ro13-9904 and Disease-Models--Animal

To investigate the pathophysiological process of ceftriaxone-induced urolithiasis and its associated acute kidney injury (AKI) based on an animal study and summarize the main clinical characteristics based on a Chinese clinical systematic review.. Male Sprague-Dawley rats were randomly divided into five groups of six each according to different treatments including control; ceftriaxone; ceftriaxone with calcium; calcium; and ceftriaxone, calcium with citrate, respectively. The 24-h urine volume, serum creatinine (Scr) and blood urea nitrogen (BUN) were measured; kidney histological examination and stone analysis were performed. Systematic searches of the Chinese Knowledge Database were conducted for reports on ceftriaxone-induced urolithiasis and AKI. The eligibility of each full-text publication was accessed, and qualified data were extracted and reviewed.. Kidney stones and a significantly low 24-h urine volume with increased high Scr and BUN levels were found in the group that received ceftriaxone combined with calcium. Citrate was able to inhibit these biochemical changes and stone formations. A total of 161 qualified patients were included in the Chinese clinical systematic review: The proportion of ceftriaxone-induced urolithiasis was 21.1, 19.3, 19.3, 39.1 and 1.2 % for ages <3, 3-6, 7-17, 18-60 and >60 years. 72.7 % developed acute kidney injury eventually.. Ceftriaxone-induced urolithiasis was associated with a high risk of AKI. The pathophysiological process may be related to urinary obstruction and crystalline nephropathy. Citrate was able to inhibit stone formation and prevent further kidney injury.

Topics: Acute Kidney Injury; Adult; Age Factors; Animals; Biopsy, Needle; Ceftriaxone; China; Cohort Studies; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Immunohistochemistry; Male; Prognosis; Random Allocation; Rats; Rats, Sprague-Dawley; Risk Assessment; Sex Factors; Tomography, X-Ray Computed; Urolithiasis; Young Adult

A critical analysis of two treatment trials of Chinese rhesus macaques infected with Borrelia burgdorferi indicates that insufficient attention was placed on documenting the blood levels, pharmacokinetics, and pharmacodynamic parameters of the antibiotics used in this host. Consequently, it is impossible to conclude that the findings have validity in judging the efficacy of doxycycline or ceftriaxone for the treatment of Borrelia burgdorferi in this animal model.

Topics: Animals; Anti-Bacterial Agents; Antibodies, Bacterial; Borrelia burgdorferi; Ceftriaxone; Disease Models, Animal; Doxycycline; Lyme Disease; Macaca mulatta; Reproducibility of Results; Research Design

To explore the protective effect and mechanism of Bifidobacterium bifidum TMC3115 of improving the gut microbiota disorder caused by antibiotic exposurein early life, and the possible protection of inflammatory bowel disease in adulthood in mice.. 80 newborn mice were randomly divided into 3 groups, a blank control group(n=40), a ceftriaxone exposure group(n=20), a Bifidobacterium bifidum TMC3115 intervention group(n=20). After birth, they were respectively treated with saline, ceftriaxone(100 mg/kg), and ceftriaxone(100 mg/kg) + TMC3115(1×10~9CFU/d) for 3 weeks. After 3 weeks, half of each group was randomly sacrificed, and the rest were normally fed to 6 weeks. At 6 weeks, the blank control group was randomly divided into a negative control group(n=10) and a colitis model group(n=10). The negative control group drunk pure water freely, and the other three groups were added 3% DSS to the drinking water for 4 days to induce colitis. At 6 weeks and 4 days, the remaining mice were sacrificed. The weight change, spleen coefficient, gut microbiota analysis based on second-generation sequencing and serum tumor necrosis factor-α(TNF-α), interleukin-6(IL-6), and interleukin-10(IL-10)levels of the mice at 3 weeks and after DSS intervention were recorded. In addition, the colon length and inflammation pathology score of the mice after DSS intervention were also measured.. At 3 weeks, compared with the control, antibiotic exposure in the early life inhibited the weight gain and reduced the diversity and uniformity of the gut microbiota of the mice(P<0.05). The intervention of TMC3115 under antibiotic exposure during this period increased the relative abundance of Bifidobacterium in the intestines(P<0.05), and the effect still existed after DSS stimulation in adulthood, laying the foundation for TMC3115 to exert long-term benefits. After DSS stimulation in adulthood, mice showed significant weight gain inhibition, colon length shorteningand inflammation pathology scoreincrease compared with the negative control(P<0.05), showed the inflammatory bowel disease(IBD)model was successfully constructed. The relative abundance of beneficial bacteria such as Lactobacillus in the Bifidobacterium bifidum TMC3115 intervention group increased compared with the ceftriaxone exposure group(P<0.05), while the relative abundance of harmful bacteria such as Staphylococcus, Clostridium, and Desulfovibrio decreased(P<0.05). Furthermore, the mice exposed to antibiotic in early life produced a stronger immune response, but the mice which received TMC3115 intervention at the same time had a significant decrease in serum TNF-α and IL-6 levels and increase in IL-10 level compared with the mice which only interfered with antibiotics(P<0.05).. Antibiotic exposure in early life is a negative factor for long-term inflammatory bowel disease, and TMC3115 has preventive significance for long-term inflammatory bowel disease under the background of antibiotic exposure. The mechanism of TMC3115 may be to adjust the gut microbiota and balance the immune system.

Topics: Animals; Anti-Bacterial Agents; Bifidobacterium bifidum; Ceftriaxone; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Inflammation; Inflammatory Bowel Diseases; Interleukin-10; Interleukin-6; Mice; Mice, Inbred C57BL; Tumor Necrosis Factor-alpha; Weight Gain

The pathophysiological changes that occur after traumatic brain injury (TBI) can lead to the development of post-traumatic epilepsy, a life-long complication of brain trauma. The etiology of post-traumatic epilepsy remains unknown, but TBI brains exhibit an abnormal excitatory / inhibitory balance. In this study, we examine how brain injury alters susceptibility to chemically-induced seizures in C57Bl/6J mice, and if pharmacological enhancement of glutamate transporters can reduce chronic post-traumatic seizures. We found that controlled cortical impact (CCI) mice display delayed susceptibility to pentylenetetrazol (PTZ)-induced seizures. While CCI mice have no change in seizure susceptibility at 7d post-injury (dpi), at 70dpi they have reduced latency to PTZ-induced seizure onset, higher seizure frequency and longer seizure duration. Quantification of glutamate transporter mRNA showed that levels of Scl1a2 and Scl1a3 mRNA were increased at 7dpi, but significantly decreased at 70dpi. To test if increased levels of glutamate transporters can ameliorate delayed-onset seizure susceptibility in TBI mice, we exposed a new cohort of mice to CCI and administered ceftriaxone (200mg/kg/day) for 14d from 55-70dpi. We found that ceftriaxone significantly increased Scl1a2 and Scl1a3 in CCI mouse brain at 70dpi, and prevented the susceptibility of CCI mice to PTZ-induced seizures. This study demonstrates cortical impact can induce a delayed-onset seizure phenotype in mice. Delayed (55dpi) ceftriaxone treatment enhances glutamate transporter mRNA in the CCI brain, and reduces PTZ-induced seizures in CCI mice.

Topics: Animals; Brain Injuries, Traumatic; Ceftriaxone; Disease Models, Animal; Epilepsy, Post-Traumatic; Glutamates; Humans; Mice; Mice, Inbred C57BL; Pentylenetetrazole; Seizures; Time-to-Treatment

As an "off-target" effect, cephalosporins can enhance glutamate transporter-1 expression in astrocytes to recycle glutamate from synaptic cleft, and exhibited analgesic properties in animals and humans with chronic pain.. In the present study, we focused on making a side-by-side comparison of the analgesic potentials of cefadroxil and ceftriaxone, using rodent models of peripheral neuropathic pain, inflammatory pain and incisional pain. Microdialysis technique was adopted to validate the in vivo glutamate regulatory properties of these two drugs in central nervous system.. We have shown that cefadroxil and ceftriaxone are beneficial in a variety of pain scenarios, without inducing observable side effects. The two cephalosporins worked better on neuropathic pain, rather than inflammatory pain or incisional pain, suggesting nociceptive system was differentially affected. Further, microdialysis has confirmed that cephalosporins can effectively reverse the elevated levels of glutamate in brain of animals with neuropathic pain.. The outcome of this study may guide us to identify a molecular skeleton derived from cefadroxil, based on which we could possibly develop new non-antibiotic analgesic compounds with glutamate recycling properties.

Topics: Analgesics; Animals; Cefadroxil; Ceftriaxone; Disease Models, Animal; Glutamates; Humans; Neuralgia

The rapid occurrence of gonococcal resistance to all classes of antibiotics could lead to untreatable gonorrhea. Thus, development of novel anti-Neisseria gonorrhoeae drugs is urgently needed. Neisseria gonorrhoeae FA1090 is the most used in gonococcal infection mouse models because of its natural resistance to streptomycin. Streptomycin inhibits the urogenital commensal flora that permits gonococcal colonization. However, this strain is drug-susceptible and cannot be used to investigate the efficacy of novel agents against multidrug-resistant N. gonorrhoeae. Hence, to test the in vivo efficacy of new therapeutics against N. gonorrhoeae resistant to the frontline antibiotics, azithromycin, or ceftriaxone, we constructed streptomycin-resistant mutants of N. gonorrhoeae CDC-181 (azithromycin-resistant) and WHO-X (ceftriaxone-resistant). We identified the inoculum size needed to successfully colonize mice. Both mutants, CDC-181-rpsLA128G and WHO-X-rpsLA128G, colonized the genital tract of mice for 14 days with 100% colonization observed for at least 7 days. CDC-181-rpsLA128G demonstrated better colonization of the murine genital tract compared to WHO-X-rpsLA128G. Lower inoculum of WHO-X-rpsLA128G (105 and 106 CFU) colonized mice better than higher inoculum. Overall, our results indicate that CDC-181-rpsLA128G and WHO-X-rpsLA128G can colonize the lower genital tract of mice and are suitable to be used in mouse models to investigate the efficacy of antigonococcal agents.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Ceftriaxone; Disease Models, Animal; Female; Gonorrhea; Mice; Microbial Sensitivity Tests; Neisseria gonorrhoeae; Streptomycin

Niemann-Pick disease, type C1 is a progressive, lethal, neurodegenerative disorder due to endolysosomal storage of unesterified cholesterol. Cerebellar ataxia, as a result of progressive loss of cerebellar Purkinje neurons, is a major symptom of Nieman-Pick disease, type C1. Comparing single cell RNAseq data from control (Npc1

Topics: Animals; Astrocytes; Ceftriaxone; Cells, Cultured; Disease Models, Animal; Excitatory Amino Acid Transporter 1; Female; Glutamic Acid; Humans; Male; Mice; Mice, Inbred BALB C; Niemann-Pick C1 Protein; Niemann-Pick Disease, Type C; Riluzole

It is known that hippocampal epileptogenesis is accompanied by hyperexcitability, glutamate-related neuronal dysfunctions and consequently cognitive deficits. However, the neuroprotective role of astrocytic glutamate uptake through the Glutamate Transporter-1 (GLT-1) remains to be unknown in these processes. Therefore, to assess the effect of glutamate uptake, pharmacological upregulation of GLT-1 using ceftriaxone administration (200 mg/kg/day, i.p, 5 days) was utilized in Li-PIL animal models of temporal lobe epilepsy (TLE). Glutamate concentration and glutamine synthetase activity were analyzed using biochemical assays. In addition, GLT-1 gene expression was assessed by RT-qPCR. Finally, cognitive function was studied using Morris water maze (MWM) test and novel object recognition task (NORT). Our results demonstrated that the acute phase of epileptogenesis (first 72 hours after Status Epilepticus) was accompanied by an increase in the hippocampal glutamate and downregulation of GLT-1 mRNA expression compared to controls. Ceftriaxone administration in epileptic animals led to a reduction of glutamate along with elevation of the level of glutamine synthetase activity and GLT-1 expression in the acute phase. In the chronic phase of epileptogenesis (4 weeks after Status Epilepticus), glutamate levels and GLT-1 expression were decreased compared to controls. Ceftriaxone treatment increased the levels of GLT-1 expression. Furthermore, impaired learning and memory ability in the chronic phase of epileptogenesis was rescued by Ceftriaxone administration. This study shows that astrocytic glutamate uptake can profoundly impact the processes of hippocampal epileptogenesis through the reduction of glutamate-induced excitotoxicity and consequently rescuing of cognitive deficits caused by epilepsy.

Topics: Animals; Ceftriaxone; Cognitive Dysfunction; Disease Models, Animal; Epilepsy, Temporal Lobe; Excitatory Amino Acid Transporter 2; Male; Maze Learning; Neuroprotective Agents; Rats; Rats, Wistar; Recognition, Psychology; Treatment Outcome; Up-Regulation

Studying the impact of antibiotic treatment on otitis media (OM), the leading cause of primary care office visits during childhood, is critical to develop appropriate treatment strategies. Tracking dynamic middle ear conditions during antibiotic treatment is not readily applicable in patients, due to the limited diagnostic techniques available to detect the smaller amount and variation of middle ear effusion (MEE) and middle ear bacterial biofilm, responsible for chronic and recurrent OM. To overcome these challenges, a handheld optical coherence tomography (OCT) system has been developed to monitor in vivo response of biofilms and MEEs in the OM-induced chinchilla model, the standard model for human OM. As a result, the formation of MEE as well as biofilm adherent to the tympanic membrane (TM) was longitudinally assessed as OM developed. Various types of MEEs and biofilms in the chinchilla model were identified, which showed comparable features as those in humans. Furthermore, the effect of antibiotics on the biofilm as well as the amount and type of MEEs was investigated with low-dose and high-dose treatment (ceftriaxone). The capability of OCT to non-invasively track and examine middle ear conditions is highly beneficial for therapeutic OM studies and will lead to improved management of OM in patients.

Topics: Animals; Anti-Bacterial Agents; Biofilms; Ceftriaxone; Chinchilla; Disease Models, Animal; Ear, Middle; Humans; Otitis Media; Otitis Media with Effusion; Tomography, Optical Coherence; Tympanic Membrane

Gut colonization by ESBL-producing Enterobacteriaceae (ESBL-PE) is widespread and is promoted by antibiotic exposure. Higher fecal abundance of ESBL-PE promotes the dissemination of the bacteria in the environment and is associated with increased risk of infection. Ceftriaxone and temocillin are commonly used antibiotics with a different activity on gut flora. Their impact on fecal abundance of ESBL-producing Enterobacteriaceae has not been studied. The objective of this study was to compare the propensity of ceftriaxone and temocillin to modify the abundance of ESBL-producing Escherichia coli in feces of colonized mice.. Mice received broad-spectrum antibiotics in order to disrupt their normal gut flora. A CTX-M-type ESBL-producing E. coli clinical isolate was then administered orally, leading to durable colonization. Thirty days later, mice received either temocillin or ceftriaxone with drinking water at a concentration simulating human intestinal exposure. Third-generation-cephalosporin resistant (3GCR) E. coli were enumerated in feces on selective medium before, 2 days and 10 days after the end of antibiotic exposure. The experiment was performed with two E. coli isolates with different temocillin minimum inhibitory concentrations.. Exposure to ceftriaxone induced an increase in the fecal abundance of 3GCR E. coli. In contrast, temocillin had no effect or transiently decreased the number of 3GCR E. coli. Results obtained with the two strains were similar.. Contrary to ceftriaxone, temocillin does not promote expansion of ESBL-producing E. coli in feces of colonized mice. Thus temocillin may be a therapeutic of choice when a temocillin-susceptible strain infection is suspected or proven to prevent the expansion of ESBL-PE in a previously colonized patient.

Topics: Animals; Anti-Bacterial Agents; beta-Lactamases; Ceftriaxone; Disease Models, Animal; Enterobacteriaceae; Escherichia coli; Escherichia coli Infections; Feces; Female; Humans; Male; Mice; Microbial Sensitivity Tests; Penicillins

Topics: Alzheimer Disease; Amino Acid Transport System A; Amyloid beta-Protein Precursor; Animals; Anti-Bacterial Agents; Ceftriaxone; Disease Models, Animal; Excitatory Amino Acid Transporter 2; Gene Knockdown Techniques; Glutamic Acid; Glutaminase; Mice; Mice, Transgenic; Presenilin-1; Presynaptic Terminals; Synaptic Vesicles; Vesicular Glutamate Transport Protein 1; Vesicular Glutamate Transport Protein 2

The complement C1q plays a critical role in microglial phagocytosis of glutamatergic synapses and in the pathogenesis of neuroinflammation in Alzheimer's disease (AD). We recently reported that upregulation of metabotropic glutamate receptor signaling is associated with increased synaptic C1q production and subsequent microglial phagocytosis of synapses in the rodent models of AD. Here, we explored the role of astrocytic glutamate transporter in the synaptic C1q production and microglial phagocytosis of hippocampal glutamatergic synapses in a rat model of AD. Activation of astrocyte and reduction glutamate transporter 1 (GLT1) were noted after bilateral microinjection of amyloid-beta (Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Aspartic Acid; Astrocytes; CA1 Region, Hippocampal; Ceftriaxone; Cognition Disorders; Complement C1q; Disease Models, Animal; Excitatory Amino Acid Transporter 2; Glutamic Acid; Male; Microglia; Morris Water Maze Test; Neurons; Patch-Clamp Techniques; Peptide Fragments; Phagocytosis; Rats; Rats, Sprague-Dawley; Receptors, Glutamate; Synapses; Up-Regulation

Fetal alcohol spectrum disorders (FASD) describe a wide range of ethanol-induced developmental disabilities, including craniofacial dysmorphology, and neurochemical and behavioral impairments. Zebrafish has become a popular animal model to evaluate the long-lasting effects of, both, severe and milder forms of FASD, including alterations to neurotransmission. Glutamate is one of the most affected neurotransmitter systems in ethanol-induced developmental disabilities. Therefore, the aim of the present study was to evaluate the functionality of the glutamatergic neurotransmitter system in an adult zebrafish FASD model. Zebrafish larvae (24 h post-fertilization) were exposed to ethanol (0.1 %, 0.25 %, 0.5 %, and 1%) for 2 h. After 4 months, the animals were euthanized and their brains were removed. The following variables were measured: glutamate uptake, glutamate binding, glutamine synthetase activity, Na+/K + ATPase activity, and high-resolution respirometry. Embryonic ethanol exposure reduced Na+-dependent glutamate uptake in the zebrafish brain. This reduction was positively modulated by ceftriaxone treatment, a beta-lactam antibiotic that promotes the expression of the glutamate transporter EAAT2. Moreover, the 0.5 % and 1% ethanol groups demonstrated reduced glutamate binding to brain membranes and decreased Na+/K + ATPase activity in adulthood. In addition, ethanol reduced glutamine synthetase activity in the 1% EtOH group. Embryonic ethanol exposure did not alter the immunocontent of the glutamate vesicular transporter VGLUT2 and the mitochondrial energetic metabolism of the brain in adulthood. Our results suggest that embryonic ethanol exposure may cause significant alterations in glutamatergic neurotransmission in the adult zebrafish brain.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Disease Models, Animal; Ethanol; Female; Fetal Alcohol Spectrum Disorders; Glutamate-Ammonia Ligase; Glutamic Acid; Male; Mitochondria; Sodium-Potassium-Exchanging ATPase; Synaptic Transmission; Vesicular Glutamate Transport Protein 2; Zebrafish

Sepsis is a life-threatening organ dysfunction resulting from inflammatory responses instigated by toxins secreted by bacteria. Immunomodulatory effect of clindamycin is earlier reported in a murine lipopolysaccharide (LPS)-induced sepsis model. There are no studies demonstrating the immunomodulatory effect of clindamycin in combination with ceftriaxone in a clinically relevant murine polymicrobial sepsis model induced by cecal ligation and puncture (CLP). Ceftriaxone is combined to control the bacterial growth. Following 3 h of CLP challenge, Swiss albino mice were administered vehicle, ceftriaxone alone (100 mg/kg, subcutaneously), and in combination with clindamycin at immunomodulatory dose (200 mg/kg, intraperitoneally). Survival was assessed for 5 days, and bacterial count and biochemical and physiological parameters were measured after 18 h of CLP challenge. Ceftriaxone alone caused significant reduction in bacterial count in blood, peritoneal fluid, lung, liver, and kidney homogenate which was not further substantially reduced by ceftriaxone and clindamycin combination. Day 5 survival was greatly improved by combination compared with ceftriaxone alone which was also evident through marked drop in blood glucose, total white blood cell (WBC) count, and body temperature. The combination group significantly mitigated the cytokine (tumor necrosis factor (TNF)-α and interleukin (IL)-6) and myeloperoxidase (MPO) levels in plasma, lung, liver, and kidney of CLP-challenged mice, which further helped in significantly suppressing the elevated levels of liver and kidney function parameters. Clindamycin at immunomodulatory dose in combination with ceftriaxone attenuated organ damage and improved survival of septic mice by suppressing infection, inflammatory responses, and oxidative stress.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antioxidants; Bacterial Load; Ceftriaxone; Clindamycin; Disease Models, Animal; Drug Therapy, Combination; Female; Inflammation Mediators; Interleukin-6; Mice; Oxidative Stress; Peroxidase; Sepsis; Tumor Necrosis Factor-alpha

Global dissemination of the

Topics: Alleles; Animals; Anti-Bacterial Agents; Ceftriaxone; Disease Models, Animal; Drug Resistance, Bacterial; Female; Genetic Fitness; Gonorrhea; Lithocholic Acid; Mice; Microbial Sensitivity Tests; Mutation; Neisseria gonorrhoeae; Palmitic Acid

Emotional stress plays a role in the exacerbation and development of interstitial cystitis/bladder pain syndrome (IC/BPS). Given the significant overlap of brain circuits involved in stress, anxiety, and micturition, and the documented role of glutamate in their regulation, we examined the effects of an increase in glutamate transport on central amplification of stress-induced bladder hyperalgesia, a core feature of IC/BPS.. Wistar-Kyoto rats were exposed to water avoidance stress (WAS, 1 hour/day x 10 days) or sham stress, with subgroups receiving daily administration of ceftriaxone (CTX), an activator of glutamate transport. Thereafter, cystometrograms were obtained during bladder infusion with visceromotor responses (VMR) recorded simultaneously. Cerebral blood flow (CBF) mapping was performed by intravenous injection of [. WAS elicited visceral hypersensitivity during bladder filling as demonstrated by a decreased pressure threshold and VMR threshold triggering the voiding phase. Brain maps revealed stress effects in regions noted to be responsive to bladder filling. CTX diminished visceral hypersensitivity and attenuated many stress-related cerebral activations within the supraspinal micturition circuit and in overlapping limbic and nociceptive regions, including the posterior midline cortex (posterior cingulate/anterior retrosplenium), somatosensory cortex, and anterior thalamus.. CTX diminished bladder hyspersensitivity and attenuated regions of the brain that contribute to nociceptive and micturition circuits, show stress effects, and have been reported to demonstrated altered functionality in patients with IC/BPS. Glutamatergic pharmacologic strategies modulating stress-related bladder dysfunction may be a novel approach to the treatment of IC/BPS.

Topics: Animals; Ceftriaxone; Cystitis, Interstitial; Disease Models, Animal; Female; Hyperalgesia; Neural Pathways; Nociception; Pelvic Pain; Rats; Rats, Inbred WKY; Urination

Meningococcal meningitis (MM) is a life-threatening disease associated with approximately 10% case fatality rates and neurological sequelae in 10-20% of the cases. Recently, we have shown that the matrix metalloproteinase (MMP) inhibitor BB-94 reduced brain injury in a mouse model of MM. The present study aimed to assess whether doxycycline (DOX), a tetracycline that showed a neuroprotective effect as adjuvant therapy in experimental pneumococcal meningitis (PM), would also exert a beneficial effect when given as adjunctive therapy to ceftriaxone (CRO) in experimental MM.. BALB/c mice were infected by the intracisternal route with a group C Neisseria meningitidis strain. Eighteen h post infection (hpi), animals were randomised for treatment with CRO [100 mg/kg subcutaneously (s.c.)], CRO plus DOX (30 mg/kg s.c.) or saline (control s.c.). Antibiotic treatment was repeated 24 and 40 hpi. Mouse survival and clinical signs, bacterial counts in cerebella, brain damage, MMP-9 and cyto/chemokine levels were assessed 48 hpi.. Analysis of bacterial load in cerebella indicated that CRO and CRO + DOX were equally effective at controlling meningococcal replication. No differences in survival were observed between mice treated with CRO (94.4%) or CRO + DOX (95.5%), (p > 0.05). Treatment with CRO + DOX significantly diminished both the number of cerebral hemorrhages (p = 0.029) and the amount of MMP-9 in the brain (p = 0.046) compared to untreated controls, but not to CRO-treated animals (p > 0.05). Levels of inflammatory markers in the brain of mice that received CRO or CRO + DOX were not significantly different (p > 0.05). Overall, there were no significant differences in the parameters assessed between the groups treated with CRO alone or CRO + DOX.. Treatment with CRO + DOX showed similar bactericidal activity to CRO in vivo, suggesting no antagonist effect of DOX on CRO. Combined therapy significantly improved mouse survival and disease severity compared to untreated animals, but addition of DOX to CRO did not offer significant benefits over CRO monotherapy. In contrast to experimental PM, DOX has no adjunctive activity in experimental MM.

