment. However, the effect of ceftriaxone on extracellular glutamate concentrations in NAc after chronic ethanol-drinking has not yet been studied. In the present study, male P rats were treated with ceftriaxone (100 mg/kg/day, i.p.) for five consecutive days following five-weeks of free choice ethanol (15% and 30%) drinking. In vivo microdialysis was performed to measure the extracellular glutamate concentrations in NAc and the effect of blockade of GLT-1 with dihydrokainic acid (DHK) on extracellular glutamate in NAc of ceftriaxone-treated rats was determined. Ceftriaxone treatment attenuated ethanol intake as well as ethanol preference. Extracellular glutamate was significantly higher in NAc after five-weeks of ethanol drinking in saline-treated compared to water control rats. Ceftriaxone treatment blocked the increase extracellular glutamate produced by ethanol intake. Blockade of GLT-1 by DHK reversed the effects of ceftriaxone on glutamate and implicated the role of GLT-1 in the normalization of extracellular glutamate by ceftriaxone. In addition, GLT-1 protein was decreased in ethanol exposed animals and ceftriaxone treatment reversed this deficit. Ceftriaxone treatment also increased glutamine synthetase activity in NAc but not in PFC as compared to ethanol drinking saline-treated rats. Our present study demonstrates that ceftriaxone treatment prevents ethanol drinking in part through normalization of extracellular glutamate concentrations in NAc of male P rats via GLT-1.

Topics: Alcohol Deterrents; Alcohol Drinking; Alcoholism; Animals; Ceftriaxone; Central Nervous System Depressants; Disease Models, Animal; Ethanol; Excitatory Amino Acid Transporter 2; Extracellular Space; Glutamate-Ammonia Ligase; Glutamic Acid; Kainic Acid; Male; Microdialysis; Nucleus Accumbens; Rats

Infections in cirrhotic patients with upper gastrointestinal bleeding are a common event causing severe complication and mortality. This study aimed to identify risk factors that may predict rebleeding, bacterial infections, and the impact of antibiotic prophylaxis on mortality at different stages of cirrhosis following acute peptic ulcer bleeding (PUB).. A hospital-based retrospective cohort study was conducted on 235 cirrhotic patients with acute peptic ulcer hemorrhage who underwent therapeutic endoscopic procedures between January 2008 and January 2014 (n = 235); of these, 88 patients received prophylactic intravenous ceftriaxone (antibiotic group) and 147 patients did not (nil-antibiotic group). The recorded outcomes were length of hospital stay, bacterial infection, rebleeding, and in-hospital mortality.. Forty-eight (20.4%) patients experienced ulcer rebleeding and 46 (19.6%) developed bacterial infections. More patients suffered from infection and recurrent bleeding in the nil-antibiotic group than the antibiotic group (25.2% vs. 10.2%, p = 0.005 and 30.6% vs. 3.4%; p < 0.001, respectively). The predictive risk factors for rebleeding were the Rockall score (p = 0.004), units of blood transfusion (p = 0.031), and no antibiotic prophylaxis (p <0.001); for bacterial infections, they were the Child-Pugh score (p = 0.003), active alcoholism (p = 0.035), and no antibiotic prophylaxis (p = 0.009). Overall, 40 (17%) patients died during hospitalization. The Rockall score and rebleeding were predictive factors for in-hospital mortality. In subgroup analysis, survival was significantly reduced in decompensated patients (p = 0.034).. This study suggests that antibiotic prophylaxis after endoscopic hemostasis for acute PUB prevented infections and reduced rebleeding events in cirrhotic patients. Antibiotic prophylaxis improved survival among decompensated cohort following PUB. The Rockall score and rebleeding were predictive risk factors for in-hospital mortality.

Topics: Aged; Alcoholism; Anti-Bacterial Agents; Antibiotic Prophylaxis; Bacterial Infections; Blood Transfusion; Ceftriaxone; Female; Hemostasis, Endoscopic; Hospital Mortality; Humans; Length of Stay; Liver Cirrhosis; Male; Middle Aged; Peptic Ulcer Hemorrhage; Recurrence; Retrospective Studies; Risk Factors; Severity of Illness Index; Survival Rate