Topics: Animals; Anti-Bacterial Agents; Bacterial Load; Ceftriaxone; Cerebral Hemorrhage; Chemokines; Disease Models, Animal; Doxycycline; Drug Therapy, Combination; Female; Humans; Kaplan-Meier Estimate; Matrix Metalloproteinase 9; Meningitis, Meningococcal; Mice; Mice, Inbred BALB C; Neisseria meningitidis, Serogroup C; Random Allocation; Treatment Outcome

Currently, the potential role of the alterations occurring in the liver immune system and intestinal flora in liver injury remains unknown. Our study aimed to explore the impacts of intestinal microbial barrier damage induced by ceftriaxone on liver immunity. We developed the BALB/c mice model by administering ceftriaxone. The intestinal microbial barrier damage was observed by 16S rRNA, and the pathological changes of intestines and livers were detected by H&E or transmission electron microscope. The activation of immunocytes were tested by Flow Cytometry; the expression of LPS, ALT, AST, IL-6 and TNF-α were detected by Limulus Test or ELISA. Compared to the control, the intestinal microbes significantly decreased in ceftriaxone group. Additionally, the weight of cecum contents increased, the intestinal wall became thinner and the villus in the small intestine and cecum were damaged. The expression of LPS and the ratio of liver lymphocytes were significantly increased. H&E results indicated the structures of liver arose the pathologic changes. Meanwhile, the content of serum ALT, AST, IL-6 and TNF-α increased. Collectively, our study indicates that the damages of gut microbial barrier induced by ceftriaxone prompted activation of immunocytes and release of inflammatory cytokines, which may lead to chronic inflammation in liver.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Cecum; Ceftriaxone; Cytokines; Disease Models, Animal; Dysbiosis; Gastrointestinal Microbiome; High-Throughput Nucleotide Sequencing; Host Microbial Interactions; Intestinal Mucosa; Lipopolysaccharides; Liver; Male; Mice; Mice, Inbred BALB C; RNA, Ribosomal, 16S

Escherichia coli is the most common cause of Gram-negative prosthetic joint infections (PJIs) and ciprofloxacin is the first-line antibiofilm antibiotic. Due to the emergence of fluoroquinolone resistance, management of E. coli PJIs has become challenging and is associated with high treatment failure rates. We evaluated the efficacy of a newly isolated bacteriophage ɸWL-3 as a therapeutic agent in combination with ciprofloxacin, fosfomycin, gentamicin, meropenem or ceftriaxone against biofilm of a ciprofloxacin/ceftriaxone-resistant E. coli strain and the ATCC 25922 reference strain. ɸWL-3 was first characterised in terms of virion morphology, absorption rate, burst size and killing kinetics against both E. coli strains. The tested antibiotics presented high inhibitory concentrations (ranging from 16 to >1024 μg/mL) when tested alone against biofilms. Co-administration of ɸWL-3 with antibiotics improved the antibiotic efficacy against biofilm, especially after staggered exposure, reducing the minimum biofilm bactericidal concentration (MBBC) up to 512 times. The in vivo antimicrobial activity of ɸWL-3/fosfomycin combination against both E. coli strains was assessed in a Galleria mellonella invertebrate infection model. Treatment of infected larvae after lethal doses of E. coli resulted in enhanced survival rates when combinatorial therapy with ɸWL-3/fosfomycin was applied on E. coli ATCC 25922-infected larvae compared with monotherapy, but not for EC1-infected larvae, which we speculated could be due to higher release of endotoxins in a shorter period in EC1-infected larvae exposed to ɸWL-3. Our study provides new insights into the use of bacteriophages and antibiotics in the treatment of biofilm-associated infections caused by antibiotic-resistant bacteria.

Topics: Animals; Anti-Bacterial Agents; Bacteriophages; Biofilms; Ceftriaxone; Ciprofloxacin; Combined Modality Therapy; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Escherichia coli; Escherichia coli Infections; Fluoroquinolones; Fosfomycin; Gentamicins; Meropenem; Microbial Sensitivity Tests; Moths; Phage Therapy; Prosthesis-Related Infections

The combination of ampicillin (AMP) and ceftriaxone (CRO) is considered synergistic against Enterococcus faecalis based on in vitro tests and the rabbit endocarditis model, however, in vitro assays are limited by the use of fixed antibiotic concentrations and the rabbit model by poor bacterial growth, high variability, and the use of point dose-effect estimations, that may lead to inaccurate assessment of antibiotic combinations and hinder optimal translation. Here, we tested AMP+CRO against two strains of E. faecalis and one of E. faecium in an optimized mouse thigh infection model that yields high bacterial growth and allows to define the complete dose-response relationship. By fitting Hill's sigmoid model and estimating the parameters maximal effect (Emax) and effective dose 50 (ED50), the following interactions were defined: synergism (Emax increase ≥2 log10 CFU/g), antagonism (Emax reduction ≥1 log10 CFU/g) and potentiation (ED50 reduction ≥50% without changes in Emax). AMP monotherapy was effective against the three strains, yielding valid dose-response curves in terms of dose and the index fT>MIC. CRO monotherapy showed no effect. The combination AMP+CRO against E. faecalis led to potentiation (59-81% ED50 reduction) and not synergism (no changes in Emax). Against E. faecium, the combination was indifferent. The optimized mouse infection model allowed to obtain the complete dose-response curve of AMP+CRO and to define its interaction based on pharmacodynamic parameter changes. Integrating these results with the pharmacokinetics will allow to derive the PK/PD index bound to the activity of the combination, essential for proper translation to the clinic.

Topics: Ampicillin; Animals; Ceftriaxone; Disease Models, Animal; Drug Therapy, Combination; Endocarditis, Bacterial; Enterococcus faecalis; Enterococcus faecium; Gram-Positive Bacterial Infections; Mice; Rabbits

Alexander disease (AxD) is a rare astrogliopathy caused by heterozygous mutations, either inherited or arising de novo, on the glial fibrillary acid protein (GFAP) gene (17q21). Mutations in the GFAP gene make the protein prone to forming aggregates which, together with heat-shock protein 27 (HSP27), αB-crystallin, ubiquitin, and proteasome, contribute to form Rosenthal fibers causing a toxic effect on the cell. Unfortunately, no pharmacological treatment is available yet, except for symptom reduction therapies, and patients undergo a progressive worsening of the disease. The aim of this study was the production of a zebrafish model for AxD, to have a system suitable for drug screening more complex than cell cultures. To this aim, embryos expressing the human

Topics: Alexander Disease; Animals; Animals, Genetically Modified; Ceftriaxone; Disease Models, Animal; Drug Evaluation, Preclinical; Gene Expression; Glial Fibrillary Acidic Protein; Humans; Mutation; Zebrafish

Ascorbate is a low-cost compound with a known bactericidal-synergy to antibitics. However, the synergy depends on concentrations and organisms. Thus, the synergy test by time-kill assay might be appropriate for the screening of the synergy.. We aimed to test the adjuvant property of ascorbate with ceftriaxone, a frequently prescribed β-lactam antibiotic.. Ascorbate was tested with several bacteria from the American Type Culture Collection (ATCC) including Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii and Escherichia coli for i) bactericidal property of ascorbate, alone or with ceftriaxone-combination, by time-kill assay, ii) an influence on the killing-activity of bone -marrow-derived macrophage and iii) the attenuation of myositis mouse model.. The bactericidal synergy (determined with time-kill assay at 24 h) against S. aureus, but not other selected bacteria, was demonstrated in ascorbate (10 and 40 mM) plus ceftriaxone at the minimal inhibitory concentration (1x MIC). Ascorbate alone, without antibiotic, enhanced macrophage killing-activity and directly eliminated bacteria at the concentration 10-40mM and 250mM, respectively (both properties presented against S. aureus and P. aeruginosa, but not other bacteria). Ascorbate with ceftriaxone also reduced bacterial burdens in muscle and serum cytokines of S. aureus -myositis mouse model. Moreover, the synergy against the clinical isolated methicillin resistant S. aureus (MRSA) by time-kill assay and myositis model also presented.. Ascorbate-ceftriaxone synergy against S. aureus was demonstrated by time-kill assay and myositis model. Time-kill assy might be valuable as a screening test to select the patients that potentially benefit from ascorbate- ceftriaxone adjuvant therapy.

Topics: Animals; Anti-Bacterial Agents; Ascorbic Acid; Bacteria; Ceftriaxone; Cytotoxicity, Immunologic; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Macrophages; Male; Mice; Phagocytosis; Staphylococcal Infections; Staphylococcus aureus

Commonly used antibiotics exert their effects predominantly on rapidly growing bacterial cells; yet, the growth dynamics taking place during infection in a complex host environment remain largely unknown. Hence, a means to measure

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Ciprofloxacin; Disease Models, Animal; Escherichia coli; Escherichia coli Infections; Gentamicins; Mice; Peritonitis

Traumatic brain injury (TBI) results in a decrease in glutamate transporter-1 (GLT-1) expression, the major mechanism for glutamate removal from synapses. Coupled with an increase in glutamate release from dead and dying neurons, this causes an increase in extracellular glutamate. The ensuing glutamate excitotoxicity disproportionately damages vulnerable GABAergic parvalbumin-positive inhibitory interneurons, resulting in a progressively worsening cortical excitatory:inhibitory imbalance due to a loss of GABAergic inhibitory tone, as evidenced by chronic post-traumatic symptoms such as epilepsy, and supported by neuropathologic findings. This loss of intracortical inhibition can be measured and followed noninvasively using long-interval paired-pulse transcranial magnetic stimulation with mechanomyography (LI-ppTMS-MMG). Ceftriaxone, a β-lactam antibiotic, is a potent stimulator of the expression of rodent GLT-1 and would presumably decrease excitotoxic damage to GABAergic interneurons. It may thus be a viable antiepileptogenic intervention. Using a rat fluid percussion injury TBI model, we utilized LI-ppTMS-MMG, quantitative PCR, and immunohistochemistry to test whether ceftriaxone treatment preserves intracortical inhibition and cortical parvalbumin-positive inhibitory interneuron function after TBI in rat motor cortex. We show that neocortical GLT-1 gene and protein expression are significantly reduced 1 week after TBI, and this transient loss is mitigated by ceftriaxone. Importantly, whereas intracortical inhibition declines progressively after TBI, 1 week of post-TBI ceftriaxone treatment attenuates the loss of inhibition compared to saline-treated controls. This finding is accompanied by significantly higher parvalbumin gene and protein expression in ceftriaxone-treated injured rats. Our results highlight prospects for ceftriaxone as an intervention after TBI to prevent cortical inhibitory interneuron dysfunction, partly by preserving GLT-1 expression.

Topics: Animals; Anti-Bacterial Agents; Brain Injuries, Traumatic; Ceftriaxone; Disease Models, Animal; Excitatory Amino Acid Transporter 2; GABAergic Neurons; Gene Expression; Interneurons; Male; Motor Cortex; Parvalbumins; Rats, Sprague-Dawley

Cocaine use disorder is a significant public health problem and currently no medications are FDA-approved to reduce cocaine relapse. Drug-associated cues are reported to elicit craving and cocaine-seeking in humans. Repeated, non-reinforced presentations of drug-associated cues (cue extinction) have been proposed to reduce the ability of such cues to prompt drug-seeking. In rodent models of cocaine relapse, cue extinction reduces cocaine relapse when such extinction occurs in the same context as cocaine self-administration, which is not akin to the manner in which treatment would occur in humans. Here we sought to determine whether cue extinction outside of the cocaine self-administration context would reduce relapse in the drug context. We also hypothesized that ceftriaxone, an antibiotic consistently shown to attenuate cocaine relapse in rats, would enhance the relapse-preventing effects of cue extinction.. Rats self-administered intravenous cocaine for 12 days followed by 20-21 days of abstinence. Immediately preceding the relapse test, rats either underwent 6 single daily cue extinction sessions (1 h/day) outside the self-administration context or no extinction with daily handling. Rats also received vehicle or ceftriaxone (200 mg/kg IP) on those six days.. Ceftriaxone attenuated cued relapse relative to vehicle-treated rats, but there was no additive effect of cue extinction on cocaine-seeking. Cue extinction alone did not attenuate relapse.. Thus, in agreement with work in humans, when cue extinction is conducted outside the drug-associated context it does not reduce the risk of relapse alone. Ceftriaxone remains a strong possibility for medication to reduce cocaine relapse in humans.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Cocaine; Cocaine-Related Disorders; Craving; Cues; Disease Models, Animal; Drug-Seeking Behavior; Extinction, Psychological; Male; Rats; Rats, Sprague-Dawley; Recurrence; Self Administration

Ceftriaxone and ciprofloxacin are the drugs of choice in treatment of invasive Salmonella infections. This study discovered a novel type of plasmid, pSa44-CIP-CRO, which was recovered from a S. London strain isolated from meat product and comprised genetic determinants that encoded resistance to both ciprofloxacin and ceftriaxone. This plasmid could be resolved into two daughter plasmids and co-exist with such daughter plasmids in a dynamic form in Salmonella; yet it was only present as a single plasmid in Escherichia coli. One daughter plasmid, pSa44-CRO, was found to carry the bla

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Ciprofloxacin; Disease Models, Animal; Drug Resistance, Bacterial; Escherichia coli; Genes, Bacterial; Meat Products; Mice; Plasmids; Recombination, Genetic; Salmonella; Salmonella Infections; Treatment Failure

Drug resistance traits are rapidly disseminated across bacteria by horizontal gene transfer, especially through plasmids. Plasmid curing agents that are active both in vitro and in vivo will resensitize Multi Drug Resistant (MDR) bacteria to antimicrobial agents. Pectin capped platinum nanoparticles (PtNPs) at sub MIC (20 µM) concentration was effective, in causing loss of Extended Spectrum Beta Lactamase (ESBL) harboring plasmid as evidenced by, absence of plasmid in agarose gel and by a concomitant (16-64 fold) drop in MIC for cell wall inhibitors ceftriaxone and meropenem, in carbapenem resistant Escherichia coli (CREC). Interestingly, the plasmid cured strain exhibited small colony morphology and displayed slower growth both in vitro and in vivo. Complementation of cured strain with plasmid from the wild type strain restored resistance towards meropenem and ceftriaxone. Relative to wild type, plasmid cured strain displayed 50% reduction in biofilm formation. Plasmid curing also occurred in vivo in infected zebrafish with curing efficiency of 17% for nanoparticle + meropenem treatment. PtNPs + meropenem reduced bioburden of CREC in infected zebrafish by 2.4 log CFU. Mechanistic studies revealed that nanoparticle interacted with cell surface and perturbed inner membrane integrity. PtNPs did not induce ROS, yet it caused plasmid DNA cleavage, as evidenced by gyrase inhibition assay. Our study for the first time reveals that PtNPs as plasmid curing agent can resensitize MDR bacteria to selective antimicrobial agents in vivo.

Topics: Animals; Anti-Bacterial Agents; Biofilms; Ceftriaxone; Cell Membrane; Disease Models, Animal; DNA Cleavage; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Escherichia coli; Escherichia coli Infections; Gene Transfer, Horizontal; Humans; Meropenem; Metal Nanoparticles; Microbial Sensitivity Tests; Plasmids; Platinum; Zebrafish

Although most patients with Lyme disease can be cured with a 2-4 week antibiotic therapy, about 10-20% of patients continue to suffer prolonged persistent symptoms, a condition called post-treatment Lyme disease syndrome (PTLDS). The cause for PTLDS is unclear and hotly debated. Borrelia burgdorferi develops morphological variants under stress conditions but their significance is not clear. Here we isolated the biofilm-like microcolony (MC) and planktonic (spirochetal form and round body) (SP) variant forms from the stationary phase culture of B. burgdorferi and showed that the MC and SP variant forms were not only more tolerant to the current Lyme antibiotics but also caused more severe arthritis in mice than the log phase spirochete form (LOG). We propose to divide the persistent Lyme disease into two categories: (1) early development of persistent disease from inoculation with persister/biofilm at the beginning of infection introduced by tick bites, or Type I persistent disease (i.e., PTLDS); and (2) late development of persistent disease due to initial infection not being diagnosed or treated in time such that the infection develops into late persistent disease, or Type II persistent disease. Importantly, we show that the murine infection caused by LOG could be eradicated by ceftriaxone whereas the persistent infection established with MC could not be eradicated by doxycycline (Doxy), ceftriaxone (CefT), or vancomycin (Van), or Doxy+CefT or Van+CefT, but could only be eradicated by the persister drug combination daptomycin+doxycycline+ceftriaxone. We conclude that varying levels of persistence and pathologies of Borrelia infection and the corresponding different treatment responses are mostly dictated by the heterogeneous B. burgdorferi variant forms inoculated at the time of tick bites. These findings may have broad implications for understanding pathogenesis and treatment of not only persistent Lyme disease but also other persistent infections in general and call for studies to evaluate if treatment of persistent infections with persister drug combination regimens is more effective than the current mostly single-antibiotic monotherapy.

Topics: Animals; Biofilms; Borrelia burgdorferi; Ceftriaxone; Disease Models, Animal; Female; Lyme Disease; Mice; Post-Lyme Disease Syndrome; Treatment Failure

The aim of this study was to test whether the perioperative composition of intestinal microbiota can contribute to variable outcomes following vertical sleeve gastrectomy (VSG).. Although bariatric surgery is the most effective treatment for obesity, metabolic outcomes are variable.. Diet-induced obese mice were randomized to VSG or sham surgery, with or without exposure to antibiotics that selectively suppress mainly gram-positive (fidaxomicin, streptomycin) or gram-negative (ceftriaxone) bacteria on postoperative days (POD) 1-4. Fecal microbiota was characterized before surgery and on POD 7 and 28. Mice were metabolically characterized on POD 30-32 and euthanized on POD 35.. VSG resulted in weight loss and shifts in the intestinal microbiota composition relative to sham-operated mice. Antibiotic exposure resulted in sustained reductions in alpha (within-sample) diversity of microbiota and shifts in its composition. All antibiotic treatments proved to be detrimental to metabolic VSG outcomes, regardless of antimicrobial specificity of antibiotics. These effects involved functionally distinct pathways. Specifically, fidaxomicin and streptomycin markedly altered hepatic bile acid signaling and lipid metabolism, while ceftriaxone resulted in greater reduction of key antimicrobial peptides. However, VSG mice exposed to antibiotics, regardless of their specificity, had significantly increased subcutaneous adiposity and impaired glucose homeostasis without changes in food intake relative to control VSG mice.. Dysbiosis induced by brief perioperative antibiotic exposure attenuates weight loss and metabolic improvement following VSG. Potential mechanisms include disruption of bile acid homeostasis and reduction in the production of gut antimicrobial peptides. Results of this study implicate the intestinal microbiota as an important contributor to metabolic homeostasis and a potentially modifiable target influencing clinical outcomes following VSG.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Disease Models, Animal; Fidaxomicin; Gastrectomy; Gastrointestinal Microbiome; Male; Mice; Mice, Inbred C57BL; Obesity; Streptomycin; Treatment Failure; Weight Loss

Pneumonic plague, caused by Yersinia pestis, is a rapidly progressing contagious disease. In the plague mouse model, a single immunization with the EV76 live attenuated Y. pestis strain rapidly induced the expression of hemopexin and haptoglobin in the lung and serum, both of which are important in iron sequestration. Immunization against a concomitant lethal Y. pestis respiratory challenge was correlated with temporary inhibition of disease progression. Combining EV76-immunization and second-line antibiotic treatment, which are individually insufficient, led to a synergistic protective effect that represents a proof of concept for efficient combinational therapy in cases of infection with antibiotic-resistant strains.

Topics: Animals; Anti-Bacterial Agents; Bacterial Vaccines; Ceftriaxone; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Female; Haptoglobins; Hemopexin; Iron; Mice; Mice, Inbred C57BL; Plague; Post-Exposure Prophylaxis; Treatment Outcome; Vaccines, Live, Unattenuated; Yersinia pestis

Pneumococcal meningitis is associated with high risk of neurological sequelae such as cognitive impairment and hearing loss. These sequelae are due to parenchymal brain and inner ear damage primarily induced by the excessive inflammatory reaction in response to bacterial brain invasion. Metformin-a biguanide drug to treat diabetes mellitus type 2-was recently found to suppress neuroinflammation and induce neuroregeneration. This study evaluated the effect of metformin adjunctive to antibiotics on neuroinflammation, brain and inner ear damage, and neurofunctional outcome in experimental pediatric pneumococcal meningitis.. Upon pneumococcal infection, metformin treatment significantly reduced levels of inflammatory cytokines and nitric oxide production in cerebrospinal fluid and in astroglial cell cultures in vitro (p < 0.05). Compared to animals receiving ceftriaxone monotherapy, adjunctive metformin significantly reduced cortical necrosis (p < 0.02) during acute infection and improved median click-induced hearing thresholds (60 dB vs. 100 dB, p < 0.002) 5 weeks after infection. Adjuvant metformin significantly improved pure tone hearing thresholds at all assessed frequencies compared to ceftriaxone monotherapy (p < 0.05) and protected from PM-induced spiral ganglion neuron loss in the inner ear (p < 0.05).. Adjuvant metformin reduces brain injury during pneumococcal meningitis by decreasing the excessive neuroinflammatory response. Furthermore, it protects spiral ganglion neurons in the inner ear and improves hearing impairments after experimental pneumococcal meningitis. These results identify adjuvant metformin as a promising therapeutic option to improve the outcome after pediatric pneumococcal meningitis.

Topics: Animals; Anti-Bacterial Agents; Apoptosis; Ceftriaxone; Cytokines; Disease Models, Animal; Drug Therapy, Combination; Hearing Loss; Hippocampus; Meningitis, Pneumococcal; Metformin; Neurons; Neuroprotective Agents; Rats; Rats, Wistar; Spiral Ganglion; Treatment Outcome

Following nerve injury, down-regulation of astroglial glutamate transporters (GluTs) with subsequent extracellular glutamate accumulation is a key factor contributing to hyperexcitability within the spinal dorsal horn. Some β-lactam antibiotics can up-regulate GluTs, one of which, ceftriaxone, displays analgesic effects in rodent chronic pain models.. Here, the antinociceptive actions of another β-lactam clavulanic acid, which possesses negligible antibiotic activity, were compared with ceftriaxone in rats with chronic constriction injury (CCI)-induced neuropathic pain. In addition, the protein expression of glutamate transporter-1 (GLT1), its splice variant GLT1b and glutamate-aspartate transporter (GLAST) was measured in the spinal cord of CCI rats. Finally, protein expression of the same GluTs was evaluated in cultured astrocytes obtained from rodents and humans.. Repeated injection of ceftriaxone or clavulanic acid over 10 days alleviated CCI-induced mechanical hypersensitivity, whilst clavulanic acid was additionally able to affect the thermal hypersensitivity. In addition, clavulanic acid up-regulated expression of GLT1b within the spinal cord of CCI rats, whereas ceftriaxone failed to modulate expression of any GluTs in this model. However, both clavulanic acid and ceftriaxone up-regulated GLT1 expression in rat cortical and human spinal astrocyte cultures. Furthermore, clavulanic acid increased expression of GLT1b and GLAST in rat astrocytes in a dose-dependent manner.. Thus, clavulanic acid up-regulates GluTs in cultured rodent- and human astroglia and alleviates CCI-induced hypersensitivity, most likely through up-regulation of GLT1b in spinal dorsal horn.. Chronic dosing of clavulanic acid alleviates neuropathic pain in rats and up-regulates glutamate transporters both in vitro and in vivo. Crucially, a similar up-regulation of glutamate transporters in human spinal astrocytes by clavulanic acid supports the development of novel β-lactam-based analgesics, devoid of antibacterial activity, for the clinical treatment of chronic pain.

Topics: Analgesics; Animals; Astrocytes; Ceftriaxone; Cells, Cultured; Clavulanic Acid; Disease Models, Animal; Dose-Response Relationship, Drug; Excitatory Amino Acid Transporter 2; Glutamic Acid; Humans; Male; Neuralgia; Pain Threshold; Rats; Rats, Sprague-Dawley; Spinal Cord; Up-Regulation

Pneumococci are the major cause of bacterial meningitis globally. To cause meningitis pneumococci interact with the 2 endothelial receptors, polymeric immunoglobulin receptor (pIgR) and platelet endothelial cell adhesion molecule (PECAM-1), to penetrate the blood-brain barrier (BBB) and invade the brain.. C57BL/6 mice were infected intravenously with bioluminescent pneumococci, and treated with ceftriaxone (1 hour postinfection) and anti-pIgR and PECAM-1 antibodies (1 or 5 hours postinfection), then monitored for 5 and 10 days. Bacterial brain invasion was analyzed using IVIS imaging and bacterial counts.. Ceftriaxone, given early after pneumococcal challenge, cleared pneumococci from the blood but not from the brain. After combining ceftriaxone with receptor blockade, using anti-pIgR and PECAM-1 antibodies, we found 100% survival after 5 and 10 days of infection, in contrast to 60% for ceftriaxone alone. Combined antibiotic and antibody treatment resulted in no or few viable bacteria in the brain and no microglia activation. Antibodies remained bound to the receptors during the study period. Receptor blockade did not interfere with antibiotic permeability through the BBB.. We suggest that adjunct treatment with pIgR and PECAM-1 antibodies to antibiotics may prevent pneumococcal meningitis development and associated brain damages. However, further evaluations are required.

Topics: Animals; Anti-Bacterial Agents; Antibodies; Bacterial Load; Ceftriaxone; Disease Models, Animal; Drug Therapy, Combination; Intravital Microscopy; Meningitis, Pneumococcal; Mice, Inbred C57BL; Platelet Endothelial Cell Adhesion Molecule-1; Receptors, Polymeric Immunoglobulin; Survival Analysis; Treatment Outcome

Glutamate is a major excitatory neurotransmitter and plays an important role in neuropathic pain, which is frequently caused by nerve damage. According to recent studies, nerve injury induces changes in glutamatergic transmission in the spinal cord and several supraspinal regions, including the periaqueductal gray (PAG). Among glutamate signaling components, accumulating evidence suggests that the glial glutamate transporter GLT1 plays a critical role in neuropathic pain. Indeed, GLT1 expression is reduced in the spinal cord but increased in the PAG after nerve injury, suggesting that the role of GLT1 in neuropathic pain may vary according to the brain region. In this study, we generated PAG-specific and spinal cord-specific GLT1 knockout mice. Nerve injury-induced neuropathic pain was enhanced in spinal cord-specific GLT1 knockout mice but alleviated in PAG-specific GLT1 knockout mice. Thus, nerve injury may enhance glutamatergic neurotransmission from primary sensory neurons to the post-synaptic dorsal horn following downregulation of GLT1 in the spinal cord and result in inadequate descending pain inhibition caused by GLT1 upregulation in the PAG, resulting in neuropathic pain. In addition, ceftriaxone upregulated GLT1 expression in the spinal cord, but not the PAG, of control mice and attenuated tactile hypersensitivity in nerve-injured control mice but not in nerve-injured spinal cord-specific GLT1 knockout mice. Based on these results, the anti-neuropathic pain effect of ceftriaxone is mediated by the upregulation of GLT1 expression in the spinal cord. Thus, selective upregulation of spinal GLT1 and/or downregulation of GLT1 in the PAG represents a potentially novel strategy for the treatment of neuropathic pain.

Topics: Analgesics, Non-Narcotic; Animals; Ceftriaxone; Disease Models, Animal; Excitatory Amino Acid Transporter 2; Hot Temperature; Hyperalgesia; Male; Mice, Inbred C57BL; Mice, Transgenic; Neural Pathways; Neuralgia; Periaqueductal Gray; Sciatic Nerve; Spinal Cord; Touch

The dominant hypothesis about the pathogenesis of Alzheimer's disease (AD) is the "amyloid cascade" concept and modulating the expression of proteins involved in the metabolism of amyloid-beta (Aβ) is proposed as an effective strategy for the prevention and therapy of AD. Recently, we found that an antibiotic ceftriaxone (CEF), which possesses neuroprotective activity, reduced cognitive deficits and neurodegenerative changes in OXYS rats, a model of sporadic AD. The molecular mechanisms of this effect are not completely clear, we suggested that the drug might serve as the regulator of the expression of the genes involved in the metabolism of Aβ and the pathogenesis of AD. The study was aimed to determine the effects of CEF on mRNA levels of Bace1 (encoding β-secretase BACE1 involved in Aβ production), Mme, Ide, Ece1, Ace2 (encoding enzymes involved in Aβ degradation), Epo (encoding erythropoietin related to endothelial function and clearance of Aβ across the blood brain barrier) in the frontal cortex, hippocampus, striatum, hypothalamus, and amygdala of OXYS and Wistar (control strain) male rats. Starting from the age of 14 weeks, animals received CEF (100 mg/kg/day, i.p., 36 days) or saline. mRNA levels were evaluated with RT-qPCR method. Biochemical parameters of plasma were measured for control of system effects of the treatment.. To better understand strain variations studied here, we compared the gene expression between untreated OXYS and Wistar rats. This comparison showed a significant decrease in mRNA levels of Ace2 in the frontal cortex and hypothalamus, and of Actb in the amygdala of untreated OXYS rats. Analysis of potential effects of CEF revealed its novel targets. In the compound-treated OXYS cohort, CEF diminished mRNA levels of Bace1 and Ace2 in the hypothalamus, and Aktb in the frontal cortex. Furthermore, CEF augmented Mme, Ide, and Epo mRNA levels in the amygdala as well as the levels of Ece1 and Aktb in the striatum. Finally, CEF also attenuated the activity of ALT and AST in plasma of OXYS rats.. Those findings disclosed novel targets for CEF action that might be involved into neuroprotective mechanisms at early, pre-plaque stages of AD-like pathology development.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Ceftriaxone; Disease Models, Animal; Gene Expression; Male; Neuroprotective Agents; Rats, Wistar; RNA, Messenger

Sepsis is a life-threatening systemic inflammatory condition triggered as a result of an excessive host immune response to infection. In the past, immunomodulators have demonstrated a protective effect in sepsis. Azithromycin (a macrolide antibiotic) has immunomodulatory activity and was therefore evaluated in combination with ceftriaxone in a clinically relevant murine model of sepsis induced by cecal ligation and puncture (CLP). First, mice underwent CLP and 3 h later were administered the vehicle or a subprotective dose of ceftriaxone (100 mg/kg of body weight subcutaneously) alone or in combination with an immunomodulatory dose of azithromycin (100 mg/kg intraperitoneally). Survival was monitored for 5 days. In order to assess the immunomodulatory activity, parameters such as plasma and lung cytokine (interleukin-6 [IL-6], IL-1β, tumor necrosis factor alpha) concentrations, the plasma glutathione (GSH) concentration, plasma and lung myeloperoxidase (MPO) concentrations, body temperature, blood glucose concentration, and total white blood cell count, along with the bacterial load in blood, peritoneal lavage fluid, and lung homogenate, were measured 18 h after CLP challenge. Azithromycin in the presence of ceftriaxone significantly improved the survival of CLP-challenged mice. Further, the combination attenuated the elevated levels of inflammatory cytokines and MPO in plasma and lung tissue and increased the body temperature and blood glucose and GSH concentrations, which were otherwise markedly decreased in CLP-challenged mice. Ceftriaxone produced a significant reduction in the bacterial load, while coadministration of azithromycin did not produce a further reduction. Therefore, the survival benefit offered by azithromycin was due to immunomodulation and not its antibacterial action. The findings of this study indicate that azithromycin, in conjunction with appropriate antibacterial agents, could provide clinical benefits in sepsis.

Topics: Animals; Azithromycin; Bacterial Load; Ceftriaxone; Disease Models, Animal; Drug Therapy, Combination; Escherichia coli; Escherichia coli Infections; Female; Glutathione; Inflammation; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Lung; Mice; Sepsis; Tumor Necrosis Factor-alpha

Pneumococcal meningitis is associated with high mortality and morbidity rates. Up to 50% of survivors show neurologic sequelae including hearing loss, cognitive impairments and learning disabilities, being particularly detrimental in affected infants and children where adjuvant therapy with dexamethasone has no proven beneficial effect. We evaluated the effect of concomitantly targeting specific pathophysiological mechanisms responsible for brain damage-i.e. matrix-metalloproteinase (MMP) activity and the exacerbated cerebral inflammation provoked through antibiotic-induced bacterial lysis. Here, we combined adjunctive therapies previously shown to be neuroprotective when used as single adjuvant therapies.. Eleven-day-old Wistar rats were infected intracisternally with 6.44 ± 2.17 × 10. We found significantly reduced apoptosis in the hippocampal subgranular zone in infant rats receiving adjuvant Trocade (p < 0.01) or combined adjuvant therapy (p < 0.001). Cortical necrosis was significantly reduced in rats treated with adjuvant daptomycin (p < 0.05) or combined adjuvant therapy (p < 0.05) compared to ceftriaxone monotherapy. Six hours after treatment initiation, CSF cytokine levels were significantly reduced for TNF-α (p < 0.01), IL-1β (p < 0.01), IL-6 (p < 0.001) and IL-10 (p < 0.01) in animals receiving combined adjuvant intervention compared to ceftriaxone monotherapy. Importantly, combined adjuvant therapy significantly improved learning and memory performance in infected animals and reduced hearing loss (77.14 dB vs 60.92 dB, p < 0.05) by preserving low frequency hearing capacity, compared to ceftriaxone monotherapy.. Combined adjuvant therapy with the non-bacteriolytic antibiotic daptomycin and the MMP inhibitor Trocade integrates the neuroprotective effects of both single adjuvants in experimental paediatric pneumococcal meningitis by reducing neuroinflammation and brain damage, thereby improving neurofunctional outcome. This strategy represents a promising therapeutic option to improve the outcome of paediatric patients suffering from pneumococcal meningitis.

Topics: Animals; Animals, Newborn; Anti-Bacterial Agents; Apoptosis; Brain Injuries; Ceftriaxone; Cerebral Cortex; Cytokines; Daptomycin; Disease Models, Animal; Drug Therapy, Combination; Evoked Potentials, Auditory, Brain Stem; Hearing Disorders; Hippocampus; Learning Disabilities; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Maze Learning; Memory Disorders; Meningitis, Pneumococcal; Rats; Streptococcus pneumoniae

Dementia with Lewy bodies (DLB) is characterized by neuronal deficits and

Topics: alpha-Synuclein; Animals; Brain; Ceftriaxone; China; Dementia; Disease Models, Animal; Hippocampus; Lewy Bodies; Lewy Body Disease; Magnetic Resonance Imaging; Male; Neurodegenerative Diseases; Neurons; Rats; Rats, Wistar

Alzheimer's disease (AD) is characterized by progressive impairment of learning, memory, and cognitive deficits. Glutamate is the major excitatory neurotransmitter in the central nervous system and plays an important role in learning, memory, and cognition. The homeostasis and reutilization of glutamate are dependent on astrocytic uptake by glutamate transporter-1 (GLT-1) and the subsequent glutamate-glutamine cycle. Increasing evidence showed impairments in GLT-1 expression and uptake activity and glutamate-glutamine cycle in AD. Ceftriaxone (Cef) has been reported to upregulate the expression and uptake of GLT-1. Therefore, the present study was undertaken to explore whether Cef can improve cognitive deficits of APP/PS1 mice in early stage of AD by upregulating GLT-1 expression, and then promoting the glutamate-glutamine cycle. It was shown that Cef treatment significantly alleviated the cognitive deficits measured by Morris water maze test and upregulated GLT-1 protein expression in the hippocampus of APP/PS1 mice. Particularly, the activity of glutamine synthetase (GS) and the protein expression of system N glutamine transporter 1 (SN1), which are the key factors involved in the glutamate-glutamine cycle, were significantly upregulated as well after the Cef treatment. Furthermore, inhibition of GLT-1 uptake activity by dihydrokainic acid, an inhibitor of GLT-1, blocked the Cef-induced improvement on the cognitive deficits, GS activity, and SN1 expression. The above results suggested that Cef could improve cognitive deficits of APP/PS1 mice in early stage of AD by upregulating the GLT-1 expression, GS activity, and SN1 expression, which would lead to stimulating the glutamate-glutamine cycle.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Anti-Bacterial Agents; Ceftriaxone; Cognition; Disease Models, Animal; Excitatory Amino Acid Transporter 2; Glutamic Acid; Glutamine; Hippocampus; Maze Learning; Mice; Mice, Transgenic; Presenilin-1; Up-Regulation

Rats of OXYS strain are characterized by genetically defined accelerated senescence. Ceftriaxone (CEF) exerts neuroprotective effects by decreasing the excitotoxicity and activation of antioxidant system. Here, we studied the effects of CEF (50 or 100mg/kg/day, i.p., 36 days) on cognitive and neuronal deficits in 5-month-old OXYS rats. Chronic CEF administration in a dose of 100mg/kg partially inhibited impairments of movement and restored the deficit in the novel object recognition in OXYS rats. Neuromorphologically, control OXYS rats exhibited a lowered neuronal density in the hippocampal CA1 area and there was a tendency to decrease in the substantia nigra pars compacta compared to Wistar controls. Both doses of CEF increased the density of pyramidal neurons in the CA1 area in OXYS rats. Control OXYS rats demonstrated a tendency to lower tyrosine hydroxylase (TH) immunoreactivity in the striatum compared with Wistar rats, while CEF treatment at a dose of 50mg/kg significantly augmented this parameter. In control OXYS rats, the levels of neurogenesis in the subgranular zone of the dentate gyrus of the hippocampus were significantly higher than in Wistar rats indicating compensatory processes that probably prevented the further induction of neurogenesis by CEF. Restoration of the recognition function and neuronal density in the CA1 area in OXYS rats after CEF treatment might be related to activation of the mechanisms that provide survival of newborn and mature neurons. The data suggested CEF as a promising pharmacological tool for the prevention of cognitive decline at accelerated aging.

Topics: Aging; Animals; Antioxidants; Brain; CA1 Region, Hippocampal; Ceftriaxone; Cognition; Dentate Gyrus; Disease Models, Animal; Dopaminergic Neurons; Hippocampus; Male; Neurogenesis; Neurons; Neuroprotective Agents; Pars Compacta; Pyramidal Cells; Rats; Rats, Wistar; Tyrosine 3-Monooxygenase

Sepsis, which is induced by severe bacterial infections, is a major cause of death worldwide, and therapies combating the disease are urgently needed. Because many drugs have failed in clinical trials despite their efficacy in mouse models, the development of reliable animal models of sepsis is in great demand. Several studies have suggested that rabbits reflect sepsis-related symptoms more accurately than mice. In this study, we evaluated a rabbit model of acute sepsis caused by the intravenous inoculation of Salmonella enterica. The model reproduces numerous symptoms characteristic of human sepsis including hyperlactatemia, hyperglycemia, leukopenia, hypothermia and the hyperproduction of several pro-inflammatory cytokines. Hence, it was chosen to investigate the proposed ability of Pep19-2.5-an anti-endotoxic peptide with high affinity to lipopolysaccharide and lipoprotein-to attenuate sepsis-associated pathologies in combination with an antibiotic (ceftriaxone). We demonstrate that a combination of Pep19-2.5 and ceftriaxone administered intravenously to the rabbits (1) kills bacteria and eliminates bacteremia 30 min post challenge; (2) inhibits Toll-like receptor 4 agonists in serum 90 min post challenge; (3) reduces serum levels of pro-inflammatory cytokines (interleukin-6 and tumor necrosis factor α); and (4) reverts to hypothermia and gives rise to temperature values indistinguishable from basal levels 330 min post challenge. The two components of the combination displayed synergism in some of these activities, and Pep19-2.5 notably counteracted the endotoxin-inducing potential of ceftriaxone. Thus, the combination therapy of Pep19-2.5 and ceftriaxone holds promise as a candidate for human sepsis therapy.

Topics: Animals; Anti-Bacterial Agents; Bacteremia; Ceftriaxone; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; HEK293 Cells; Humans; Hyperlactatemia; Hypothermia; Interleukin-6; Leukopenia; Lipopolysaccharides; Male; Peptides; Rabbits; Salmonella enterica; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Increased extracellular glutamate may contribute to l-dopa induced dyskinesia, a debilitating side effect faced by Parkinson's disease patients 5 to 10 years after l-dopa treatment. Therapeutic strategies targeting postsynaptic glutamate receptors to mitigate dyskinesia may have limited success because of significant side effects. Increasing glutamate uptake may be another approach to attenuate excess glutamatergic neurotransmission to mitigate dyskinesia severity or prolong the time prior to onset. Initiation of a ceftriaxone regimen at the time of nigrostriatal lesion can attenuate tyrosine hydroxylase loss in conjunction with increased glutamate uptake and glutamate transporter GLT-1 expression in a rat 6-hydroxydopamine model. In this article, we examined if a ceftriaxone regimen initiated 1 week after nigrostriatal lesion, but prior to l-dopa, could reduce l-dopa-induced dyskinesia in an established dyskinesia model.. Ceftriaxone (200 mg/kg, intraperitoneal, once daily, 7 consecutive days) was initiated 7 days post-6-hydroxydopamine lesion (days 7-13) and continued every other week (days 21-27, 35-39) until the end of the study (day 39 postlesion, 20 days of l-dopa).. Ceftriaxone significantly reduced abnormal involuntary movements at 5 time points examined during chronic l-dopa treatment. Partial recovery of motor impairment from nigrostriatal lesion by l-dopa was unaffected by ceftriaxone. The ceftriaxone-treated l-dopa group had significantly increased striatal GLT-1 expression and glutamate uptake. Striatal tyrosine hydroxylase loss in this group was not significantly different when compared with the l-dopa alone group.. Initiation of ceftriaxone after nigrostriatal lesion, but prior to and during l-dopa, may reduce dyskinesia severity without affecting l-dopa efficacy or the reduction of striatal tyrosine hydroxylase loss. © 2017 International Parkinson and Movement Disorder Society.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Disease Models, Animal; Dopamine Agents; Dyskinesia, Drug-Induced; Excitatory Amino Acid Transporter 2; Levodopa; Male; Oxidopamine; Parkinson Disease; Rats; Rats, Sprague-Dawley; Sympatholytics

Ser/Thr protein kinase (STK1) plays a critical role in cell wall biosynthesis of and drug resistance in methicillin-resistant Staphylococcus aureus (MRSA). MRSA strains lacking STK1 become susceptible to failing cephalosporins, such as Ceftriaxone and Cefotaxime. STK1, despite being nonessential protein for MRSA survival, it can serve as an important therapeutic agent for combination therapy. Here, we report a novel small molecule quinazoline compound, Inh2-B1, which specifically inhibits STK1 activity by directly binding to its ATP-binding catalytic domain. Functional analyses encompassing in vitro growth inhibition of MRSA, and in vivo protection studies in mice against the lethal MRSA challenge indicated that at high concentration neither Inh2-B1 nor Ceftriaxone or Cefotaxime alone was able to inhibit the growth of bacteria or protect the challenged mice. However, the growth of MRSA was inhibited, and a significant protection in mice against the bacterial challenge was observed at a micromolar concentration of Ceftriaxone or Cefotaxime in the presence of Inh2-B1. Cell-dependent minimal to no toxicity of Inh2-B1, and its abilities to down-regulate cell wall hydrolase genes and disrupt the biofilm formation of MRSA clearly indicated that Inh2-B1 serves as a therapeutically important "antibiotic-resistance-breaker," which enhances the bactericidal activity of Ceftriaxone/Cefotaxime against highly pathogenic MRSA infection.

Topics: Adenosine Triphosphate; Amino Acid Sequence; Animals; Anti-Bacterial Agents; Binding Sites; Biofilms; Catalytic Domain; Cefotaxime; Ceftriaxone; Cell Line; Cell Wall; Disease Models, Animal; Drug Resistance, Microbial; Drug Resistance, Multiple, Bacterial; Female; Gene Deletion; Genes, Bacterial; Humans; Methicillin-Resistant Staphylococcus aureus; Mice; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Sepsis; Small Molecule Libraries; Virulence Factors

In the present study, we sought to evaluate the feasibility of targeting vascular adhesion protein-1 (VAP-1) by positron emission tomography (PET) for the longitudinal quantitative assessment of Borrelia burgdorferi infection-induced inflammation in mice.. Explicit joint swelling and

Topics: Amine Oxidase (Copper-Containing); Animals; Anti-Bacterial Agents; Arthritis; Borrelia burgdorferi; Ceftriaxone; Cell Adhesion Molecules; Disease Models, Animal; Gallium Radioisotopes; Host-Pathogen Interactions; Humans; Immunohistochemistry; Lyme Disease; Mice; Positron Emission Tomography Computed Tomography; Sialic Acid Binding Immunoglobulin-like Lectins

To evaluate the actual incidence of both microlithiasis and acute cholecystitis during treatment with intravenous ceftriaxone in a new rabbit model.. New Zealand rabbits were treated with intravenous ceftriaxone or saline for 21 days. Ultrasound monitoring of the gallbladder was performed every seven days until the 21st day when histopathology, immunohistochemistry for proliferating cell nuclear antigen (PCNA), pro-caspase-3 and CD68, liver enzyme biochemistry, and chromatography analysis of the bile and sediments were also performed.. All animals treated with ceftriaxone developed acute cholecystitis, confirmed by histopathology (P<0.05) and biliary microlithiasis, except one that exhibited sediment precipitation. In the group treated with ceftriaxone there was an increase in pro-caspase-3, gamma-glutamyl transpeptidase concentration, PCNA expression and in the number of cells positive for anti-CD68 (P<0.05). In the ceftriaxone group, the cholesterol and lecithin concentrations increased in the bile and a high concentration of ceftriaxone was found in the microlithiasis.. Ceftriaxone administered intravenously at therapeutic doses causes a high predisposition for lithogenic bile formation and the development of acute lithiasic cholecystitis.

Topics: Administration, Intravenous; Animals; Anti-Bacterial Agents; Ceftriaxone; Cholecystectomy; Cholecystectomy, Laparoscopic; Cholecystitis, Acute; Cholelithiasis; Disease Models, Animal; Gallbladder; Rabbits; Translational Research, Biomedical

Topics: Actins; Animals; Biomarkers; Bromodeoxyuridine; Ceftriaxone; Cell Proliferation; Cisplatin; Creatinine; Cytoprotection; Disease Models, Animal; Fibrosis; Kidney; Kidney Diseases; Male; Protective Agents; Rats, Wistar; Transforming Growth Factor beta1; Urea; Uric Acid

Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Fatality rates are substantial, and long-term sequelae develop in about half of survivors. Disease outcome has been related to the severity of the pro-inflammatory response in the subarachnoid space. The complement system, which mediates key inflammatory processes, has been implicated as a modulator of pneumococcal meningitis disease severity in animal studies.. We investigated mannose-binding lectin-associated serine protease (MASP-2) levels in cerebrospinal fluid (CSF) samples derived from the diagnostic lumbar puncture, which was available for 307 of 792 pneumococcal meningitis episodes included in our prospective nationwide cohort study (39%), and the association between these levels and clinical outcome. Subsequently, we studied the role of MASP-2 in our experimental pneumococcal meningitis mouse model using Masp2. MASP-2 levels in cerebrospinal fluid of patients with bacterial meningitis were correlated with poor functional outcome. Consistent with these human data, Masp2-deficient mice with pneumococcal meningitis had lower cytokine levels and increased survival compared to WT mice. Adjuvant treatment with MASP-2-specific monoclonal antibodies led to reduced complement activation and decreased disease severity.. MASP-2 contributes to poor disease outcome in human and mice with pneumococcal meningitis. MASP-2-specific monoclonal antibodies can be used to attenuate the inflammatory response in pneumococcal meningitis.

Topics: Aged; Animals; Anti-Bacterial Agents; Antibodies; Ceftriaxone; Cohort Studies; Cytokines; Disease Models, Animal; Female; Freund's Adjuvant; Gene Expression Regulation; Glasgow Outcome Scale; Humans; Male; Mannose-Binding Protein-Associated Serine Proteases; Meningitis, Pneumococcal; Mice; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Time Factors

In the present study, enhancement of the the antibacterial activity of ceftriaxone against Gram-positive (meticillin-resistant Staphylococcus aureus; MRSA) and Gram-negative (Escherichia coli) bacteria with a biodegradable polymer was attempted.. MRSA and E. coli were collected and identified by biochemical and molecular tests. Blank and ceftriaxone-loaded chitosan nanoparticles (CNPs) were prepared by the ionic gelation method. In vitro antibiotic-susceptibility studies were performed by disc diffusion, agar well plate method, Etest and time-kill assay. In vivo activity was assessed using the neutropenic mouse thigh model and cytotoxicity was estimated by MTT (methylthiazolyldiphenyl tetrazolium bromide) assay with the MCF-7 cancer cell line.. MRSA showed 97 % and E. coli 83 % resistance against ceftriaxone in the disc diffusion test. The isolates showing a ≥1024 mg l-1 MIC value for ceftriaxone were selected for further evaluation. In the agar well plate method, the mean zones of inhibition for blank and ceftriaxone-loaded CNPs were 17 and 23 mm, respectively, for MRSA isolates and 15 and 25 mm, respectively, for E. coli isolates. In the time-kill assay, ~1 log10 to ~2.5 log10 reduction in viability was seen with both isolates when treated with ceftriaxone-loaded CNPs over 24 h. The in vivo studies also showed the enhanced antibacterial activity of ceftriaxone-loaded CNPs, with a 41 % reduction in MRSA and a 27 % reduction in E. coli burden. A low cytotoxicity of blank and ceftriaxone-loaded CNPs was seen, with a slight reduction in the percentage viability of cells from 87 to 83 % and from 88 to 81 %, respectively.. The synergistic effect of ceftriaxone-loaded CNPs is a useful finding for the treatment of MRSA and E. coli infections.