Alterations in glutamatergic neurotransmission have been suggested to affect many aspects of neuroplasticity associated with alcohol/drug addiction. We have previously shown that ceftriaxone, a β-lactam antibiotic known to upregulate glutamate transporter 1 (GLT1), reduced ethanol intake after 5 weeks of free choice ethanol drinking paradigm in male alcohol-preferring (P) rats. Evidence suggests that differential effects involving alterations of glutamatergic neurotransmission occur after long-term ethanol consumption. In this study, we tested whether the efficacy of administration of ceftriaxone persists after 14 weeks of free access to 15 and 30 % ethanol in male P rats. After 14 weeks of ethanol consumption, male P rats were administered ceftriaxone (100 mg/kg, intraperitoneal (i.p.)) or saline vehicle for 5 days. We found that ceftriaxone treatment resulted in a significant reduction in ethanol intake starting from day 2 (48 h after the first i.p. injections of ceftriaxone) through day 14, 10 days after final injection. Western blot analysis of brain samples from animals euthanized 24 h after treatment with the last dose of ceftriaxone revealed a significant upregulation of cystine/glutamate exchanger (xCT) and GLT1 levels in prefrontal cortex, nucleus accumbens, and amygdala as compared to saline vehicle-treated group. These findings demonstrated the effectiveness of ceftriaxone in attenuating ethanol intake in a chronic consumption paradigm. These might be due in part through the upregulation of both xCT and GLT1 levels in brain reward regions. Thus, the drug has a potential therapeutic action for the treatment of alcohol dependence.

Topics: Alcoholism; Amino Acid Transport Systems, Acidic; Animals; Brain; Ceftriaxone; Excitatory Amino Acid Transporter 2; Glutamic Acid; Male; Rats; Up-Regulation

Evidence suggests that glutamate transporter 1 (GLT-1) and cystine/glutamate exchanger transporter (xCT) are critical in maintaining glutamate homeostasis. We have recently demonstrated that ceftriaxone treatment induced upregulation of GLT1 levels and attenuated ethanol intake; however, less is known about the involvement of xCT on ethanol intake. In this study, we investigated the effects of ceftriaxone on the levels of xCT in both continuous and relapse-like ethanol drinking, as well as GLT-1 isoforms, and glutamate aspartate transporter (GLAST) in relapse-like ethanol intake.. P rats received free choice of 15 and 30 % ethanol and water for 5 weeks and then deprived of ethanol for 2 weeks. Rats were treated with ceftriaxone (100 mg/kg, i.p.) or saline during the last 5 days of the 2-week deprivation period. After deprivation period, P rats were re-exposed to free choice of 15 and 30 % ethanol and water for nine consecutive days. A second group of P rats was given continuous ethanol access for 5 weeks, then ceftriaxone (100 mg/kg, i.p.) or saline throughout the week 6.. Ceftriaxone significantly attenuated relapse-like ethanol intake. Importantly, this effect of ceftriaxone was associated in part with upregulation of the levels of GLT-1a and GLT-1b isoforms and xCT in the prefrontal cortex (PFC) and the nucleus accumbens (NAc). There were no significant differences in GLAST expression among all groups. We also found that ceftriaxone treatment increased xCT levels in both PFC and NAc in continuous ethanol intake.. These findings suggest that xCT and GLT-1 isoforms might be target proteins for the treatment of alcohol dependence.

Topics: Alcohol Drinking; Alcoholism; Amino Acid Transport Systems, Acidic; Animals; Ceftriaxone; Ethanol; Excitatory Amino Acid Transporter 1; Excitatory Amino Acid Transporter 2; Glutamic Acid; Male; Nucleus Accumbens; Prefrontal Cortex; Protein Isoforms; Rats; Up-Regulation

Increased glutamatergic neurotransmission appears to mediate the reinforcing properties of drugs of abuse, including ethanol (EtOH). We recently reported that the administration of ceftriaxone (CEF), a β-lactam antibiotic known to upregulate glutamate transporter 1 (GLT1) levels/activity, decreased the maintenance of EtOH intake in adult male alcohol-preferring (P) rats. In the present study, we tested whether CEF administration would reduce the acquisition and maintenance of EtOH drinking in adolescent and adult female P rats. The rats were treated with saline or 200mg/kg ceftriaxone for 7 days (starting at 35 or 75 days old, respectively) followed by the EtOH acquisition test. Five weeks later the effects of CEF were examined regarding the maintenance of EtOH intake. For the maintenance test, half of the animals that received CEF during acquisition received CEF for 7 days and the other half received saline for 7 days. Saline-treated acquisition animals were treated similarly. The results indicated that pretreatment with ceftriaxone reduced the maintenance of EtOH intake in both animals that started as adolescents and those that started as adults. However, the beneficial effect of CEF was more pronounced in rats pretreated with CEF as adults compared with rats pretreated as adolescents. Reductions in EtOH intake by ceftriaxone were paralleled by an upregulation of GLT1 protein levels in both the nucleus accumbens (∼25% in rats starting at both ages) and prefrontal cortex (∼50% in rats starting as peri-adolescents and ∼65% in those starting as adults). These findings provide further support for GLT1-associated mechanisms in high alcohol-consuming behavior, and hold promise for the development of effective treatments targeting alcohol abuse and dependence.