Topics: Animals; Anti-Bacterial Agents; Biocompatible Materials; Ceftriaxone; Chitosan; Disease Models, Animal; Drug Synergism; Escherichia coli; Escherichia coli Infections; Methicillin-Resistant Staphylococcus aureus; Mice; Microbial Sensitivity Tests; Microbial Viability; Nanoparticles; Neutropenia; Staphylococcal Infections

We previously reported isolating vancomycin (VAN) highly resistant Staphylococcus aureus (VRSA) strains from clinical methicillin-resistant S. aureus strains by repeating steps of in vitro mutagenesis and VAN selection. Here we describe that the in vitro susceptibility of these VRSA strains to VAN was markedly increased by combined treatment with β-lactams such as ceftriaxone and oxacillin. Furthermore, in an in vivo silkworm infection model with VRSA, a combination of VAN and ceftriaxone exhibited therapeutic effects, whereas a combination of VAN and oxacillin did not. These findings suggest that combining VAN with an appropriate β-lactam, such as ceftriaxone, is therapeutically effective against infectious diseases caused by VRSA.

Topics: Animals; Anti-Bacterial Agents; beta-Lactams; Bombyx; Ceftriaxone; Disease Models, Animal; Drug Synergism; Microbial Sensitivity Tests; Oxacillin; Staphylococcal Infections; Staphylococcus aureus; Vancomycin; Vancomycin Resistance

There are few reports of in vivo muscle strength measurements in animal models of ICU-acquired weakness (ICU-AW). In this study we investigated whether the Escherichia coli (E. coli) septic peritonitis mouse model may serve as an ICU-AW model using in vivo strength measurements and myosin/actin assays, and whether development of ICU-AW is age-dependent in this model.. Young and old mice were injected intraperitoneally with E. coli and treated with ceftriaxone. Forelimb grip strength was measured at multiple time points, and the myosin/actin ratio in muscle was determined.. E. coli administration was not associated with grip strength decrease, neither in young nor in old mice. In old mice, the myosin/actin ratio was lower in E. coli mice at t = 48 h and higher at t = 72 h compared with controls.. This E. coli septic peritonitis mouse model did not induce decreased grip strength. In its current form, it seems unsuitable as a model for ICU-AW.

Topics: Actins; Age Factors; Aging; Animals; Anti-Bacterial Agents; Body Weight; Ceftriaxone; Disease Models, Animal; Escherichia coli; Intensive Care Units; Male; Mice; Mice, Inbred C57BL; Muscle Weakness; Muscle, Skeletal; Myosins; Peritonitis

Psychological stress exacerbates interstitial cystitis/bladder pain syndrome (IC/BPS), a lower urinary tract pain disorder characterized by increased urinary frequency and bladder pain. Glutamate (Glu) is the primary excitatory neurotransmitter modulating nociceptive networks. Glt1, an astrocytic transporter responsible for Glu clearance, is critical in pain signaling termination. We sought to examine the role of Glt1 in stress-induced bladder hyperalgesia and urinary frequency. In a model of stress-induced bladder hyperalgesia with high construct validity to human IC/BPS, female Wistar-Kyoto (WKY) rats were subjected to 10-day water avoidance stress (WAS). Referred hyperalgesia and tactile allodynia were assessed after WAS with von Frey filaments. After behavioral testing, we assessed Glt1 expression in the spinal cord by immunoblotting. We also examined the influence of dihydrokainate (DHK) and ceftriaxone (CTX), which downregulate and upregulate Glt1, respectively, on pain development. Rats exposed to WAS demonstrated increased voiding frequency, increased colonic motility, anxiety-like behaviors, and enhanced visceral hyperalgesia and tactile allodynia. This behavioral phenotype correlated with decreases in spinal Glt1 expression. Exogenous Glt1 downregulation by DHK resulted in hyperalgesia similar to that following WAS. Exogenous Glt1 upregulation via intraperitoneal CTX injection inhibited the development of and reversed preexisting pain and voiding dysfunction induced by WAS. Repeated psychological stress results in voiding dysfunction and hyperalgesia that correlate with altered central nervous system glutamate processing. Manipulation of Glu handling altered the allodynia developing after psychological stress, implicating Glu neurotransmission in the pathophysiology of bladder hyperalgesia in the WAS model of IC/BPS.

Topics: Animals; Behavior, Animal; Ceftriaxone; Disease Models, Animal; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Transporter 2; Female; Gastrointestinal Motility; Hyperalgesia; Kainic Acid; Rats; Rats, Inbred WKY; Spinal Cord; Stress, Physiological; Urinary Bladder; Visceral Pain

The relation between glutamate homeostasis and PPAR gamma has got tremendous importance in nerve trauma and pain. Present study has been designed to elucidate the interaction between the GLT-1 activator (ceftriaxone) and PPAR gamma agonist (pioglitazone) in the spinal nerve ligation induced neuropathic pain.. Male SD rats were subjected to spinal nerve ligation to induce neuropathic pain. Pioglitazone, ceftriaxone and their combination treatments were given for 28 days. Various behavioral, biochemical, neuroinflammatory and apoptotic mediators were assessed subsequently.. In the present study, ligation of L5 and L6 spinal nerves resulted in marked hyperalgesia and allodynia to different mechanical and thermal stimuli. In addition there is marked increase in oxidative-nitrosative stress parameters, inflammatory and apoptotic markers in spinal cord of spinal nerve ligated rats. Treatment with pioglitazone and ceftriaxone significantly prevented these behavioral, biochemical, mitochondrial and cellular alterations in rats. Further, combination of pioglitazone (10mg/kg, ip) with ceftriaxone (100mg/kg, ip) significantly potentiated the protective effects as compared to their effects per se.. Based on these results we propose that possible interplay between the neuroprotective effects of pioglitazone and ceftriaxone exists in suppressing the behavioral, biochemical, mitochondrial, neuroinflammatory and apoptotic cascades in spinal nerve ligation induced neuropathic pain in rats.

Topics: Animals; Ceftriaxone; Disease Models, Animal; Drug Delivery Systems; Drug Therapy, Combination; Excitatory Amino Acid Transporter 2; Male; Neuralgia; Neuroprotective Agents; Pain Measurement; Pioglitazone; PPAR gamma; Rats; Rats, Sprague-Dawley; Signal Transduction; Thiazolidinediones

Glutamate (Glu) plays a key role in excitotoxicity-related injury in cerebral ischemia. In the brain, Glu homeostasis depends on Glu transporters, including the excitatory amino acid transporters and the cysteine/Glu antiporter (xc-). We hypothesized that drugs acting on Glu transporters, such as ceftriaxone (CEF, 200 mg/kg, i.p.) and N-acetylcysteine (NAC, 150 mg/kg, i.p.), administered repeatedly for 5 days before focal cerebral ischemia in rats and induced by a 90-min middle cerebral artery occlusion (MCAO), may induce brain tolerance to ischemia. We compared the effects of these drugs on brain infarct volume, neurological deficits and the mRNA and protein expression of the Glu transporter-1 (GLT-1) and xc- with the effects of ischemic preconditioning and chemical preconditioning using 3-nitropropionic acid. Administration of CEF and NAC significantly reduced infarct size and neurological deficits caused by a 90-min MCAO. These beneficial effects were accompanied by changes in GLT-1 expression caused by a 90-min MCAO at both the mRNA and protein levels in the frontal cortex, hippocampus, and dorsal striatum. Thus, the results of this study suggest that the regulation of GLT-1 and xc- plays a role in the development of cerebral tolerance to ischemia and that this regulation may be a novel approach in the therapy of brain ischemia.

Topics: Acetylcysteine; Analysis of Variance; Animals; Brain; Brain Edema; Brain Infarction; Ceftriaxone; Disease Models, Animal; Drug Administration Schedule; Enzyme-Linked Immunosorbent Assay; Excitatory Amino Acid Transporter 2; Gene Expression Regulation; Infarction, Middle Cerebral Artery; Male; Nervous System Diseases; Neuroprotective Agents; Rats; Rats, Wistar; RNA, Messenger

Streptococcus pneumoniae is a common cause of sepsis. Effective complement activation is an important component of host defence against invading pathogens, whilst excessive complement activation has been associated with endothelial dysfunction and organ damage. The alternative pathway amplification loop is important for the enhancement of complement activation. Factor H is a key negative regulator of the alternative pathway amplification loop and contributes to tight control of complement activation. We assessed the effect of inhibition of the alternative pathway on sepsis associated inflammation and disease severity using human factor H treatment in a clinically relevant mice model of pneumococcal sepsis. Mice were infected intravenously with live Streptococcus pneumoniae. At the first clinical signs of infection, 17 hours post-infection, mice were treated with ceftriaxone antibiotic. At the same time purified human factor H or in controls PBS was administered. Treatment with human factor H did not attenuate disease scores, serum pro-inflammatory cytokines, or vascular permeability and did not significantly affect C3 and C3a production at 26 h post-infection. Therefore, we conclude that inhibition of the alternative complement pathway by exogenous human factor H fails to attenuate inflammation and vascular leakage at a clinically relevant intervention time point in pneumococcal sepsis in mice.

Topics: Animals; Anti-Bacterial Agents; Capillary Permeability; Ceftriaxone; Complement Factor H; Cytokines; Disease Models, Animal; Female; Humans; Mice; Mice, Inbred C57BL; Pneumococcal Infections; Sepsis; Streptococcus pneumoniae

Manganese-enhanced magnetic resonance imaging (MEMRI) is a widely used technique for detecting neuronal activity in the brain of a living animal. Ceftriaxone (CEF) has been shown to have neuroprotective effects in neurodegenerative diseases. The present study was aimed at clarifying whether, in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) rat model, the known CEF-induced neuronal protection was accompanied by neurogenesis and decreased loss of neuronal activity. After MPTP lesioning (day 0), the rats were treated with CEF (100mg/kg/day, i.p.) or saline for 15 days. They were then injected with MnCl2 (40mg/kg, i.p.) on day 13 and underwent a brain MRI scan on day 14, then the brain was taken for histological evaluation on day 15. The results showed that MPTP lesioning resulted in decreased neuronal activity and density in the nigrostriatal dopaminergic (DAergic) system and the hippocampal CA1, CA3, and dentate gyrus (DG) areas and reduced neurogenesis in the DG, but in hyperactivity in the subthalamic nucleus (STN). These neuronal changes were prevented by CEF treatment. Positive correlations between MEMRI R1 values and neuronal density in the hippocampus were evidenced. Neuronal densities in the hippocampus and SNc were positively correlated. In addition, the R1 value of the STN showed a positive correlation with its neuronal activity but showed a negative correlation with the density of DAergic neurons in the SNc. Therefore, MEMRI R1 value may serve as a good indicator for PD severity and the effect of treatment. To our knowledge, this is the first study showing that CEF prevents loss of neuronal activity and neurogenesis in the brain of PD rats. CEF may therefore have clinical potential in the treatment of PD.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Analysis of Variance; Animals; Brain; Brain Mapping; Bromodeoxyuridine; Ceftriaxone; Disease Models, Animal; Electron Transport Complex IV; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; MPTP Poisoning; Neurodegenerative Diseases; Neurogenesis; Neuroprotective Agents; Rats; Rats, Wistar; Statistics as Topic; Tyrosine 3-Monooxygenase

Community-acquired pneumonia is a common disease with considerable morbidity and mortality, for which Streptococcus pneumoniae is accepted as a leading cause. Although β-lactam-plus-macrolide combination therapy for this disease is recommended in several guidelines, the clinical efficacy of this strategy against pneumococcal pneumonia remains controversial. In this study, we examined the effects of β-lactam-plus-macrolide combination therapy on lethal mouse pneumococcal pneumonia and explored the mechanisms of action in vitro and in vivo We investigated survival, lung bacterial burden, and cellular host responses in bronchoalveolar lavage fluids obtained from mice infected with pneumonia and treated with ceftriaxone, azithromycin, or both in combination. Although in vitro synergy was not observed, significant survival benefits were demonstrated with combination treatment. Lung neutrophil influx was significantly lower in the ceftriaxone-plus-azithromycin-treated group than in the ceftriaxone-treated group, whereas no differences in the lung bacterial burden were observed on day 3 between the ceftriaxone-plus-azithromycin-treated group and the ceftriaxone-treated group. Notably, the analysis of cell surface markers in the ceftriaxone-plus-azithromycin combination group exhibited upregulation of presumed immune checkpoint ligand CD86 and major histocompatibility complex class II in neutrophils and CD11b-positive CD11c-positive (CD11b(+) CD11c(+)) macrophages and dendritic cells, as well as downregulation of immune checkpoint receptors cytotoxic-T lymphocyte-associated antigen 4 and programmed death 1 in T helper and T regulatory cells. Our data demonstrate that the survival benefits of ceftriaxone-plus-azithromycin therapy occur through modulation of immune checkpoints in mouse pneumococcal pneumonia. In addition, immune checkpoint molecules may be a novel target class for future macrolide research.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; B7-2 Antigen; Bacterial Load; CD11b Antigen; CD11c Antigen; Ceftriaxone; Community-Acquired Infections; Dendritic Cells; Disease Models, Animal; Drug Therapy, Combination; Female; Gene Expression; Histocompatibility Antigens Class II; Humans; Macrophages, Alveolar; Mice; Mice, Inbred CBA; Neutrophils; Pneumonia, Pneumococcal; Programmed Cell Death 1 Receptor; Streptococcus pneumoniae; Survival Analysis; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Helper-Inducer

Ischemic stroke increases the propensity to develop depression in humans and laboratory animals, and we hypothesized that such an incidence during pregnancy may increase the risk for the development of postpartum depression (PPD).. To test this hypothesis, we used bilateral common carotid arteries occlusion (BCCAO) to induce transient cerebral ischemia in pregnant rats, and evaluated its effects on subsequent development of PPD in dams. Additionally, we investigated whether ceftriaxone pretreatments before the induction of brain ischemia could alter the propensity of PPD.. We found that 15min BCCAO during pregnancy enhanced immobility time and reduced the frequency of swimming or climbing behaviors in the forced swim test, and decreased the sucrose preference in dams at postpartum day 21. Such behavioral alterations were associated with lower level of GLT-1 expression in the medial prefrontal cortical regions (mPFC) of PPD dams. Specifically, mPFC GLT-1 expression levels in dams with ischemia history were correlated with sucrose preference levels at postpartum day 21. Finally, ceftriaxone pretreatment (200mg/kg/day, 5days) before the 15min BCCAO prevented the development of PPD, and prevented the reduction of GLT-1 expression in the mPFC.. Taken together, our results suggested that ceftriaxone pretreatment before brain ischemia during pregnancy may reduce the propensity for the development of PPD by preventing the loss of GLT-1 expression in the mPFC.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Ceftriaxone; Depression, Postpartum; Disease Models, Animal; Excitatory Amino Acid Transporter 2; Female; Prefrontal Cortex; Pregnancy; Pregnancy Complications, Cardiovascular; Rats; Stroke; Swimming

The host response to Clostridium difficile infection in antibiotic-treated mice is characterized by robust recruitment of Gr-1(+) cells, increased expression of inflammatory cytokines including tumour necrosis factor-α (TNF-α), and the development of severe epithelial damage. To investigate the role of Gr-1(+) cells and TNF-α during C. difficile colitis, we treated infected mice with monoclonal antibodies against Gr-1 or TNF-α. Mice were challenged with vegetative cells of C. difficile strain VPI 10463 following treatment with the third-generation cephalosporin ceftriaxone. Ceftriaxone treatment alone was associated with significant changes in cytokine expression within the colonic mucosa but not overt inflammatory histopathological changes. In comparison, C. difficile infection following ceftriaxone treatment was associated with increased expression of inflammatory cytokines and chemokines including Cxcl1, Cxcl2, Il1b, Il17f and Tnfa, as well as robust recruitment of Ly6C(Mid)  Gr-1(High) neutrophils and Ly6C(High) Gr-1(Mid) monocytes and the development of severe colonic histopathology. Anti-Gr-1 antibody treatment resulted in effective depletion of both Ly6C(Mid) Gr-1(High) neutrophils and Ly6C(High) Gr-1(Mid) monocytes: however, we observed no protection from the development of severe pathology or reduction in expression of the pro-inflammatory cytokines Il1b, Il6, Il33 and Tnfa following anti-Gr-1 treatment. By contrast, anti-TNF-α treatment did not affect Gr-1(+) cell recruitment, but was associated with increased expression of Il6 and Il1b. Additionally, Ffar2, Ffar3, Tslp, Tff and Ang4 expression was significantly reduced in anti-TNF-α-treated animals, in association with marked intestinal histopathology. These studies raise the possibility that TNF-α may play a role in restraining inflammation and protecting the epithelium during C. difficile infection.

Topics: Animals; Anti-Inflammatory Agents; Antibodies, Monoclonal; Ceftriaxone; Clostridioides difficile; Colon; Disease Models, Animal; Enterocolitis, Pseudomembranous; Gene Expression Regulation; Host-Pathogen Interactions; Inflammation Mediators; Intestinal Mucosa; Male; Mice, Inbred C57BL; Microbiota; Monocytes; Neutrophils; Receptors, Cell Surface; Signal Transduction; Time Factors; Tumor Necrosis Factor-alpha

There is increasing evidence implicating astrocytes in multiple forms of chronic pain, as well as in the specific context of chemotherapy-induced peripheral neuropathy (CIPN). However, it is still unclear what the exact role of astrocytes may be in the context of CIPN. Findings in oxaliplatin and paclitaxel models have displayed altered expression of astrocytic gap junctions and glutamate transporters as means by which astrocytes may contribute to observed behavioral changes. The current study investigated whether these changes were also generalizable to the bortezomib CIPN. Changes in mechanical sensitivity were verified in bortezomib-treated animals, and these changes were prevented by co-treatment with a glial activation inhibitor (minocycline), a gap junction decoupler (carbenoxolone), and by a glutamate transporter upregulator (ceftriaxone). Immunohistochemistry data at day 30 in bortezomib-treated animals showed increases in expression of glial fibrillary acidic protein (GFAP) and connexin 43 but a decrease in GLAST expression. These changes were prevented by co-treatment with minocycline. Follow-up Western blotting data showed a shift in connexin 43 from a non-phosphorylated state to a phosphorylated state, indicating increased trafficking of expressed connexin 43 to the cell membrane. These data suggest that increases in behavioral sensitivity to cutaneous stimuli may be tied to persistent synaptic glutamate resulting from increased calcium flow between spinal astrocytes.

Topics: Animals; Astrocytes; Bortezomib; Carbenoxolone; Ceftriaxone; Central Nervous System Agents; Connexin 43; Disease Models, Animal; Excitatory Amino Acid Transporter 1; Excitatory Amino Acid Transporter 2; Gap Junctions; Glial Fibrillary Acidic Protein; Hyperalgesia; Male; Minocycline; Pain Threshold; Peripheral Nervous System Diseases; Rats, Sprague-Dawley; Spinal Cord

Despite the development of new antibiotic agents, mortality of pneumococcal meningitis remains high. In addition, meningitis results in severe long-term morbidity, most prominently cognitive deficits. Granulocyte colony-stimulating factor (G-CSF) stimulates proliferation and differentiation of hematopoietic progenitor cells and increases the number of circulating neutrophil granulocytes. This study investigated the effect of adjuvant G-CSF treatment on cognitive function after pneumococcal meningitis. C57BL/6 mice were infected by subarachnoid injection of Streptococcus pneumoniae serotype 3 and treated with ceftriaxone and G-CSF subcutaneously or ceftriaxone alone for 5 days. Clinical scores, motor performance, and mortality during bacterial meningitis were unaffected by adjuvant G-CSF treatment. No effect of G-CSF treatment on production of proinflammatory cytokines or activation of microglia or astrocytes was observed. The G-CSF treatment did, however, result in hippocampal neurogenesis and improved spatial learning performance 6 weeks after meningitis. These results suggest that G-CSF might offer a new adjuvant therapeutic approach in bacterial meningitis to reduce long-term cognitive deficits.

Topics: Adult Stem Cells; Animals; Anti-Bacterial Agents; Ceftriaxone; Cell Differentiation; Cognition Disorders; Cytokines; Disease Models, Animal; Granulocyte Colony-Stimulating Factor; Hippocampus; Male; Maze Learning; Meningitis, Pneumococcal; Mice; Mice, Inbred C57BL; Motor Activity; Neurogenesis; Phosphorylation; Streptococcus pneumoniae; Time Factors

Spinocerebellar ataxia type 28 (SCA28) is a neurodegenerative disease caused by mutations of the mitochondrial protease AFG3L2. The SCA28 mouse model, which is haploinsufficient for Afg3l2, exhibits a progressive decline in motor function and displays dark degeneration of Purkinje cells (PC-DCD) of mitochondrial origin. Here, we determined that mitochondria in cultured Afg3l2-deficient PCs ineffectively buffer evoked Ca²⁺ peaks, resulting in enhanced cytoplasmic Ca²⁺ concentrations, which subsequently triggers PC-DCD. This Ca²⁺-handling defect is the result of negative synergism between mitochondrial depolarization and altered organelle trafficking to PC dendrites in Afg3l2-mutant cells. In SCA28 mice, partial genetic silencing of the metabotropic glutamate receptor mGluR1 decreased Ca²⁺ influx in PCs and reversed the ataxic phenotype. Moreover, administration of the β-lactam antibiotic ceftriaxone, which promotes synaptic glutamate clearance, thereby reducing Ca²⁺ influx, improved ataxia-associated phenotypes in SCA28 mice when given either prior to or after symptom onset. Together, the results of this study indicate that ineffective mitochondrial Ca²⁺ handling in PCs underlies SCA28 pathogenesis and suggest that strategies that lower glutamate stimulation of PCs should be further explored as a potential treatment for SCA28 patients.

Topics: Animals; ATP-Dependent Proteases; ATPases Associated with Diverse Cellular Activities; Calcium; Calcium Signaling; Ceftriaxone; Dendrites; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Mice, Inbred BALB C; Mice, Transgenic; Mitochondria; Psychomotor Performance; Purkinje Cells; Spinocerebellar Ataxias; Spinocerebellar Degenerations

Glutamatergic hyperactivity plays an important role in the pathophysiology of Parkinson's disease (PD). Ceftriaxone increases expression of glutamate transporter 1 (GLT-1) and affords neuroprotection. This study was aimed at clarifying whether ceftriaxone prevented, or reversed, behavioral and neuronal deficits in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model. Male Wistar rats were injected daily with either ceftriaxone starting 5 days before or 3 days after MPTP lesioning (day 0) or saline and underwent a bar-test on days 1-7, a T-maze test on days 9-11, and an object recognition test on days 12-14, then the brains were taken for histological evaluation on day 15. Dopaminergic degeneration in the substantia nigra pars compacta and striatum was observed on days 3 and 15. Motor dysfunction in the bar test was observed on day 1, but disappeared by day 7. In addition, lesioning resulted in deficits in working memory in the T-maze test and in object recognition in the object recognition task, but these were not observed in rats treated pre- or post-lesioning with ceftriaxone. Lesioning also caused neurodegeneration in the hippocampal CA1 area and induced glutamatergic hyperactivity in the subthalamic nucleus, and both changes were suppressed by ceftriaxone. Increased GLT-1 expression and its co-localization with astrocytes were observed in the striatum and hippocampus in the ceftriaxone-treated animals. To our knowledge, this is the first study showing a relationship between ceftriaxone-induced GLT-1 expression, neuroprotection, and improved cognition in a PD rat model. Ceftriaxone may have clinical potential for the prevention and treatment of dementia associated with PD.

Topics: Animals; Astrocytes; Brain; Ceftriaxone; Disease Models, Animal; Dopaminergic Neurons; Excitatory Amino Acid Transporter 2; Male; Maze Learning; Motor Activity; Neuroprotective Agents; Parkinsonian Disorders; Rats; Rats, Wistar; Recognition, Psychology

Deltamethrin (DLM) is a synthetic class II pyrethroid acaricide and insecticide widely used for veterinary and agricultural purposes. However, its animal and human exposure leads to nephrotoxicity. Our experimental objective was to evaluate protective effects of ceftriaxone and/or ascorbic acid against DLM-induced renal injury in male Wistar albino rats. DLM-treated animals revealed significant alterations in serum biochemical parameters related to renal injury; urea, uric acid and creatinine. There was a significant increase in renal lipid peroxidation and a significant inhibition in antioxidant biomarkers. Moreover, DLM significantly reduced serum acetylcholinesterase (AChE) activity. In addition, It induced serum and kidney tumor necrosis factor-α (TNF-α). Both ceftriaxone and ascorbic acid protect against DLM-induced biochemical alterations in serum and renal tissue when used alone or in combination along with DLM-intoxication. Furthermore, both ceftriaxone and ascorbic acid produced synergetic nephroprotective and antioxidant effects. Therefore, it could be concluded that ceftriaxone and/or ascorbic acid administration able to minimize the toxic effects of DLM through their free radical-scavenging and potent antioxidant activity.

Topics: Acetylcholinesterase; Animals; Antioxidants; Ascorbic Acid; Ceftriaxone; Creatinine; Disease Models, Animal; Insecticides; Kidney Diseases; Lipid Peroxidation; Male; Nitriles; Oxidative Stress; Protective Agents; Pyrethrins; Rats; Rats, Wistar; Treatment Outcome; Tumor Necrosis Factor-alpha; Uric Acid

Decorin binding proteins A and B (DbpA and B) of Borrelia burgdorferi are of critical importance for the virulence of the spirochete. The objective of the present study was to further clarify the contribution of DbpA and B to development of arthritis and persistence of B. burgdorferi after antibiotic treatment in a murine model of Lyme borreliosis. With that goal, mice were infected with B. burgdorferi strains expressing either DbpA or DbpB, or both DbpA and B, or with a strain lacking the adhesins. Arthritis development was monitored up to 15 weeks after infection, and bacterial persistence was studied after ceftriaxone and immunosuppressive treatments. Mice infected with the B. burgdorferi strain expressing both DbpA and B developed an early and prominent joint swelling. In contrast, while strains that expressed DbpA or B alone, or the strain that was DbpA and B deficient, were able to colonize mouse joints, they caused only negligible joint manifestations. Ceftriaxone treatment at two or six weeks of infection totally abolished joint swelling, and all ceftriaxone treated mice were B. burgdorferi culture negative. Antibiotic treated mice, which were immunosuppressed by anti-TNF-alpha, remained culture negative. Importantly, among ceftriaxone treated mice, B. burgdorferi DNA was detected by PCR uniformly in joint samples of mice infected with DbpA and B expressing bacteria, while this was not observed in mice infected with the DbpA and B deficient strain. In conclusion, these results show that both DbpA and B adhesins are crucial for early and prominent arthritis development in mice. Also, post-treatment borrelial DNA persistence appears to be dependent on the expression of DbpA and B on B. burgdorferi surface. Results of the immunosuppression studies suggest that the persisting material in the joints of antibiotic treated mice is DNA or DNA containing remnants rather than live bacteria.

Topics: Adhesins, Bacterial; Animals; Anti-Bacterial Agents; Borrelia burgdorferi; Ceftriaxone; Disease Models, Animal; DNA, Bacterial; Immunosuppressive Agents; Lyme Disease; Mice; Treatment Outcome

High mortality and morbidity rates are observed in patients with bacterial meningitis (BM) and urge for new adjuvant treatments in addition to standard antibiotic therapies. In BM the hippocampal dentate gyrus is injured by apoptosis while in cortical areas ischemic necrosis occurs. Experimental therapies aimed at reducing the inflammatory response and brain damage have successfully been evaluated in animal models of BM. Fluoxetine (FLX) is an anti-depressant of the selective serotonin reuptake inhibitors (SSRI) and was previously shown to be neuroprotective in vitro and in vivo. We therefore assessed the neuroprotective effect of FLX in experimental pneumococcal meningitis.. Infant rats were infected intracisternally with live Streptococcus pneumoniae. Intraperitoneal treatment with FLX (10mgkg(-1)d(-1)) or an equal volume of NaCl was initiated 15min later. 18, 27, and 42h after infection, the animals were clinically (weight, clinical score, mortality) evaluated and subject to a cisternal puncture and inflammatory parameters (i.e., cyto-/chemokines, myeloperoxidase activity, matrix metalloproteinase concentrations) were measured in cerebrospinal fluid (CSF) samples. At 42h after infection, animals were sacrificed and the brains collected for histomorphometrical analysis of brain damage.. A significant lower number of animals treated with FLX showed relevant hippocampal apoptosis when compared to littermates (9/19 animals vs 18/23, P=0.038). A trend for less damage in cortical areas was observed in FLX-treated animals compared to controls (13/19 vs 13/23, P=ns). Clinical and inflammatory parameters were not affected by FLX treatment.. A significant neuroprotective effect of FLX on the hippocampus was observed in acute pneumococcal meningitis in infant rats.

Topics: Animals; Animals, Newborn; Anti-Bacterial Agents; Antidepressive Agents, Second-Generation; Apoptosis; Brain Injuries; Ceftriaxone; Cytokines; Disease Models, Animal; Fluoxetine; Granulocyte Colony-Stimulating Factor; Hippocampus; Interleukin-3; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Meningitis, Pneumococcal; Rats; Recombinant Fusion Proteins; Streptococcus pneumoniae

Glial glutamate transporter, GLT-1, is the major Na(+)-driven glutamate transporter to control glutamate levels in synapses and prevent glutamate-induced excitotoxicity implicated in neurodegenerative disorders including Alzheimer's disease (AD). Significant functional loss of GLT-1 has been reported to correlate well with synaptic degeneration and severity of cognitive impairment among AD patients, yet the underlying molecular mechanism and its pathological consequence in AD are not well understood. Here, we find the temporal decrease in GLT-1 levels in the hippocampus of the 3xTg-AD mouse model and that the pharmacological upregulation of GLT-1 significantly ameliorates the age-dependent pathological tau accumulation, restores synaptic proteins, and rescues cognitive decline with minimal effects on Aβ pathology. In primary neuron and astrocyte coculture, naturally secreted Aβ species significantly downregulate GLT-1 steady-state and expression levels. Taken together, our data strongly suggest that GLT-1 restoration is neuroprotective and Aβ-induced astrocyte dysfunction represented by a functional loss of GLT-1 may serve as one of the major pathological links between Aβ and tau pathology.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Astrocytes; Brain; Ceftriaxone; Cells, Cultured; Disease Models, Animal; Excitatory Amino Acid Transporter 2; Glutamic Acid; Mice, Inbred C57BL; Mice, Transgenic; Neurons; tau Proteins; Up-Regulation

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

Studies have shown that administration of the β-lactam antibiotic ceftriaxone (CEF) attenuates ethanol consumption and cocaine seeking behavior as well as prevents ethanol-induced downregulation of glutamate transporter 1 (GLT-1) expression in central reward brain regions. However, it is not known if these effects are compound-specific. Therefore, the present study examined the effects of two other β-lactam antibiotics, amoxicillin (AMOX) and amoxicillin/clavulanate (Augmentin, AUG), on ethanol drinking, as well as GLT-1 and phosphorylated-AKT (pAKT) levels in the nucleus accumbens (Acb) and medial prefrontal cortex (mPFC) of alcohol-preferring (P) rats. P rats were exposed to free-choice of ethanol (15% and 30%) for five weeks and were given five consecutive daily i.p. injections of saline vehicle, 100 mg/kg AMOX or 100mg/kg AUG. Both compounds significantly decreased ethanol intake and significantly increased GLT-1 expression in the Acb. AUG also increased GLT-1 expression in the mPFC. Results for changes in pAKT levels matched those for GLT-1, indicating that β-lactam antibiotic-induced reductions in ethanol intake are negatively associated with increases in GLT-1 and pAKT levels within two critical brains regions mediating drug reward and reinforcement. These findings add to a growing literature that pharmacological increases in GLT-1 expression are associated with decreases in ethanol intake and suggest that one mechanism mediating this effect may be increased phosphorylation of AKT. Thus, GLT-1 and pAKT may serve as molecular targets for the treatment of alcohol and drug abuse/dependence.

Topics: Alcohol Deterrents; Alcohol Drinking; Amoxicillin; Animals; Anti-Bacterial Agents; Ceftriaxone; Central Nervous System Depressants; Choice Behavior; Dietary Sucrose; Disease Models, Animal; Ethanol; Excitatory Amino Acid Transporter 2; Male; Nucleus Accumbens; Phosphorylation; Prefrontal Cortex; Proto-Oncogene Proteins c-akt; Random Allocation; Rats; Water

The β-lactam antibiotic ceftriaxone stimulates glutamate transporter GLT-1 expression and is effective in neuropathic and visceral pain models. This study examined the effects of ceftriaxone and its interactions with different analgesics (ibuprofen, celecoxib, paracetamol, and levetiracetam) in somatic and visceral pain models in rodents.. The effects of ceftriaxone (intraperitoneally/intraplantarly), analgesics (orally), and their combinations were examined in the carrageenan-induced paw inflammatory hyperalgesia model in rats (n = 6-12) and in the acetic acid-induced writhing test in mice (n = 6-10). The type of interaction between ceftriaxone and analgesics was determined by isobolographic analysis.. Pretreatment with intraperitoneally administered ceftriaxone (10-200 mg/kg per day) for 7 days produced a significant dose-dependent antihyperalgesia in the somatic inflammatory model. Acute administration of ceftriaxone, via either intraperitoneal (10-200 mg/kg) or intraplantar (0.05-0.2 mg per paw) routes, produced a significant and dose-dependent but less efficacious antihyperalgesia. In the visceral pain model, significant dose-dependent antinociception of ceftriaxone (25-200 mg/kg per day) was observed only after the 7-day pretreatment. Isobolographic analysis in the inflammatory hyperalgesia model revealed approximately 10-fold reduction of doses of both drugs in all examined combinations. In the visceral nociception model, more than 7- and 17-fold reduction of doses of both drugs was observed in combinations of ceftriaxone with ibuprofen/paracetamol and celecoxib/levetiracetam, respectively.. Ceftriaxone exerts antihyperalgesia/antinociception in both somatic and visceral inflammatory pain. Its efficacy is higher after a 7-day pretreatment than after acute administration. The two-drug combinations of ceftriaxone and the nonsteroidal analgesics/levetiracetam have synergistic interactions in both pain models. These results suggest that ceftriaxone, particularly in combinations with ibuprofen, celecoxib, paracetamol, or levetiracetam, may provide useful approach to the clinical treatment of inflammation-related pain.

Topics: Acetaminophen; Analgesics; Analgesics, Non-Narcotic; Animals; Anti-Bacterial Agents; Ceftriaxone; Celecoxib; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Hyperalgesia; Ibuprofen; Inflammation; Levetiracetam; Male; Pain; Piracetam; Pyrazoles; Rats; Rats, Wistar; Sulfonamides

Traumatic brain injury (TBI) is a leading cause of mortality and disability in children and young adults worldwide. Neurologic impairment is caused by both immediate brain tissue disruption and post-injury cellular and molecular events that worsen the primary neurologic insult. The β-lactam antibiotic ceftriaxone (CTX) has been reported to induce neuroprotection in animal models of diverse neurologic diseases via up-regulation of GLT-1. However, no studies have addressed the neuroprotective role of CTX in the setting of TBI, and whether the mechanism is involved in the modulation of neuronal autophagy remains totally unclear. The present study was designed to determine the hypothesis that administration of CTX could significantly enhance functional recovery in a rat model of TBI and whether CTX treatment could up-regulate GLT-1 expression and suppress post-TBI neuronal autophagy. The results demonstrated that daily treatment with CTX attenuated TBI-induced brain edema and cognitive function deficits in rats. GLT-1 is down-regulated following TBI and this phenomenon can be reversed by treatment of CTX. In addition, we also found that CTX significantly reduced autophagy marker protein, LC3 II, in hippocampus compared to the TBI group. These results suggest that CTX might provide a new therapeutic strategy for TBI and this protection might be associated with up-regulation of GLT-1 and suppression of neuronal autophagy.

Topics: Animals; Autophagy; Brain Edema; Brain Injuries; Ceftriaxone; Cognition Disorders; Disease Models, Animal; Excitatory Amino Acid Transporter 2; Hippocampus; Male; Maze Learning; Microtubule-Associated Proteins; Neuroprotective Agents; Random Allocation; Rats, Sprague-Dawley; Recovery of Function; Up-Regulation

Pneumococcal meningitis often results in death or neurological sequelae, but the underlying pathogenetic mechanisms remain poorly understood. In C57BL/6J mice subjected to intracerebroventricular (icv) challenge with Streptococcus pneumoniae, the chemokine CCL2 and cytokines interferon-γ, interleukin (IL)-1β, IL-6 and tumour necrosis factor were prominently expressed in the brain during the acute phase of the disease. The upregulation of these immune mediators was markedly diminished in IL-18-deficient mice. Uninfected IL-18(-/-) mice exhibited decreases in anxiety phenotype and licking behaviour, and an increase in behavioural habituation, in an automated monitoring system (the IntelliCage). Without antibiotic intervention, a majority of IL-18(+/+) mice developed irreversible disease after icv S. pneumoniae but this was significantly improved by deleting IL-18 gene function. IL-18(+/+) mice cured of pneumococcal meningitis with four doses of ceftriaxone, initiated at 20 h post-inoculation, showed enduring sequelae. These included abnormal behavioural phenotypes featuring diurnal hypoactivity and nocturnal hyperactivity, light phobia and disrupted cognitive function. While the hyperactive phenotype was absent in the corresponding IL-18(-/-) survivors, cognitive impairments and behavioural deficits were still present. Overall, the results suggest that the high levels of cytokines and/or chemokines released after pneumococcal challenge provoked a series of pathological events, ultimately causing acute death. Furthermore, since only a subset of behavioural phenotypes were ameliorated in the pneumococcus-infected IL-18(-/-) mice, the pathological pathways causing mortality may be, at least in part, distinct from those leading to long-term neurological sequelae.

Topics: Animals; Anti-Bacterial Agents; Anxiety; Ceftriaxone; Chemokines; Circadian Rhythm; Cognition Disorders; Cytokines; Disease Models, Animal; Disease Progression; Drinking Behavior; Exploratory Behavior; Female; Habituation, Psychophysiologic; Interleukin-18; Meningitis, Pneumococcal; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Photic Stimulation

Early brain injury (EBI) after subarachnoid hemorrhage (SAH) is characterized by a reduction in excitatory amino acid transporter 2 (EAAT2) expression and severe amino acid excitotoxicity. The aim of this study was to explore the neuroprotective effect of ceftriaxone (CEF), a potent compound that up-regulates EAAT2, against EBI and the potential mechanisms using in vitro experiments and a rat model of SAH. Intracisternal treatment with CEF significantly improved neurological outcomes and alleviated extracellular glutamate accumulation after SAH. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL) staining and Western blot analysis of cleaved caspase 3 showed that CEF decreased hippocampal neuronal apoptosis following SAH. Immunofluorescent staining and Western blotting revealed that CEF significantly reversed the down-regulation of EAAT2 expression following SAH. In Morris water maze (MWM) tests, CEF remarkably ameliorated the SAH-induced cognitive dysfunction in spatial learning memory and reference memory. CEF promoted the nuclear translocation of p65 as well as the activation of Akt in hippocampal astrocytes in vitro and in vivo. These findings suggest that CEF may exert significant protective effects against EBI following SAH by modulating the PI3K/Akt/NF-κB signaling pathway.

Topics: Animals; Apoptosis; Astrocytes; Brain Injuries; Caspase 3; Ceftriaxone; Cells, Cultured; Cognition Disorders; Disease Models, Animal; Excitatory Amino Acid Transporter 2; Glutamic Acid; Hippocampus; Male; Neoplasm Proteins; Neurons; Neuroprotective Agents; NF-kappa B; Nucleocytoplasmic Transport Proteins; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Signal Transduction; Subarachnoid Hemorrhage

We aimed to evaluate the microbiological and immunological effects of tissue plasminogen activator (tPA) in a rat model of peritonitis.. Twenty-four male Wistar albino rats were divided equally into three groups. Peritonitis and thereafter laparotomy and partial omentectomy were performed in all rats. The control group (C) had no further treatment. The antibiotics group (A) received metronidazole and ceftriaxone. The antibiotic and tPA group (A+T) received the same antibiotics as well as tPA. For microbiological and immunological analysis, blood samples were obtained at the 24th hour, and peritoneal fluid samples were obtained at the 24th and 72nd hours. On the fifth day after surgery, all rats were sacrificed, and the macroscopic findings of the peritoneal cavity were recorded.. The mean number of intraperitoneal abscesses was significantly higher in the control group and the lowest in the two treatment group (A+T). The levels of cytokines were not significantly different between groups. Giving tPA reduced the number and sizes of the abscesses with no significant difference in inflammatory response.. In this experimental peritonitis model, it can be postulated that tPA decreased abscess formation without exaggerating the inflammatory response.

Topics: Abdominal Abscess; Animals; Anti-Bacterial Agents; Ascitic Fluid; Ceftriaxone; Cytokines; Disease Models, Animal; Male; Metronidazole; Peritonitis; Rats; Rats, Wistar; Tissue Plasminogen Activator

Reducing the enduring vulnerability to relapse is a therapeutic goal in treating drug addiction. Studies with animal models of drug addiction show a marked increase in extrasynaptic glutamate in the core subcompartment of the nucleus accumbens (NAcore) during reinstated drug seeking. However, the synaptic mechanisms linking drug-induced changes in extrasynaptic glutamate to relapse are poorly understood. Here, we discovered impaired glutamate elimination in rats extinguished from heroin self-administration that leads to spillover of synaptically released glutamate into the nonsynaptic extracellular space in NAcore and investigated whether restoration of glutamate transport prevented reinstated heroin seeking. Through multiple functional assays of glutamate uptake and analyzing NMDA receptor-mediated currents, we show that heroin self-administration produced long-lasting downregulation of glutamate uptake and surface expression of the transporter GLT-1. This downregulation was associated with spillover of synaptic glutamate to extrasynaptic NMDA receptors within the NAcore. Ceftriaxone restored glutamate uptake and prevented synaptic glutamate spillover and cue-induced heroin seeking. Ceftriaxone-induced inhibition of reinstated heroin seeking was blocked by morpholino-antisense targeting GLT-1 synthesis. These data reveal that the synaptic glutamate spillover in the NAcore results from reduced glutamate transport and is a critical pathophysiological mechanism underling reinstated drug seeking in rats extinguished from heroin self-administration.

Topics: Animals; Aspartic Acid; Ceftriaxone; Conditioning, Operant; Disease Models, Animal; Down-Regulation; Drug-Seeking Behavior; Excitatory Postsynaptic Potentials; Glutamic Acid; Heroin; Heroin Dependence; In Vitro Techniques; Male; Morpholinos; Neurons; Nucleus Accumbens; Potassium; Rats; Rats, Sprague-Dawley; Secondary Prevention; Synapses

Pneumococcal meningitis is a lethal form of bacterial infection in the central nervous system that often causes lifelong neurological sequelae, despite therapeutic advances. The contemporary view is that the inflammatory response to infection contributes to the functional disabilities among survivors of this disease. We previously have established a mouse model of neurobehavioural deficits, using an automated IntelliCage™ system that revealed long-term behavioural and cognitive deficits in C57BL/6J female mice cured of meningitis by ceftriaxone treatment. We now have investigated the roles of two kynurenine pathway enzymes, indoleamine dioxygenase-1 (IDO1) and tryptophan dioxygenase-2 (TDO2), in the pathomechanisms of pneumococcal meningitis. Since tryptophan metabolism has long been implicated in behavioural and cognitive modulation through the production of neuroactive compounds, we hypothesised that preventing the actions of these enzymes through gene knockout would be beneficial in mice subjected to pneumococcal infection. We found no significant effect of IDO1 or TDO2 on mortality. Post-meningitic wild-type mice showed long-term diurnal hypoactivity and nocturnal hyperactivity when they were exposed to an Intellicage adaptation test throughout both the light and dark phases. These changes were not apparent in IDO1(-/-) survivors, but were present in the TDO2(-/-) survivors. Both IDO1(-/-) and TDO2(-/-) survivors were not protected against developing long-term cognitive deficits as measured in IntelliCage-based patrolling or reversal tasks. Collectively, these observations suggest (i) involvement of the kynurenine pathway in causing some behavioural sequelae of pneumococcal meningitis and (ii) that this pathway might operate synergistically with, or independently of, other pathways to cause other aspects of neurological sequelae.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Cognition; Disease Models, Animal; Female; Indoleamine-Pyrrole 2,3,-Dioxygenase; Kynurenine; Meningitis, Pneumococcal; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Neuropsychological Tests; Tryptophan

Pneumococcal meningitis is associated with neurologic sequelae, such as learning and memory impairment. Most recently, a nonbacteriolytic antibiotic has been investigated to minimise the inflammatory host response and prevent cognitive damage. In this study, we compared daptomycin (DPTO) or ceftriaxone (CFX) treatment on the inflammatory parameters and on the blood-brain barrier (BBB) integrity in experimental pneumococcal meningitis. In the first experiment, the animals received 10 µl of a Streptococcus pneumoniae suspension or artificial cerebrospinal fluid by intracerebroventricular (i.c.v.) and were treated with CFX or DPTO at 18 h post-infection. The animals were euthanised at 18, 20, 24, 36 and 40 h post-infection. In the hippocampus, brain-derived neurotrophic factor (BDNF), tumour necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and IL-10 levels were not different between treatment groups; however, IL-4 and cytokine-induced neutrophil chemoattractant 1 (CINC-1) levels decreased in the CFX group. In the frontal cortex, TNF-α, IL- 4, IL-6, IL-10 and BDNF levels were not different between treatment groups. Only CINC-1 levels decreased at 40 h postinfection with CFX treatment. In the second experiment, the animals received DPTO or CFX for 7 days and were euthanised 10 days after pneumococcal meningitis induction. TNF-α, IL-6, IL-10, CINC-1 and BDNF levels were not different between treatment groups in the hippocampus; however, IL-4 levels decreased in CFX group. In the third experiment, the animals received 10 µl of an S. pneumoniae suspension or artificial CSF by i.c.v. and were treated with a single dose of CFX or DTPO antibiotic; assessment of the BBB breakdown showed that both antibiotics prevented the BBB disruption. Both treatments equally protected the BBB integrity, and there were no significant difference in cytokine production.

Topics: Animals; Anti-Bacterial Agents; Blood-Brain Barrier; Brain-Derived Neurotrophic Factor; Ceftriaxone; Cytokines; Daptomycin; Disease Models, Animal; Dose-Response Relationship, Drug; Hippocampus; Male; Meningitis, Pneumococcal; Rats; Rats, Wistar; Streptococcus pneumoniae; Time Factors

Neonatal Escherichia coli meningitis continues to be an important cause of mortality and morbidity in newborns worldwide. The aim of this study was to investigate the cytokines/chemokines, brain-derived neurotrophic factor (BDNF) levels, blood-brain barrier integrity in neonatal rats following E. coli K1 experimental meningitis infection and subsequent behavioural parameters in adulthood. In the hippocampus, interleukin increased at 96 h, IL-6 at 12, 48 and 96 h, IL-10 at 96 h, cytokine-induced neutrophil chemoattractant-1 at 6, 12, 24, 48 and 96 h, and BDNF at 48 and 96 h. In the cerebrospinal fluid, tumour necrosis factor alpha levels increased at 6, 12, 24, 48 and 96 h. The BBB breakdown occurred at 12 h in the hippocampus, and at 6h in the cortex. We evaluated behavioural parameters in adulthood: habituation to the open-field, step-down inhibitory avoidance, object recognition, continuous multiple-trials step-down inhibitory avoidance and forced swimming tasks. In adulthood, the animals showed habituation and aversive memory impairment. The animals needed a significant increase in the number of training periods to learn and not had depressive-like symptoms.