Topics: Alcohol Drinking; Alcoholism; Animals; Anti-Bacterial Agents; Blotting, Western; Brain; Ceftriaxone; Female; Glucose Transporter Type 1; Rats

Studies have demonstrated that deletion of equilibrative nucleoside transporter 1 (ENT1) is associated with reduced glutamate transporter 1 (GLT1) level, and consequently increased ethanol intake. In this study, we measured changes in GLT1 and ENT1 levels in prefrontal cortex (PFC), and nucleus accumbens (NAc) core and shell associated with alcohol drinking in alcohol-preferring (P) rats. We examined, then, whether ceftriaxone (CEF) would affect both GLT1 and ENT1 levels in these brain regions. P rats were given 24-h concurrent access to 15 and 30% ethanol, water, and food for 5 weeks. On Week 6, P rats received 100 mg/kg CEF (i.p.) or a saline vehicle for five consecutive days. Ethanol intake was measured daily for 8 days starting on the first day of injections. We found a significant reduction in daily ethanol intake in CEF-treated group, starting on Day 2 of injections. Western blot for GLT1 and binding assay for ENT1 revealed downregulation of GLT1 level, whereas ENT1 levels were increased in the NAc core and NAc shell, respectively, but not in the PFC in saline vehicle group. Importantly, CEF treatment reversed these effects in both NAc core and shell. These findings provide evidence for potential regulatory effects of CEF on both GLT1 and ENT1 expression in reducing ethanol intake.

Topics: Alcohol Drinking; Alcoholism; Animals; Carrier Proteins; Ceftriaxone; Down-Regulation; Equilibrative Nucleoside Transporter 1; Excitatory Amino Acid Transporter 2; Nucleus Accumbens; Organ Specificity; Prefrontal Cortex; Rats; Rats, Inbred Strains

E. coli meningitis is a disease that occurs in predisposed patients, either as a result of trauma or in neonates after neurosurgery. Recurrent E. coli meningitis in an adult without any apparent predisposition is uncommon, and hydrocephalus complicating bacterial meningitis is even more rare. We report a unique case of a 67-year-old alcoholic man who had had 2 consecutive episodes of E. coli meningitis within 2 months. In both episodes there was a favorable response to ceftriaxone. However, normotensive hydrocephalus appeared a few weeks later, with mental and physical deterioration.

Topics: Aged; Alcoholism; Ceftriaxone; Cephalosporins; Escherichia coli Infections; Humans; Hydrocephalus, Normal Pressure; Male; Meningitis, Bacterial; Recurrence; Tomography, X-Ray Computed

Topics: Aged; Alcoholism; Ceftriaxone; Humans; Male; Middle Aged; Neurosyphilis; Penicillin Resistance

Twenty-four alcoholic patients with community-acquired pneumonia were studied for 2 years in order to define clinical signs and etiology. Blood cultures and serological profiles were done for all patients in addition to standard blood analyses. All had an invasive procedure -transthoracic puncture with an ultrafine 25G needle (20 patients) or telescopic catheter with bacteriologic brush (4 patients). When we were unable to obtain a good sputum sample (5 patients), a culture was grown. The patients' mean age was 48 and 83% had an acute clinical profile (< or = 7 days with symptoms) with "typical" signs. The X-rays showed an alveolar pattern in all patients, with cavitation in 29%. Etiological diagnosis was reached in 17 (71%) cases, with St. Pneumoniae (25%), anaerobic microorganisms (20%) and C. burnetii (12.5%) being the germs found most frequently. The invasive techniques were more useful (54%) than the blood cultures (17%) or sputum cultures (4%), and they were well tolerated and uncomplicated. Empirical antibiotic treatment was modified for 12 patients (50%). Seventeen percent required intensive care treatment and mortality was 12.5%.

Topics: Adult; Alcoholism; Bacteria; Bacterial Infections; Ceftriaxone; Clindamycin; Community-Acquired Infections; Humans; Male; Middle Aged; Pneumonia; Prospective Studies; Spain