Topics: Animals; Animals, Newborn; Anti-Bacterial Agents; Avoidance Learning; Blood-Brain Barrier; Brain-Derived Neurotrophic Factor; Ceftriaxone; Cytokines; Disease Models, Animal; Escherichia coli Infections; Gene Expression Regulation, Bacterial; Learning Disabilities; Male; Memory Disorders; Meningitis, Bacterial; Rats; Rats, Wistar; Reaction Time; Recognition, Psychology; Time Factors

In this study, our objective was to determine whether a synergistic antimicrobial combination in vitro would be beneficial in the downregulation of pneumococcal virulence genes and whether the associated inflammation of the lung tissue induced by multidrug-resistant Streptococcus pneumoniae infection in vivo needs to be elucidated in order to consider this mode of therapy in case of severe pneumococcal infection. We investigated in vivo changes in the expression of these virulence determinants using an efficacious combination determined in previous studies. BALB/c mice were infected with 10(6) CFU of bacteria. Intravenous levofloxacin at 150 mg/kg and/or ceftriaxone at 50 mg/kg were initiated 18 h postinfection; the animals were sacrificed 0 to 24 h after the initiation of treatment. The levels of cytokines, chemokines, and C-reactive protein (CRP) in the serum and lungs, along with the levels of myeloperoxidase and nitric oxide the inflammatory cell count in bronchoalveolar lavage fluid (BALF), changes in pneumolysin and autolysin gene expression and COX-2 and inducible nitric oxide synthase (iNOS) protein expression in the lungs were estimated. Combination therapy downregulated inflammation and promoted bacterial clearance. Pneumolysin and autolysin expression was downregulated, with a concomitant decrease in the expression of COX-2 and iNOS in lung tissue. Thus, the combination of levofloxacin and ceftriaxone can be considered for therapeutic use even in cases of pneumonia caused by drug-resistant isolates.

Topics: Animals; Anti-Bacterial Agents; Bacteremia; Bacterial Proteins; Bronchoalveolar Lavage Fluid; Ceftriaxone; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Levofloxacin; Male; Mice; Mice, Inbred BALB C; N-Acetylmuramoyl-L-alanine Amidase; Pneumococcal Infections; Pneumonia; Pneumonia, Pneumococcal; Streptococcus pneumoniae; Streptolysins; Virulence; Virulence Factors

Although the neuroprotective effect of ceftriaxone (CTX) has been reported, the underlying mechanisms are still uncertain. In this study, we investigated if rats recover better from CTX pretreatment against cerebral ischemia by inhibiting the inflammatory response.. Rats were pretreated with CTX (200 mg/kg, 1/day, i.p.) for 5 d. At 24 h after the end of the last CTX pretreatment, focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 120 min in male Sprague Dawley rats. The neurological deficit scores (NDS) and infarct volumes were evaluated. Microglia cells were observed by immunofluorescence staining and IL-1β was assayed by ELISA and Western Blot.. The results showed that CTX pretreatment improved the neurological deficit scores and decreased the infarct volumes 24 h after reperfusion. The activation of microglia cells was reduced and the expression of IL-1β was partially inhibited 24 h after reperfusion.. These findings demonstrate that CTX pretreatment may provide a neuroprotective effect against transient cerebral ischemic injury, partially inhibit in microglial activation and reduce the expression of IL-1β.

Topics: Animals; Brain Infarction; Brain Injuries; CD11b Antigen; Ceftriaxone; Disease Models, Animal; Drug Administration Schedule; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Infarction, Middle Cerebral Artery; Interleukin-1beta; Male; Microglia; Neurologic Examination; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Renal Circulation; Reperfusion

In our previous study, ceftriaxone, a beta-lactam antibiotic, elicited antinociceptive effects in the chronic constriction injury (CCI) of neuropathic pain. In this study, we assessed apoptosis and oxidative stress in the spinal cord of neuropathic rats treated with ceftriaxone.. 45 male Wistar rats were divided as naïve, sham, normal saline-treated CCI rats, and CCI animals treated with the effective dose of ceftriaxone. Involvement of Bax, Bcl2, and caspases 3 and 9, important contributors of programmed cell death (apoptosis), was determined using western blotting at days 3 and 7. The markers of oxidative stress including malondialdehyde (MDA) and reduced glutathione (GSH) were measured on days 3 and 7.. Increased Bax/Bcl2 ratio and cleaved active forms of caspases 3 and 9 were observed in the spinal cord of CCI rats on day 3. Ceftriaxone attenuated the increased levels of Bax and cleaved forms of caspases 3 and 9, while it increased Bcl2 levels. Bax and active forms of caspases declined by day 7. Consequently, comparison among groups showed no difference at this time. CCI enhanced MDA and decreased GSH on days 3 and 7, while ceftriaxone protected against the CCI-induced oxidative stress.. Our results suggest that ceftriaxone, an upregulator/activator of GLT1, could concomitantly reduce oxidative stress and apoptosis and producing its new analogs lacking antimicrobial activity may represent a novel approach for neuropathic pain treatment.

Topics: Animals; Anti-Bacterial Agents; Apoptosis; Apoptosis Regulatory Proteins; Ceftriaxone; Disease Models, Animal; Glutathione; Male; Malondialdehyde; Neuralgia; Oxidative Stress; Rats; Rats, Wistar; Time Factors

Previously it was reported that combining antibiotics with L-97-1, an adenosine A1 receptor antagonist, significantly improves survival and blocks acute lung injury induced by Yersinia pestis CO 99 in a rat model of pneumonic plague. In the current studies using a conscious rat model of cecal ligation and puncture (CLP) sepsis, L-97-1 was administered in daily intravenous infusions in combination with antibiotics to simulate the use of L-97-1 as an anti-sepsis therapeutic in the clinical setting. In these studies, when administered at 12 h following CLP, in combination with broad spectrum antibiotics, ceftriaxone and clindamycin, L-97-1 improves 7 day (d) survival [25%, 35%, and 75% for L-97-1 (10 mg/kg/h, 12.5 mg/kg/h, and 15 mg/kg/h, respectively) versus (vs.) 25% for antibiotics alone] in a dose-dependent manner. The addition of L-97-1, 15 mg/kg/h to antibiotics significantly increased 7 d survival following CLP compared to therapy with either antibiotics alone (P=0.002) or L-97-1 at 15 mg/kg/h alone (P<0.001) and was not significantly different than survival in sham CLP animals (Log-rank (Mantel-Cox) test with Bonferroni׳s correction for multiple comparisons). Moreover, in these studies, in combination with antibiotics L-97-1 dose-dependently protects the kidney, significantly improving renal function at 24 h post CLP at 10 mg/kg/h (P<0.001), 12.5 mg/kg/h (P<0.0001), and 15 mg/kg/h (P<0.0001) vs. antibiotics alone (ANOVA followed by Tukey׳s post-hoc test for pair-wise comparisons). The results of these studies support efficacy for L-97-1 as an anti-sepsis therapeutic.

Topics: Adenosine A1 Receptor Antagonists; Animals; Anti-Bacterial Agents; Blood Urea Nitrogen; Cecum; Ceftriaxone; Clindamycin; Cytokines; Disease Models, Animal; Drug Therapy, Combination; Kidney; Ligation; Male; Peritonitis; Protective Agents; Purines; Rats, Sprague-Dawley; Sepsis

Recent studies showed that both sepsis and antibiotic therapy are associated with cell death and linked to reactive oxygen species generation. This study investigated the effects of intratracheal administration of combinations of antioxidants (n-acetyl cysteine (NAC), vitamins C and E) in the treatment of sepsis-induced lung injury.. Ninety-six male Wistar rats subjected to sepsis were treated with ceftriaxone plus NAC with or without vitamins C and E and compared to appropriate controls. As an index of oxidative damage protein carbonyls, sulfhydryl groups, lipid peroxidation and superoxide anion were measured, as well as superoxide dismutase and catalase. Histopathological alterations and mortality rate were also analyzed.. Twenty-four hours after sepsis induction, markers of oxidative stress increased in all lungs examined. Ceftriaxone plus intratracheal combination of NAC, vitamins C and E decreased lung injury in infected animals by reducing superoxide anion production (54%), lipid peroxidation (53%) and protein carbonyl (58%) and restored the redox status (7.5 times). This therapy also reduced the imbalance of antioxidant enzymes activities and attenuated the alveolar architectural disorganization, inflammatory cell infiltration and pulmonary oedema. Survival increased from 66.6% with ceftriaxone to 83.2% with ceftriaxone plus antioxidants.. Ceftriaxone plus intratracheal co-administration of antioxidants provides better protection, by decreasing pulmonary oxidative stress, limiting histophatological alterations and improving survival. Antioxidants should be explored as a co-adjuvant in the treatment of severe lung injury.

Topics: Acetylcysteine; Animals; Anti-Bacterial Agents; Antioxidants; Ascorbic Acid; Ceftriaxone; Disease Models, Animal; Drug Administration Routes; Drug Therapy, Combination; Lung Injury; Male; Rats; Rats, Wistar; Sepsis; Trachea; Vitamin E

Peripheral neuropathy is a common adverse effect of bortezomib-based chemotherapy. In this study we have investigated the role played by subtype 5 of metabotropic receptors in bortezomib induced peripheral neuropathy. Rats were administered with bortezomib three times weekly at 0.20 mg/kg for a total of 4 weeks in presence or absence of mGluR5 antagonist MPEP. The animals were submitted to paw-pressure test and tail sensory nerve conduction measurement more times during the treatment and follow-up. Bortezomib treatment induced a progressively increasing hyperalgesia in rat which was accompanied by a significant reduction in sensory nerve conduction velocity (SNCV). MPEP prevented the emergence of bortezomib-induced pain and counteracted SNCV reduction when co-administered with bortezomib treatment. Spinal extracellular glutamate levels increased in rats treated with bortezomib. Bortezomib-induced onset of the hyperalgesia and SNCV decrease could be prevented by agents that promote the reuptake of glutamate maintaining spinal glutamate at basal level. Our data support the manipulation of the glutamatergic system through the mGluR5 receptor in bortezomib induced peripheral neuropathy. The use of antagonists at the mGluR5, initiated at the same time as bortezomib-chemotherapy, might reduce the number of patients who develop painful peripheral chemo-neuropathy.

Topics: Analgesics; Animals; Boronic Acids; Bortezomib; Ceftriaxone; Cell Line, Tumor; Cell Survival; Central Nervous System Agents; Disease Models, Animal; Excitatory Amino Acid Antagonists; Glutamic Acid; Humans; Hyperalgesia; Injections, Spinal; Male; Neural Conduction; Neuralgia; Peripheral Nervous System Diseases; Pyrazines; Pyridines; Random Allocation; Rats; Receptor, Metabotropic Glutamate 5

To investigate the expression of glutamate transporter 1 (GLT-1) and determine the effect of GLT-1 overexpression on the visceromotor response ( VMR ) to colorectal distention (CRD) following exposure to post-traumatic stress disorder (PTSD)-like stress.. A beta-lactam antibiotic, ceftriaxone (CTX) was used to selectively induce transcription of the gene encoding GLT-1 and upregulate GLT-1 expression as an agonist. SD rats were divided into five groups, including control group, PTSD group, CTX-treated group, PTSD+CTX group, PTSD+CTX+ dihydrokainate (DHK) group. Seven rats in each VMR-CRD group eventually completed the study. Ten rats in each group were used to test immunofluorescence of GLT-1, however, 8, 9, 8, 10, 7 rats completed the test respectively. The animal model of PTSD was established using basal ovalbumin (OVA)-sensitization combined with single-prolonged stress model (SPS). The alteration of visceral sensitivity following exposure to PTSD-like stress was evaluated by measuring the VMR to CRD. Spinal GLT-1 expression was evaluated by immunofluorescence using confocal laser scanning microscopy.. By immunofluorescence analysis, CTX-treated rats exhibited an increased GLT-1 expression in spinal cord compared with the control group (absorbance: 141.38 ± 2.91 vs 106.25 ± 3.32, P = 0.001). Absorbance of GLT-1 in spinal cord was significantly decreased in PTSD rats, compared with the control rats (86.11 ± 2.73 vs 106.25 ± 3.32, P = 0.001). GLT-1 expression in PTSD rats treated with CTX was significantly increased compared with PTSD group (98.70 ± 3.19 vs 86.11 ± 2.73, P = 0.004 ). VMR to CRD significantly elevated in PTSD group compared with the control group at 20, 40, 60 and 80 mmHg (all P < 0.05, 1 mmHg = 0.133 kPa). VMR significantly declined in PTSD rats treated with CTX when compared with the vehicle at graded CRD pressure (all P < 0.01), however, one-hour pretreatment with selective GLT-1 antagonist dihydrokainate reversed the blunted VMR to CRD produced by CTX (P = 0.002). VMR significantly decreased in CTX group compared with the control group at 40, 60 and 80 mmHg (all P < 0.05).. The study suggests that the PTSD alters visceral sensitivity and GLT-1 overexpression mediated the analgesic effect of CTX following exposure to PTSD-like stress, identifying a specific molecular mechanism for visceral hypersensitivity which may pave the way for novel therapeutic strategies for PTSD-like conditions.

Topics: Amino Acid Transport System X-AG; Animals; Ceftriaxone; Disease Models, Animal; Glutamates; Hyperalgesia; Kainic Acid; Nociception; Rats; Spinal Cord; Stress Disorders, Post-Traumatic; Up-Regulation

Urinary tract infections (UTIs) due to extended-spectrum-β-lactamase (ESBL)-producing Enterobacteriaceae in children are becoming more frequent, and they are commonly treated initially with a second- or third-generation cephalosporin. We developed a murine model of ascending UTI caused by ESBL-producing Escherichia coli. Using this model, we investigated the renal bacterial burden, interleukin-6 (IL-6) expression, and histopathological alterations caused by ESBL- and non-ESBL-producing bacteria after 1, 2, or 6 days with or without ceftriaxone therapy. The renal bacterial burden, IL-6 concentration, and histological inflammatory lesions were not significantly different between mice infected with ESBL- and non-ESBL-producing bacteria without treatment at any of the time points examined. Following ceftriaxone administration, the bacterial burden was eliminated in the kidneys of mice infected with ESBL- and non-ESBL-producing bacteria on the 6th postinfection day. The histological analysis demonstrated that among mice treated with ceftriaxone, those infected with ESBL-producing bacteria had more profound renal alterations than those infected with non-ESBL-producing bacteria on the 6th day (P < 0.001). In comparison, microbiological outcomes did not differ significantly between mice infected with ESBL- and non-ESBL-producing bacteria at any of the time points examined. The effectiveness of ceftriaxone in mice with UTIs due to ESBL-producing E. coli may have therapeutic implications; it is, however, hampered by limited activity on the histopathological lesions, a finding that needs further investigation.

Topics: Animals; Anti-Bacterial Agents; Bacterial Load; beta-Lactamases; Ceftriaxone; Disease Models, Animal; Escherichia coli; Escherichia coli Infections; Female; Gene Expression; Interleukin-6; Kidney; Mice; Mice, Inbred BALB C; Pyelonephritis; Treatment Outcome

Evidence has demonstrated that matrix metalloproteinases (MMPs) contribute to the pathophysiology of bacterial meningitis; therefore, MMP inhibitors may be a neuroprotective treatment for brain injury caused by meningitis because of their antiinflammatory effects. The objective of this study was to evaluate the effect of the MMP inhibitor GM6001 in a rat model of S. pneumoniae meningitis. For these experiments, 7-day-old Sprague-Dawley rats were randomly divided into an uninfected group, meningitis group, antibiotic group and GM6001+antibiotic group. Uninfected animals were sham infected with sterile saline. Rats in the other three groups were inoculated with S. pneumoniae and left untreated, treated with ceftriaxone, or treated with ceftriaxone combined with GM6001. Rats in the meningitis group were severely ill, and MMP-9 was significantly up-regulated. The change in brain water content was consistent with the MMP-9 level. A significant loss of neurons and impaired learning function were observed in the meningitis group. Treatment with the antibiotic and GM6001 significantly down-regulated the level of MMP-9, decreased the brain water content, attenuated neuronal injury and improved learning. Conclusions: GM6001 protected the brain from damage caused by S. pneumoniae, and this effect may occur via downregulating MMP-9 and decreasing brain water content.

Topics: Analysis of Variance; Animals; Animals, Newborn; Anti-Bacterial Agents; Brain Edema; Ceftriaxone; Dipeptides; Disease Models, Animal; Gelatinases; Gene Expression Regulation; Matrix Metalloproteinase 1; Matrix Metalloproteinase 9; Maze Learning; Meningitis, Pneumococcal; Rats; Rats, Sprague-Dawley; Spatial Learning; Spatial Memory

Repeated injections of the antibiotic ceftriaxone cause analgesia in rodents by upregulating the glutamate transporter, GLT-1. No evidence is available in humans. We studied the effect of a single intravenous administration of ceftriaxone in patients undergoing decompressive surgery of the median or ulnar nerves. Forty-five patients were randomized to receive saline, ceftriaxone (2 g), or cefazolin (2 g), 1 hour before surgery. Cefazolin, which is structurally related to ceftriaxone, was used as a negative control. Pain thresholds were measured 10 minutes before drug injections and then 4 to 6 hours after surgery. Ceftriaxone caused analgesia in all patients, whereas cefazolin was inactive. We also performed animal studies to examine whether a single dose of ceftriaxone was sufficient to induce analgesia. A single intraperitoneal injection of ceftriaxone (200 mg/kg), but not cefazoline (200 mg/kg), caused analgesia in mouse models of inflammatory or postsurgical pain, and upregulated GLT-1 in the spinal cord. Ceftriaxone-induced analgesia was additive to that produced by blockade of mGlu5 receptors, which are activated by extrasynaptic glutamate. These data indicate that a single dose of ceftriaxone causes analgesia in humans and mice and suggest that ceftriaxone should be used for preoperative antimicrobial prophylaxis when a fast relief of pain is desired.. The study reports for the first time that a single preoperative dose of ceftriaxone causes analgesia in humans. A single dose of ceftriaxone could also relieve inflammatory and postsurgical pain and upregulate GLT-1 expression in mice. Ceftriaxone should be preferred to other antibiotics for antimicrobial prophylaxis to reduce postoperative pain.

Topics: Adult; Aged; Aged, 80 and over; Analgesics; Animals; Brain; Cefazolin; Ceftriaxone; Decompression, Surgical; Disease Models, Animal; Double-Blind Method; Excitatory Amino Acid Transporter 2; Female; Gene Expression Regulation; Humans; Male; Mice; Mice, Inbred C57BL; Middle Aged; Motor Activity; Pain Measurement; Pain, Postoperative; Peripheral Nervous System Diseases; Rotarod Performance Test; Time Factors

Despite antibiotic therapy, acute and long-term complications are still frequent in pneumococcal meningitis. One important trigger of these complications is oxidative stress, and adjunctive antioxidant treatment with N-acetyl-l-cysteine was suggested to be protective in experimental pneumococcal meningitis. However, studies of effects on neurological long-term sequelae are limited. Here, we investigated the impact of adjunctive N-acetyl-l-cysteine on long-term neurological deficits in a mouse model of meningitis. C57BL/6 mice were intracisternally infected with Streptococcus pneumoniae. Eighteen hours after infection, mice were treated with a combination of ceftriaxone and placebo or ceftriaxone and N-acetyl-l-cysteine, respectively. Two weeks after infection, neurologic deficits were assessed using a clinical score, an open field test (explorative activity), a t-maze test (memory function), and auditory brain stem responses (hearing loss). Furthermore, cochlear histomorphological correlates of hearing loss were assessed. Adjunctive N-acetyl-l-cysteine reduced hearing loss after pneumococcal meningitis, but the effect was minor. There was no significant benefit of adjunctive N-acetyl-l-cysteine treatment in regard to other long-term complications of pneumococcal meningitis. Cochlear morphological correlates of meningitis-associated hearing loss were not reduced by adjunctive N-acetyl-l-cysteine. In conclusion, adjunctive therapy with N-acetyl-l-cysteine at a dosage of 300 mg/kg of body weight intraperitoneally for 4 days reduced hearing loss but not other neurologic deficits after pneumococcal meningitis in mice. These results make a clinical therapeutic benefit of N-acetyl-l-cysteine in the treatment of patients with pneumococcal meningitis questionable.

Topics: Acetylcysteine; Animals; Anti-Bacterial Agents; Ceftriaxone; Cochlea; Disease Models, Animal; Hearing Loss; Male; Meningitis, Pneumococcal; Mice; Mice, Inbred C57BL

The purpose of this study was to investigate the relationship between efficacy and percentage of time above the MIC (%T>MIC) in the cerebrospinal fluid (CSF) for different dosing regimens of meropenem against an experimental lethal meningitis model in guinea pigs with type b β-lactamase-nonproducing ampicillin-resistant Haemophilus influenzae (Hib BLNAR). Guinea pigs were intrathecally inoculated with 10(8) CFU/head of Hib BLNAR 8 h before the start of therapy. A single dose of 20, 40, or 80 mg/kg meropenem or multiple doses of 40 mg/kg meropenem were subcutaneously administered. Numbers of bacteria in CSF were counted 8 h after the start of therapy. Meropenem concentration in serum and CSF were determined in infected guinea pigs receiving a single dose of 40 mg/kg. In the single-dose regimen, 40 and 80 mg/kg meropenem significantly reduced the number of bacteria in CSF compared with the control, but 20 mg/kg meropenem did not. The %T>MIC for an 8-h period of 20, 40, and 80 mg/kg meropenem were 41, 52, and 62, respectively. Two and four doses of 40 mg/kg meropenem, for both of which %T>MIC was calculated as 100, had similar efficacy and were significantly superior to a single-dose of 40 mg/kg. In conclusion, meropenem had high efficacy when %T>MIC in the CSF was increased because of the high dose level and shortening of the dosing interval in a guinea pig meningitis model caused by Hib BLNAR, suggesting that high and frequent doses of meropenem are useful for treatment of meningitis with Hib BLNAR.

Topics: Animals; Anti-Bacterial Agents; beta-Lactam Resistance; Ceftriaxone; Disease Models, Animal; Guinea Pigs; Haemophilus influenzae type b; Male; Meningitis, Haemophilus; Meropenem; Microbial Sensitivity Tests; Thienamycins

Amyotrophic Lateral Sclerosis (ALS) is a fatal, rapidly progressive, neurodegenerative disease caused by motor neuron degeneration. Despite extensive efforts, the underlying cause of ALS and the path of neurodegeneration remain elusive. Astrocyte activation occurs in response to central nervous system (CNS) insult and is considered a double edged sword in many pathological conditions. We propose that reduced glutamatergic and trophic response of astrocytes to activation may, over time, lead to accumulative CNS damage, thus facilitating neurodegeneration. We found that astrocytes derived from the SOD1(G93A) ALS mouse model exhibit a reduced glutamatergic and trophic response to specific activations compared to their wild-type counterparts. Wild-type astrocytes exhibited a robust response when activated with lipopolysaccharide (LPS), G5 or treated with ceftriaxone in many parameters evaluated. These parameters include increased expression of GLT-1 and GLAST the two major astrocytic glutamate transporters, accompanied by a marked increase in the astrocytic glutamate clearance and up-regulation of neurtrophic factor expression. However, not only do un-treated SOD1(G93A) astrocytes take up glutamate less efficiently, but in response to activation they show no further increase in any of the glutamatergic parameters evaluated. Furthermore, activation of wild-type astrocytes, but not SOD1(G93A) astrocytes, improved their ability to protect the motor neuron cell line NSC-34 from glutamate induced excitotoxicity. Our data indicates that altered astrocyte activation may well be pivotal to the pathogenesis of ALS.

Topics: Amyotrophic Lateral Sclerosis; Animals; Astrocytes; Ceftriaxone; Cell Differentiation; Cells, Cultured; Cerebral Cortex; Disease Models, Animal; Lipopolysaccharides; Mice; Mice, Transgenic; Superoxide Dismutase; Superoxide Dismutase-1; Up-Regulation

Multiple sclerosis is associated with a high incidence of depression, cognitive impairments and neuropathic pain. Previously, we demonstrated that tactile allodynia is present at disease onset in an animal model of MS, experimental autoimmune encephalomyelitis (EAE). We have now monitored changes in object recognition in mice with EAE to determine if altered nociceptive sensitivity is also associated with behavioral signs indicative of cognitive impairment in this model. At the onset of clinical signs, mice with EAE showed impairments in the novel object recognition (NOR) assay, indicative of deficits in cognitive functioning early in the disease course. At the spinal level, we found increased gene expression for the cytokines IL-1β, IL-6 and the glutamate transporter EAAT-2 that coincide with increased nociceptive sensitivity and deficits in object recognition. Increased levels of EAAT-2 mRNA appear to be a response to perturbed protein levels of the transporter as we found a loss of EAAT-2 protein levels in the spinal cord of EAE mice. To determine if changes in the levels of EAAT-2 were responsible for the observed changes in nociceptive sensitivity and cognitive deficits, we treated EAE mice with the β-lactam antibiotic ceftriaxone, an agent known to increase glutamate transporter levels in vivo. Ceftriaxone prevented tactile hypersensitivity and normalized performance in the NOR assay in EAE mice. These findings highlight the important interrelationship between pain and cognitive function in the disease and suggest that targeting spinally mediated pain hypersensitivity is a novel therapeutic avenue to treat impairments in other higher order cortical processes.

Topics: Analysis of Variance; Animals; Brain; Ceftriaxone; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Excitatory Amino Acid Transporter 2; Exploratory Behavior; Female; Freund's Adjuvant; Gene Expression Regulation; Hyperalgesia; Interleukin-1beta; Interleukin-6; Mice; Mice, Inbred C57BL; Motor Activity; Myelin-Oligodendrocyte Glycoprotein; Pain Measurement; Pain Threshold; Peptide Fragments; Receptors, N-Methyl-D-Aspartate; Recognition, Psychology; RNA, Messenger; Rotarod Performance Test; Spinal Cord; Time Factors

We investigated the efficiency of the cephamycin cefoxitin as an alternative to carbapenems for the treatment of urinary tract infections (UTIs) due to Escherichia coli producing CTX-M-type extended-spectrum β-lactamases. The susceptible, UTI-inducing E. coli CFT073-RR strain and its transconjugant CFT073-RR Tc (pbla(CTX-M-15)), harboring a bla(CTX-M-15) carrying-plasmid, were used for all experiments. MICs of cefoxitin (FOX), ceftriaxone (CRO), imipenem (IMP), and ertapenem (ETP) for CFT073-RR and CFT073-RR Tc (pbla(CTX-M-15)) were 4 and 4, 0.125 and 512, 0.5 and 0.5, and 0.016 and 0.032 μg/ml, respectively. Bactericidal activity was similarly achieved in vitro against the two strains after 3 h of exposure to concentrations of FOX, IMI, and ETP that were 2 times the MIC, whereas CRO was not bactericidal against CFT073-RR Tc (pbla(CTX-M-15)). The frequencies of spontaneous mutants of the 2 strains were not higher for FOX than for IMP or ETP. In the murine model of UTIs, mice infected for 5 days were treated over 24 h. Therapeutic regimens in mice (200 mg/kg of body weight every 3 h or 4 h for FOX, 70 mg/kg every 6 h for CRO, 100 mg/kg every 2 h for IMP, and 100 mg/kg every 4 h for ETP) were chosen in order to reproduce the percentage of time that free-drug concentrations above the MIC are obtained in humans with standard regimens. All antibiotic regimens produced a significant reduction in bacterial counts (greater than 2 log(10) CFU) in kidneys and bladders for both strains (P < 0.001) without selecting resistant mutants in vivo, but the reduction obtained with CRO against CFT073-RR Tc (pbla(CTX-M-15)) in kidneys was significantly lower than that obtained with FOX. In conclusion, FOX appears to be an effective therapeutic alternative to carbapenems for the treatment of UTIs due to CTX-M-producing E. coli.

Topics: Animals; Anti-Bacterial Agents; Bacterial Load; beta-Lactamases; beta-Lactams; Carbapenems; Cefoxitin; Ceftriaxone; Conjugation, Genetic; Disease Models, Animal; Drug Administration Schedule; Ertapenem; Escherichia coli; Escherichia coli Infections; Female; Humans; Imipenem; Kidney; Mice; Microbial Sensitivity Tests; Mutation Rate; Plasmids; Urinary Bladder; Urinary Tract Infections

Nontyphoidal Salmonella (NTS) species cause self-limiting diarrhea and sometimes severe disease. Antibiotic treatment is considered only in severe cases and immune-compromised patients. The beneficial effects of antibiotic therapy and the consequences for adaptive immune responses are not well understood. We used a mouse model for Salmonella diarrhea to assess the effects of per os treatment with ciprofloxacin (15 mg/kg of body weight intragastrically 2 times/day, 5 days) or parenteral ceftriaxone (50 mg/kg intraperitoneally, 5 days), two common drugs used in human patients. The therapeutic and adverse effects were assessed with respect to generation of a protective adaptive immune response, fecal pathogen excretion, and the emergence of nonsymptomatic excreters. In the mouse model, both therapies reduced disease severity and reduced the level of fecal shedding. In line with clinical data, in most animals, a rebound of pathogen gut colonization/fecal shedding was observed 2 to 12 days after the end of the treatment. Yet, levels of pathogen shedding and frequency of appearance of nonsymptomatic excreters did not differ from those for untreated controls. Moreover, mice treated intraperitoneally with ceftriaxone developed an adaptive immunity protecting the mice from enteropathy in wild-type Salmonella enterica serovar Typhimurium challenge infections. In contrast, the mice treated intragastrically with ciprofloxacin were not protected. Thus, antibiotic treatment regimens can disrupt the adaptive immune response, but treatment regimens may be optimized in order to preserve the generation of protective immunity. It might be of interest to determine whether this also pertains to human patients. In this case, the mouse model might be a tool for further mechanistic studies.

Topics: Adaptive Immunity; Administration, Oral; Animals; Anti-Bacterial Agents; Ceftriaxone; Ciprofloxacin; Colony Count, Microbial; Diarrhea; Disease Models, Animal; Drug Administration Schedule; Feces; Infusions, Parenteral; Mice; Mice, Inbred C57BL; Salmonella Infections; Salmonella typhimurium; Severity of Illness Index

The Centers for Disease Control and Prevention (CDC) recommend oral or intravenous doxycycline plus a third-generation cephalosporin or fluoroquinolone alone for the treatment of Vibrio vulnificus infections. Until now, no study has compared oral with parenteral administered doxycycline with respect to their in vivo efficacy. In the present work, ICR mice infected with a high dose of V. vulnificus were administered ciprofloxacin, ceftriaxone, and doxycycline. The bacterial DNA copy number in surviving and non-surviving mice was determined using quantitative polymerase chain reaction (qPCR). In this setting, ciprofloxacin was the most effective monotherapeutic drug, but a higher survival rate (50%) was achieved using the combination therapy of intraperitoneal doxycycline plus ceftriaxone. The blood of non-surviving mice at 12 h post-infection contained at least 10(4) DNA copies/μL, in contrast to 10(2) to 10(3) DNA copies/μL in surviving mice. Thus, in the treatment of V. vulnificus infections in humans, when the intravenous form of doxycycline is unavailable, ciprofloxacin might be a better option than oral doxycycline to lower mortality. In addition, our results demonstrate that qPCR can be a useful tool for identifying the V. vulnificus load in infected patients, with the DNA copy number providing a marker of either disease severity or mortality.

Topics: Animals; Anti-Bacterial Agents; Bacterial Load; Bacteriological Techniques; Blood; Ceftriaxone; Ciprofloxacin; Disease Models, Animal; Doxycycline; Drug Monitoring; Drug Therapy, Combination; Male; Mice; Real-Time Polymerase Chain Reaction; Survival Analysis; Treatment Outcome; Vibrio Infections; Vibrio vulnificus

The beta-lactam antibiotic, ceftriaxone (CTX), has been reported to induce neuroprotection in animal models of diverse neurologic diseases. Currently, no data have explored the potential for CTX to provide neuroprotection in the animal models of traumatic brain injury (TBI). The aim of this study was to investigate the neuroprotective effect by CTX on TBI and to determine the underlying mechanisms.. Rats were immediately subjected to a lateral cortical impact injury caused by a free-falling object and divided randomly into three groups: sham-operated, trauma, and trauma + CTX treatment group. The CTX treatment group was given CTX (200 mg/kg of body weight, intravenously) immediately after injury. The cognitive function was assessed by Y-maze testing and cerebral edema was evaluated. Inflammatory cytokines expression was measured using enzyme-linked immunosorbent assay array. The expression of glutamate transporter-1 protein was identified by Western blot analysis.. This study shows that the CTX causes attenuation of TBI-induced cerebral edema and cognitive function deficits. CTX treatment significantly reduced levels of the proinflammatory cytokines interleukin-1[beta], interferon-[gamma], and tumor necrosis factor-[alpha] and up-regulated glutamate transporter-1 expression after TBI.. Our results provide in vivo evidence that CTX could exert neuroprotective effect against TBI by improving cognitive function and alleviating brain edema via reducing excitotoxicity and inflammation after TBI.

Topics: Analysis of Variance; Animals; beta-Lactams; Biopsy, Needle; Blotting, Western; Brain Edema; Brain Injuries; Ceftriaxone; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme-Linked Immunosorbent Assay; Excitatory Amino Acid Transporter 2; Immunohistochemistry; Neuroprotective Agents; Random Allocation; Rats; Rats, Sprague-Dawley; Reference Values; Survival Rate; Treatment Outcome; Up-Regulation

Topics: Amyotrophic Lateral Sclerosis; Animals; Anti-Bacterial Agents; Antioxidants; Ceftriaxone; Disease Models, Animal; Disease Progression; Drug Evaluation, Preclinical; Drug Therapy, Combination; Humans; Mice; Mice, Transgenic; Minocycline; Research Design; Superoxide Dismutase; Treatment Outcome; Vitamin E

Neuronal injury in pneumococcal meningitis is a consequence of microglial activation and direct toxicity by bacterial products and systemic inflammation.. The treatment effect of the TEPC-15 antibody recognizing teichoic and lipoteichoic acids was investigated in murine microglial cells and in a rabbit model of pneumococcal meningitis.. In vitro, the TEPC-15 antibody recognizing teichoic and lipoteichoic acids increased Streptococcus pneumoniae phagocytosis by murine microglial cells. In rabbit ceftriaxone-treated S. pneumoniae meningitis, intracisternal TEPC-15 reduced the density of apoptotic neurons in the hippocampal dentate gyrus (116 ± 70 vs. 221 ± 132/mm(2); p = 0.03). Cerebrospinal fluid inflammatory parameters (protein, lactate, leukocytes, prostaglandins) were not reduced in TEPC-15-treated rabbits.. Intracisternal treatment with the TEPC-15 antibody reduced neuronal damage probably by promoting rapid phagocytosis of bacterial products.

Topics: Animals; Anti-Bacterial Agents; Antibodies, Monoclonal; Ceftriaxone; Cells, Cultured; Dentate Gyrus; Disease Models, Animal; Lactic Acid; Leukocytes; Lipopolysaccharides; Meningitis, Pneumococcal; Mice; Mice, Inbred C57BL; Microglia; Phagocytosis; Prostaglandins; Proteins; Rabbits; Streptococcus pneumoniae; Teichoic Acids

Glutamate homeostasis and microglia activation play an important role in the development and maintenance of neuropathic pain. So far, there has been insufficient data on the relationship between glutamate transporters and cytokines in neuropathic pain. This investigation was designed to evaluate the interaction between co-administration of ceftriaxone, a specific GLT1 activator and minocycline, a specific microglia inhibitor, on the mechanical and cold allodynia of chronic constriction injury model (CCI) in rats. Moreover, alteration of the spinal concentration of proinflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) was studied. Ceftriaxone (100, 150 and 200mg/kg, i.p.) and minocycline (25, 50 and 100mg/kg, i.p.) were administered either alone or in combination for 7 days. Gabapentin (100mg/kg, i.p.) was selected as a reference drug. Behavioral evaluations were performed 1 day before and on days 3, 5, 7, 10 and 14 after surgery. Each of drugs produced a dose-dependent reversal of the neuropathic pain behaviors. Area under the curve (AUC) of combination therapy revealed that minocycline potentiated cold and mechanical antiallodynic effects of ceftriaxone. TNF-α and IL-1β increased in the spinal cord of CCI animals on days 3, 7 and 14 post-surgery. Production of studied cytokines was significantly attenuated after treatment with ceftriaxone alone and in combination with minocycline compared with control group. It is suggested that combination of these classes of drugs would be a promising approach for treatment of chronic neuropathic pain.

Topics: Analgesics; Animals; Anti-Bacterial Agents; Ceftriaxone; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Hyperalgesia; Male; Minocycline; Neuralgia; Rats; Rats, Wistar; Sciatic Neuropathy; Spinal Cord

Streptococcus (S.) pneumoniae is the most common causative pathogen in community-acquired pneumonia and a major cause of sepsis. Recombinant human tissue factor pathway inhibitor (rh-TFPI) attenuates sepsis-induced coagulation and has been evaluated in clinical trials involving patients with sepsis and community-acquired pneumonia.. To examine the effect of rh-TFPI on coagulation, inflammation and bacterial outgrowth in S. pneumoniae pneumonia in mice, with or without concurrent antibiotic treatment.. Pneumonia was induced by intranasal inoculation with S. pneumoniae. Mice were treated with placebo, rh-TFPI, ceftriaxone or rh-TFPI combined with ceftriaxone. Early (8 h) and late (24 h) initiated treatments were evaluated. Samples were obtained 24 or 48 h after infection, for early and late initiated treatment, respectively. In vitro, placebo or rh-TFPI was added to a suspension of S. pneumoniae.. Rh-TFPI reduced pneumonia-induced coagulation; rh-TFPI with ceftriaxone further attenuated coagulation relative to ceftriaxone alone. Rh-TFPI inhibited accumulation of neutrophils in lung tissue and reduced the levels of several cytokines and chemokines in lungs and plasma in mice not treated with antibiotics; in these animals, rh-TFPI initiated 24 h after infection decreased pulmonary bacterial loads. In vitro, rh-TFPI also inhibited growth of S. pneumoniae.. Therapeutic rh-TFPI attenuates coagulation, inflammation and bacterial growth during pneumococcal pneumonia, whereby the latter two effects only become apparent in the absence of concurrent antibiotic treatment.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Anticoagulants; Blood Coagulation; Ceftriaxone; Disease Models, Animal; Drug Therapy, Combination; Female; Humans; Inflammation Mediators; Injections, Intraperitoneal; Lipoproteins; Mice; Mice, Inbred C57BL; Pneumonia, Pneumococcal; Recombinant Proteins; Streptococcus pneumoniae; Time Factors

Glutamate is the principal excitatory neurotransmitter in the central nervous system. Recent evidence suggests that beta lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Moreover, these antibiotics have been shown to prevent the development of tolerance and dependence to opioids, and reduce visceral and nerve injury-induced neuropathic nociceptive responses. The aim of this study is to observe the effect of a beta lactam antibiotic, ceftriaxone, on mechanical allodynia and mechanical hyperalgesia in diabetic rats. Diabetes was produced with the injection of a single dose of streptozocin (50 mg/kg, i.p.) and this procedure resulted in neuropathic pain behaviors in the hindpaws. Mechanical allodynia was detected with an electronic aesthesiometer, and mechanical hyperalgesia was studied using the method of Randall-Selitto. With its higher doses, ceftriaxone (100, 200 mg/kg, i.p.) reduced both mechanical allodynia and hyperalgesia. Dihydrokainic acid (10 mg/kg, i.p.), a selective GLT-1 transporter inhibitor, reversed the anti-allodynic and anti-hyperalgesic effects of ceftriaxone, at doses that produced no effect on its own. Our results indicate that ceftriaxone exerts an antinociceptive effect in streptozocin-induced diabetic rats and GLT-1 activation by beta lactam antibiotics may be a promising option in the treatment of diabetic neuropathy.

Topics: Analgesics; Animals; Anti-Bacterial Agents; Ceftriaxone; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Disease Models, Animal; Male; Peripheral Nerves; Rats; Rats, Wistar

Hearing loss is a frequent long-term complication of pneumococcal meningitis (PM). Its main pathological correlate is damage to the organ of Corti and loss of spiral ganglion neurons. The only current treatment option is cochlear implants which require surviving neurons. Here, we investigated the impact of systemically applied neurotrophin-3 (NT-3) on long-term hearing loss and the survival of neurons.. Eighteen hours after infection with S. pneumoniae, C57BL/6 mice were treated with a combination of ceftriaxone with NT-3 or dexamethasone or placebo. Hearing, cochlear damage, and brain damage were assessed by audiometry and histology.. The main findings from immunohistochemical visualization of neurotrophins (NT-3, BDNF) and their receptors (TrkB, TrkC, and p75) in the cochlea were (i) enhanced staining for the cell survival-promoting receptor TrkB and (ii) increased NT-3 staining in NT-3 treated mice, showing that systemically applied NT-3 reaches the cochlea. The major effects of adjunctive NT-3 treatment were (i) a reduction of meningitis-induced hearing impairment and (ii) a reduction of spiral ganglion neuronal loss. The efficacy of NT-3 therapy was comparable to that of dexamethasone.. Systemically applied NT-3 might be an interesting candidate to improve hearing outcome after pneumococcal meningitis.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Astrocytes; Brain-Derived Neurotrophic Factor; Ceftriaxone; Cerebral Cortex; Cochlea; Dexamethasone; Disease Models, Animal; Hearing Loss; Hippocampus; Humans; Meningitis, Pneumococcal; Mice; Mice, Inbred C57BL; Neurons; Neurotrophin 3; Placebos; Receptors, Nerve Growth Factor; Spiral Ganglion

A growing body of evidence now suggested that cyclosporine A (CycA)-induced nephrotoxicity is a crucial clinical problem and oxidative stress is importantly responsible for its toxicity. Ceftriaxone induced antioxidant effect in brain and neuronal tissues against oxidative damage although its antioxidant potential effect on kidney has not been clarified. The aim of this study was to evaluate whether ceftriaxone protects CycA-induced oxidative stress kidney injury in rats. Twenty-four rats were equally divided into four groups. First group was used as control. Ceftriaxone (200 mg/kg) and CycA (15 mg/kg) were administrated to second and third groups for 10 days, respectively. The ceftriaxone and CycA combination was given to rats constituting the fourth group for 10 days. Lipid peroxidation (LP), urea nitrogen and lactate dehydrogenase (LDH) levels were higher in CycA group than in control and ceftriaxone groups although LP, urea nitrogen and LDH levels were lower in ceftriaxone + CycA group than in control and ceftriaxone groups. Glutathione peroxidase and catalase activities were lower in CycA group than in control whereas their activities were increased in control and ceftriaxone groups. Superoxide dismutase activity did not change by the treatments. Ceftriaxone administration recovered also CycA-induced atrophy, vacuolization and exfoliations of tubular epithelium and glomerular collapse in histopathological evaluation of kidney. In conclusion, we observed that ceftriaxone is beneficial on CycA-induced oxidative stress in kidney of rats by modulating oxidative and antioxidant system.

Topics: Animals; Antioxidants; Ceftriaxone; Cyclosporine; Disease Models, Animal; Female; Humans; Kidney; Kidney Diseases; Oxidative Stress; Rats; Rats, Wistar

Spinal muscular atrophy (SMA) is a devastating genetic motoneuron disease leading to infant death. No effective therapy is currently available. It has been suggested that β-lactam antibiotics such as ceftriaxone may offer neuroprotection in motoneuron diseases. Here, we investigate the therapeutic effect of ceftriaxone in a murine model of SMA. Treated animals present a modest, but significant ameliorated neuromuscular phenotype and increased survival, which correlate with protection of neuromuscular units. Whole gene expression profiling in treated mice demonstrates modifications in several genes including those involved in RNA metabolism toward wild-type. The neuroprotective effect seems to be mediated by multiple mechanisms that encompass the increase of the glutamate transporter Glt1, the transcription factor Nrf2, as well as SMN protein. This study provides the first evidence of a potential positive effect of this class of molecules in SMA. Further investigation of analogs with increased and more specific therapeutic effects warrants the development of useful therapies for SMA.

Topics: Analysis of Variance; Animals; Anti-Bacterial Agents; Blotting, Western; Ceftriaxone; Cell Count; Disease Models, Animal; Gene Expression; Immunohistochemistry; Kaplan-Meier Estimate; Mice; Mice, Transgenic; Motor Neurons; Muscle, Skeletal; Muscular Atrophy, Spinal; Neuroprotective Agents; Reverse Transcriptase Polymerase Chain Reaction; SMN Complex Proteins; Spinal Cord; Treatment Outcome

This study investigated the hypothesis that ceftriaxone preconditioning ameliorates brain damage in neonatal animals through glutamate transporter 1 (GLT-1) upregulation.. Sprague Dawley rats were pretreated with ceftriaxone, erythromycin, minocycline, or saline for 5 consecutive days starting from postnatal day 2 (P2), and GLT-1/glutamate-aspartate transporter (GLAST) messenger RNA (mRNA) and protein levels were examined in the P7 brains. After ceftriaxone or saline preconditioning, the P7 rats underwent hypoxic-ischemic (H-I) procedure or sham operation. One week after the procedure (P14), hematoxylin-eosin staining, microtubule-associated protein 2 (MAP-2) immunostaining, and transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) assay were used to examine neuronal damage and possible neurotoxicity.. Repeated ceftriaxone injections significantly increased GLT-1 mRNA and protein levels but not GLAST. Following such treatment and H-I procedure, the MAP-2-positive area increased and TUNEL-positive cells decreased.. Antenatal ceftriaxone may help to provide neuroprotection in the immature brain and become a new prophylactic strategy to reduce neonatal encephalopathy in clinical perinatal medicine.

Topics: Animals; Animals, Newborn; Apoptosis; Brain; Ceftriaxone; Disease Models, Animal; Drug Administration Schedule; Excitatory Amino Acid Transporter 1; Excitatory Amino Acid Transporter 2; Hypoxia-Ischemia, Brain; Immunohistochemistry; In Situ Nick-End Labeling; Microtubule-Associated Proteins; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; RNA, Messenger; Time Factors; Up-Regulation

Ceftriaxone is a beta-lactam antibiotic which has been found to increase the expression and function of the major glutamate transporter, GLT-1. It has previously been shown that GLT-1 expression is decreased in the nucleus accumbens following cocaine self-administration and extinction training; ceftriaxone given in the days immediately prior to reinstatement testing attenuates both cue- and cocaine-primed reinstatement. Here we tested the ability of ceftriaxone pre-treatment (for 5 days prior to the first cocaine exposure) to prevent the induction of cocaine sensitization and the acquisition of cocaine self-administration. We also tested whether ceftriaxone administered only during self-administration attenuates the reinstatement of extinguished cocaine-seeking. We found that ceftriaxone did not affect the acquisition of cocaine self-administration but was able to attenuate reinstatement weeks after ceftriaxone administration ceased. This attenuation in reinstatement was accompanied by a restoration of GLT-1 expression in the nucleus accumbens. Ceftriaxone also attenuated locomotor behavior following the first cocaine injection and prevented the induction of cocaine but not caffeine sensitization. While ceftriaxone-treated animals did not sensitize to caffeine, they displayed reduced caffeine-induced locomotion following repeated caffeine treatment, indicating a possible dopaminergic effect of ceftriaxone. Taken together, these results indicate that ceftriaxone produces enduring changes in glutamate homeostasis in the nucleus accumbens which counteract addiction-related behaviors.

Topics: Analysis of Variance; Anesthetics, Local; Animals; Ceftriaxone; Cocaine; Cocaine-Related Disorders; Conditioning, Operant; Cues; Disease Models, Animal; Excitatory Amino Acid Transporter 1; Extinction, Psychological; Male; Motor Activity; Nucleus Accumbens; Rats; Rats, Sprague-Dawley; Reinforcement, Psychology; Self Administration

Some antibiotics are suggested to exert neuroprotective effects via regulation of glial responses. Attenuation of microglial activation by minocycline prevents neuronal death in a variety of experimental models for neurological diseases, such as cerebral ischemia, Parkinson's and Huntington's disease. Ceftriaxone delays loss of neurons in genetic animal models of amyotrophic lateral sclerosis through upregulation of astrocytic glutamate transporter expression (GLT-1). However, it remains largely unknown whether these antibiotics are able to protect neurons in axotomy models for progressive motor neuron diseases. Recent studies have shown that the axotomized motoneurons of the adult rat can survive, whereas those of the adult mouse undergo neuronal degeneration. We thus examined the possible effects of ceftriaxone and minocycline on neuronal loss and glial reactions in the mouse hypoglossal nucleus after axotomy. The survival rate of lesioned motoneurons at 28 days after axotomy (D28) was significantly improved by ceftriaxone and minocycline treatment. There were no significant differences in the cellular densities of astrocytes between ceftriaxone-treated and saline-treated animals. Ceftriaxone administration increased the expression of GLT-1 in the hypoglossal nucleus, while it suppressed the reactive increase of glial fibrillary acidic protein (GFAP) expression to control level. The cellular densities of microglia at D28 were significantly lower in minocycline-treated mice than in saline-treated mice. The time course analysis showed that immediate increase in microglia at D3 and D7 was not suppressed by minocycline. The present observations show that minocycline and ceftriaxone promote survival of lesioned motoneurons in the mouse hypoglossal nucleus, and also suggest that alterations in glial responses might be involved in neuroprotective actions of antibiotics.

Topics: Animals; Astrocytes; Axotomy; Ceftriaxone; Cell Survival; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Interactions; Glial Fibrillary Acidic Protein; Hypoglossal Nerve Injuries; Male; Mice; Mice, Inbred C57BL; Microglia; Minocycline; Motor Neuron Disease; Nerve Tissue Proteins; Neurons; Neuroprotective Agents

To investigate the effect of β-lactam antibiotics ceftriaxone on the levels of glutamate in hippocampus following traumatic brain injury in rat.. Rats were divided randomly into three groups:sham group; trauma group and trauma+ceftriaxone group. Rats in the later two groups were subjected to a lateral cortical impact injury caused by a free-falling object, and trauma+ceftriaxone group was treated with ceftriaxone immediately after injury. The levels of glutamate in hippocampus was determined by HPLC at 12 h after trauma; the pathological change at 24 h after trauma was examined and water content of brain tissue at 3, 12 and 24 h after trauma was measured in three groups.. Compared with the trauma group,the water content in brain tissue (P<0.05), neuronal death in hippocampus CAl area and the levels of glutamate and aspartate in hippocampus at 12 h (P<0.05) were significantly decreased in trauma+ceftriaxone group.. β-lactam antibiotics ceftriaxone can reduce the level of brain glutamate, brain edema and neuronal death after traumatic brain injury in rat.

Topics: Animals; Brain Injuries; Ceftriaxone; Disease Models, Animal; Female; Glutamic Acid; Hippocampus; Male; Rats; Rats, Sprague-Dawley

The cystine-glutamate exchanger is downregulated after chronic cocaine, resulting in reduced extracellular levels of nucleus accumbens glutamate. The importance of cocaine-induced loss of glutamate homeostasis is revealed by N-acetylcysteine restoring cystine-glutamate exchange and attenuating reinstatement to cocaine seeking. Another regulator of extracellular glutamate is the glial glutamate transporter GLT-1. We hypothesized that cocaine self-administration reduces GLT-1 and that GLT-1 upregulation inhibits cocaine seeking.. We measured [(3)H] glutamate uptake and protein expression of GLT-1 and xCT, the catalytic subunit of the cystine-glutamate exchanger, following cocaine self-administration and 3 weeks of extinction training. We also examined the affect of ceftriaxone (previously shown to increase GLT-1) and N-acetylcysteine treatment on the expression of GLT-1 and xCT. Ceftriaxone was also tested for the capacity to inhibit cue- and cocaine-induced relapse.. Cocaine self-administration reduced glutamate uptake and the expression of both GLT-1 and xCT. Ceftriaxone restored GLT-1 and xCT levels and prevented cue- and cocaine-induced reinstatement of drug seeking. N-acetylcysteine also restored GLT-1 and xCT levels.. These results indicate that glutamate transport and cystine-glutamate exchange may be coregulated and provide further evidence that targeting glutamate homeostasis is a potential method for treating cocaine relapse.

Topics: Analysis of Variance; Animals; Antioxidants; Ceftriaxone; Cocaine; Cocaine-Related Disorders; Conditioning, Operant; Cystine; Disease Models, Animal; Dopamine Uptake Inhibitors; Excitatory Amino Acid Transporter 2; Glutamic Acid; Male; Motor Activity; Nucleus Accumbens; Rats; Rats, Sprague-Dawley; Self Administration; Time Factors; Tritium

Neurological symptoms of patients suffering from neurodegenerative diseases such as Alzheimer's dementia (AD), Parkinson's disease (PD), or amyotrophic lateral sclerosis (ALS) often worsen during infections. We assessed the disease-modulating effects of recurrent systemic infections with the most frequent respiratory pathogen, Streptococcus pneumoniae, on the course of AD, PD, and ALS in mouse models of these neurodegenerative diseases [transgenic Tg2576 mice, (Thy1)-[A30P]alpha SYN mice, and Tg(SOD1-G93A) mice]. Mice were repeatedly challenged intraperitoneally with live S. pneumoniae type 3 and treated with ceftriaxone for 3 days. Infection caused an increase of interleukin-6 concentrations in brain homogenates. The clinical status of (Thy1)-[A30P]alpha SYN mice and Tg(SOD1-G93A) mice was monitored by repeated assessment with a clinical score. Motor performance was controlled by the tightrope test and the rotarod test. In Tg2576 mice, spatial memory and learning deficits were assessed in the Morris water maze. In none of the three mouse models onset or course of the disease as evaluated by the clinical tests was affected by the recurrent systemic infections performed. Levels of alpha-synuclein in brains of (Thy1)-[A30P]alpha SYN mice did not differ between infected animals and control animals. Plaque sizes and concentrations of A beta 1-40 and A beta 1-42 were not significantly different in brains of infected and uninfected Tg2576 mice. In conclusion, onset and course of disease in mouse models of three common neurodegenerative disorders were not influenced by repeated systemic infections with S. pneumoniae, indicating that the effect of moderately severe acute infections on the course of neurodegenerative diseases may be less pronounced than suspected.

Topics: Acute Disease; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Amyotrophic Lateral Sclerosis; Animals; Anti-Bacterial Agents; Ceftriaxone; Disease Models, Animal; Disease Progression; Interleukin-6; Maze Learning; Memory Disorders; Mice; Mice, Transgenic; Neurodegenerative Diseases; Neuropsychological Tests; Parkinson Disease; Plaque, Amyloid; Pneumonia, Bacterial; Recurrence; Streptococcal Infections; Streptococcus pneumoniae; Up-Regulation

Daptomycin is a novel lipopeptide antibiotic with excellent activity against Gram-positive bacterial pathogens, but its therapeutic value for the treatment of invasive pneumococcal disease compared to that for the treatment of pneumococcal pneumonia is incompletely defined. We investigated the efficacy of daptomycin in two models of Streptococcus pneumoniae-induced lung infection, i.e., pneumococcal pneumonia and septic pneumococcal disease. Mice were infected with a bioluminescent, invasive serotype 2 S. pneumoniae strain or a less virulent serotype 19 S. pneumoniae strain and were then given semitherapeutic or therapeutic daptomycin or ceftriaxone. Readouts included survival; bacterial loads; and septic disease progression, as determined by biophotonic imaging. Semitherapeutic daptomycin treatment fully protected the mice against the progression of septic disease induced by serotype 2 S. pneumoniae, while therapeutic treatment of the mice with daptomycin or ceftriaxone led to approximately 70% or approximately 60% survival, respectively. In contrast, mice infected with serotype 19 S. pneumoniae developed severe pneumonia and lung leakage even in the presence of increased intra-alveolar daptomycin levels, resulting in only 40% survival, whereas the ceftriaxone-treated mice had 100% survival. Together, although daptomycin demonstrates little efficacy in the treatment of pneumococcal pneumonia, daptomycin is highly effective in preventing S. pneumoniae-induced septic death, thus possibly offering a therapeutic option for patients with life-threatening septic pneumococcal disease.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Daptomycin; Disease Models, Animal; Mice; Mice, Inbred C57BL; Pneumococcal Infections; Pneumonia, Pneumococcal; Sepsis; Streptococcus pneumoniae

Glial glutamate transporter-1 (GLT-1) plays an essential role in the maintenance of glutamate homeostasis and is involved in the development and maintenance of pathological pain. The present study was undertaken (1) to observe the anti-nociceptive effects of ceftriaxone (Cef) in a chronic neuropathic pain model induced by chronic constrictive nerve injury (CCI) of the sciatic nerve and (2) to identify the role of spinal GLT-1 in the process. CCI induced significant thermal hyperalgesia and mechanical allodynia, which began from postoperative day 3 and lasted to day 21. This long-term hyperalgesia was accompanied by significant down-regulation of GLT-1 expression in the L4-L6 segments of the spinal dorsal horn, as revealed by immunohistochemistry and Western blot. Intraperitoneal preventive and therapeutic administration of Cef effectively prevented or reversed, respectively, the development of thermal hyperalgesia, mechanical allodynia, and GLT-1 down-regulation in the spinal dorsal horn. To further determine whether the above anti-nociceptive effects of Cef are a result of the up-regulation of spinal GLT-1 expression and its function, we further observed the effects of intrathecal administration of Cef in the same model. It was found that intrathecal administration of Cef led to the specific up-regulation of GLT-1 expression and glutamate uptake ((3)H-glutamate) in the spinal dorsal horn, and similar anti-nociceptive effects to those of intraperitoneal administration of Cef. The above effects of intrathecal Cef administration were all significantly inhibited by intrathecal administration of GLT-1 antisense oligodeoxynucleotides (As-ODNs). These results indicate that Cef plays an anti-nociceptive role by up-regulating spinal GLT-1 expression and its function.

Topics: Analgesics; Animals; Ceftriaxone; Chronic Disease; Disease Models, Animal; Excitatory Amino Acid Transporter 2; Glutamic Acid; Hyperalgesia; Male; Oligodeoxyribonucleotides, Antisense; Pain Threshold; Physical Stimulation; Rats; Rats, Sprague-Dawley; Reaction Time; Sciatica; Spinal Cord; Time Factors; Tritium; Up-Regulation

Astrocyte dysfunction may contribute to epileptogenesis and other neurological deficits in Tuberous Sclerosis Complex (TSC). In particular, decreased expression and function of astrocyte glutamate transporters have been implicated in causing elevated extracellular glutamate levels, neuronal death, and epilepsy in a mouse model of TSC (Tsc1(GFAP)CKO mice), involving inactivation of the Tsc1 gene primarily in astrocytes. Here, we tested whether pharmacological induction of astrocyte glutamate transporter expression can prevent the neurological phenotype of Tsc1(GFAP)CKO mice. Early treatment with ceftriaxone prior to the onset of epilepsy increased expression of astrocyte glutamate transporters, decreased extracellular glutamate levels, neuronal death, and seizure frequency, and improved survival in Tsc1(GFAP)CKO mice. In contrast, late treatment with ceftriaxone after onset of epilepsy increased glutamate transporter expression, but had no effect on seizures. These results indicate that astrocyte glutamate transporters contribute to epileptogenesis in Tsc1(GFAP)CKO mice and suggest novel therapeutic strategies for epilepsy in TSC directed at astrocytes.

Topics: Animals; Astrocytes; Ceftriaxone; Cell Death; Disease Models, Animal; Down-Regulation; Epilepsy; Excitatory Amino Acid Transporter 2; Extracellular Fluid; Glial Fibrillary Acidic Protein; Glutamic Acid; Mice; Mice, Knockout; Survival Rate; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tumor Suppressor Proteins; Up-Regulation

Antibiotic-induced bacteriolysis exacerbates inflammation and brain damage in bacterial meningitis. Here the quality and temporal kinetics of cerebrospinal fluid (CSF) inflammation were assessed in an infant rat pneumococcal meningitis model for the nonbacteriolytic antibiotic daptomycin versus ceftriaxone. Daptomycin led to lower CSF concentrations of interleukin 1beta (IL-1beta), IL-10, IL-18, monocyte chemoattractant protein 1 (MCP-1), and macrophage inflammatory protein 1 alpha (MIP-1alpha) (P < 0.05). In experimental pneumococcal meningitis, daptomycin treatment resulted in more rapid bacterial killing, lower CSF inflammation, and less brain damage than ceftriaxone treatment.

Topics: Animals; Animals, Newborn; Anti-Bacterial Agents; Ceftriaxone; Cerebrospinal Fluid; Daptomycin; Disease Models, Animal; Humans; Inflammation; Meningitis, Pneumococcal; Rats; Rats, Wistar; Treatment Outcome

Recently glutamate transporters have emerged as a potential therapeutic target in a wide range of acute and chronic neurological disorders, owing to their novel mode of action. The modulation of GLT-1, a major glutamate transporter has been shown to exert neuroprotection in various models of ischemic injury and motoneuron degeneration. Therefore, an attempt was made to explore its neuroprotective potential in cerebral ischemia/reperfusion injury using ceftriaxone, a GLT-1 modulator. Pre-treatment with ceftriaxone (100mg/kg. i.v) for five days resulted in a significant reduction (P<0.01) in neurological deficit as well as cerebral infarct volume after 1h of ischemia followed by 24h of reperfusion injury. It also caused a significant (P<0.05) upregulation of GLT-1 mRNA, protein and glutamine synthetase (GS) activity. Furthermore, inhibition of ceftriaxone-mediated increased glutamine synthetase activity by dihydrokainate (DHK), a GLT-1 specific inhibitor, confirms the specific effect of ceftriaxone on GLT-1 activity. In addition, ceftriaxone also induced a significant (P<0.01) increase in [(3)H]-glutamate uptake, mediated by GLT-1 in glial enriched preparation, as evidenced by use of DHK and DL-threo-beta-benzyloxyaspartate (DL-TBOA). Thus, the present study provides overwhelming evidence that modulation of GLT-1 protein expression and activity confers neuroprotection in cerebral ischemia/reperfusion injury.

Topics: Animals; Brain; Brain Ischemia; Ceftriaxone; Cerebral Infarction; Disease Models, Animal; Excitatory Amino Acid Transporter 2; Glutamate-Ammonia Ligase; Glutamic Acid; Kainic Acid; Male; Neuroglia; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Up-Regulation

Present investigation deals with an extensive approach incorporating in vitro and in vivo experimentation to treat chronic osteomyelitis, using hydroxyapatite porous scaffolds.. Hydroxyapatite was synthesized in the laboratory by wet chemical method, different porous scaffolds have been fabricated. In vitro studies include variation of porosity with interconnectivity, pore-drug interfacial studies by SEM-EDAX and drug elution studies (by HPLC) both in contact with PBS and SBF at approximately 37 degrees C. In vivo trials were based on experimental osteomyelitis in rabbit model induced in tibia by Staphylococcus aureus. Characterizations included observation of histopathology, radiology and estimation of drug in both bone and serum for 42 days by HPLC method and subsequent bone-biomaterial interface by SEM.. It was established that lower pore percentage with a distribution of mainly micro-pores were found to be superior over the higher pore percentage both in vitro and in vivo. The criteria was matched with the 50N50H samples which had 50-55% porosity with an average pore size approximately 110 microm, having higher interconnectivity (10-100 microm), moderately high adsorption efficiency (approximately 50%) when loaded with CFS (drug combinations consisting of irreversible b-lactamase inhibitor and b-lactam antibiotic). CFS release from HAp implants were faster in PBS than SBF. Further, both the results of in vitro and in vivo drug elution after 42 days showed release higher than minimum inhibitory concentration of CFS against Staphylococcus aureus. In vivo studies also proved the superiority of CFS loaded HAp implants than parenteral group based on eradication of infection and new bone formation.. HAp based porous scaffold loaded with CFS and designed porosity (in terms of micro- and macro-porosity, interconnectivity) was found to be an ideal delivery system which could locally, sustainably release the composite antibiotic in reliable manner both in terms of in vitro drug elution behaviour in contact with SBF and in vivo animal trial.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Disease Models, Animal; Drug Compounding; Drug Delivery Systems; Durapatite; Hydrogen-Ion Concentration; Microscopy, Electron, Scanning; Osteomyelitis; Porosity; Powders; Rabbits; Staphylococcus aureus; Sulbactam; X-Ray Diffraction

Glutamate neurotransmission is highly regulated, largely by glutamate transporters. In the spinal cord, the glutamate transporter GLT-1 is primarily responsible for glutamate clearance. Downregulation of GLT-1 can occur in activated astrocytes, and is associated with increased extracellular glutamate and neuroexcitation. Among other conditions, astrocyte activation occurs following repeated opioids and in models of chronic pain. If GLT-1 downregulation occurs in these states, GLT-1 could be a pharmacological target for improving opioid efficacy and controlling chronic pain. The present studies explored whether daily intrathecal treatment of rats with ceftriaxone, a beta-lactam antibiotic that upregulates GLT-1 expression, could prevent development of hyperalgesia and allodynia following repeated morphine, reverse pain arising from central or peripheral neuropathy, and reduce glial activation in these models. Ceftriaxone pre-treatment attenuated the development of hyperalgesia and allodynia in response to repeated morphine, and prevented associated astrocyte activation. In a model of multiple sclerosis (experimental autoimmune encephalomyelitis; EAE), ceftriaxone reversed tactile allodynia and halted the progression of motor weakness and paralysis. Similarly, ceftriaxone reversed tactile allodynia induced by chronic constriction nerve injury (CCI). EAE and CCI each significantly reduced the expression of membrane-bound, dimerized GLT-1 protein in lumbar spinal cord, an effect normalized by ceftriaxone. Lastly, ceftriaxone normalized CCI- and EAE-induced astrocyte activation in lumbar spinal cord. Together, these data indicate that increasing spinal GLT-1 expression attenuates opioid-induced paradoxical pain, alleviates neuropathic pain, and suppresses associated glial activation. GLT-1 therefore may be a therapeutic target that could improve available treatment options for patients with chronic pain.

Topics: Animals; Ceftriaxone; Disease Models, Animal; Excitatory Amino Acid Transporter 2; Glutamic Acid; Male; Pain, Intractable; Rats; Rats, Sprague-Dawley; Spinal Cord; Up-Regulation

Visceral hypersensitivity is the leading complaint of functional bowel disorders. Central sensitization mediated by glutamate receptor activation is implicated in pathophysiology of visceral pain. The glial glutamate transporter EAAT2 is the principal mediator of glutamate clearance to terminate glutamate-mediated responses. Transgenic mice overexpressing human EAAT2 (EAAT2 mice), which exhibited a twofold enhanced glutamate uptake, showed 39% less writhing response to intraperitoneal acetic acid than nontransgenic littermates. Moreover, EAAT2 transgenic mice showed a 53-64% reduction in visceromotor response (VMR) to colorectal distension (CRD) in assessments of the response to graded increase in pressures. Corroborating the involvement of enhanced glutamate uptake, wild-type mice treated for 1 wk with ceftriaxone, an EAAT2 expression activator, showed a 49-70% reduction in VMR to CRD. Moreover, systemic pretreatment with the selective EAAT2 transporter blocker dihydrokainate reversed the ceftriaxone-blunted nociceptive response to CRD. However, the enhanced VMR to CRD produced by intracolonic ethanol was not significantly attenuated by 1-wk ceftriaxone pretreatment. The data suggest that enhanced glutamate uptake provides protective effects against colonic distension-induced nociception and represents an exciting new mechanistic approach leading to better therapeutic options to visceral pain disorders.

Topics: Acetic Acid; Animals; Behavior, Animal; Ceftriaxone; Colon; Disease Models, Animal; Ethanol; Excitatory Amino Acid Transporter 2; Glutamate Plasma Membrane Transport Proteins; Humans; Hyperalgesia; Kainic Acid; Mice; Mice, Transgenic; Pain; Pain Measurement; Pain Threshold; Pressure; Up-Regulation

To investigate the effects of rhubarb on intestinal flora and bacterial translocation in septic rats.. One hundred and four Sprague-Dawley (SD) rats were randomly divided into normal control group, burn group, sepsis group, and sepsis with rhubarb treatment group. All the animals except those in the normal control group were given 30% total body surface area (TBSA) III degree burn on their back followed by endotoxin challenge intraperitoneally in a dose of 20 mg/kg 24 hours after the burn injury. The animals were treated with intraperitoneal injection of ceftriaxone 24 hours after the second hit in various groups in a dose of 60 mg/kg, twice a day with a interval of 12 hours. Rhubarb was also given orally with a dose of 50 mg/kg, twice a day with an interval of 12 hours, at the same time. On 1, 3 and 9 days after treatment, intestinal bacilli in colon and the incidence of bacterial translocation in content of large intestine, liver, lung, mesenteric lymph node and blood in each group were determined.. Neither intestinal bacilli in colon nor bacterial translocation showed significant change after the burn injury [(5.86+/-0.62) log cfu/g vs. (5.52+/-0.41) log cfu/g]. The second hit with endotoxin obviously increased the number of intestinal bacilli in colon [(8.96+/-0.73) log cfu/g, P<0.01], in which Colibacillus remain the predominant flora. At the same time, the incidence of Colibacillus translocation was also very high. The antibiotic ceftriaxone markedly reduced the number of Colibacillus on the 3rd and 9th day after the therapy [(4.43+/-0.64) log cfu/g, (5.82+/-0.99) log cfu/g, both P<0.01]. However, the number of some opportunistic pathogens, such as Pseudomonas aeruginosa and Baumanii, significantly increased, and they substituted Colibacillus to become the predominant flora in gut. Furthermore, the species of bacterial translocation also switched to Pseudomonas aeruginosa and Baumanii from Colibacillus. Rhubarb could prevent the loss of enteric bacilli in gut [(8.24+/-1.32) log cfu/g]. Moreover, it also extenuated the effects of antibiotics in diminishing commensal flore in gut. Lastly, the rhubarb could inhibit bacterial translocation at the early stage of sepsis (incidence of translocation on 1 th day of the therapy: 40.62% vs. 6.25%, P<0.05).. Rhubarb can protect the gut microbiogeocoenosis, mitigate the bactericidal effect on antibiotics on commensal flora, and inhibit bacterial translocation at the early stage of sepsis.

Topics: Animals; Anti-Bacterial Agents; Bacterial Translocation; Burns; Ceftriaxone; Disease Models, Animal; Intestines; Male; Probiotics; Random Allocation; Rats; Rats, Sprague-Dawley; Rheum; Sepsis

Meropenem is a broad-spectrum carbapenem antibiotic that is highly active against the pathogens causing meningitis. The aims of this study was to determine the efficacies of meropenem alone and combined with rifampin against two Streptococcus pneumoniae strains with different susceptibility to beta-lactams using the guinea pig meningitis model and compare them with the standard ceftriaxone plus vancomycin therapy. All treatments except rifampin were bactericidal from 6 h. The addition of rifampin did not improve the activity of meropenem alone. Our results provide good evidence of the efficacy of meropenem in the treatment of penicillin- and cephalosporin-susceptible and -resistant pneumococcal meningitis similar to that of ceftriaxone plus vancomycin, suggesting that meropenem might be a good option in the management of this infection.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Colony Count, Microbial; Disease Models, Animal; Drug Therapy, Combination; Female; Guinea Pigs; Humans; Meningitis, Pneumococcal; Meropenem; Microbial Viability; Rifampin; Streptococcus pneumoniae; Thienamycins; Time Factors; Treatment Outcome; Vancomycin

In bacterial meningitis, severe systemic and local inflammation causes long-term impairment and death of affected patients. The current antibiotic therapy relies on cell wall-active beta-lactam antibiotics, which rapidly sterilize the cerebrospinal fluid (CSF). However, beta-lactams inhibit cell wall synthesis, induce bacteriolysis, and thereby evoke a sudden release of high amounts of toxic and proinflammatory bacterial products. Because tissue damage in bacterial meningitis is the result of bacterial toxins and the inflammatory host response, any reduction of free bacterial compounds promises to prevent neuronal damage.. In vitro experiments and randomized prospective animal study.. University research laboratories.. Streptococcus pneumoniae broth cultures and New Zealand White rabbits.. We evaluated a concept to improve bacterial meningitis therapy in which a short-term pretreatment with the protein synthesis-inhibiting antibiotic rifampicin precedes the standard antibiotic therapy with ceftriaxone. First, logarithmically growing pneumococcal cultures were subdivided and exposed to different antibiotics. Then, rabbits suffering from pneumococcal meningitis were randomized to receive rifampicin pretreatment or ceftriaxone alone.. In pneumococcal cultures, quantitative immunoblotting and real-time polymerase chain reaction revealed a reduced release of pneumolysin and bacterial DNA by rifampicin pretreatment for 30 minutes in comparison with ceftriaxone treatment alone. In vivo, a 1-hour rifampicin pretreatment reduced the release of bacterial products and attenuated the inflammatory host response, as demonstrated by decreased CSF levels of prostaglandin E2 and total protein and increased glucose CSF/plasma ratios. Rifampicin pretreatment reduced infection-associated neuronal apoptotic cell loss compared with ceftriaxone-treated controls.. A short-term pretreatment with rifampicin reduced the beta-lactam-induced release of deleterious bacterial products, attenuated inflammation, and thereby decreased neuronal cell loss in experimental bacterial meningitis. This concept has the potential to reduce inflammation-associated neuronal injury in bacterial meningitis and should be evaluated in a clinical trial.

Topics: Animals; Anti-Bacterial Agents; Apoptosis; Ceftriaxone; Cell Culture Techniques; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Meningitis, Pneumococcal; Neurons; Rabbits; Rifampin

To examine the routes, dynamics and correlates of cochlear inflammation in meningitis to provide information on the pathogenesis of the associated hearing loss and indications for rational pharmacotherapeutical intervention.. A well-established rat model of Streptococcus pneumoniae meningitis was employed.. Eight rats were inoculated intrathecally and not treated, whereas 26 were inoculated and treated with ceftriaxone. Six rats were sham-inoculated, making a total of 40 rats. The rats were sacrificed when reaching terminal illness or after 7 days, followed by light microscopy. Routes of cochlear inflammatory infiltration were examined. The volume fraction of inflammatory infiltration was estimated and correlated to bacterial and leukocyte counts in cerebrospinal fluid (CSF) and blood.. The perilymphatic space was infiltrated with inflammatory cells via cochlear aqueduct, whereas the endolymphatic space was infiltrated from the spiral ligament. Rosenthal's canal was infiltrated through osseous spiral lamina canaliculi. In the untreated group, the degree of inflammation correlated with time of death, whereas antibiotic treatment reversed this development. Perilymphatic inflammation correlated significantly with the CSF leukocyte count, whereas endolymphatic inflammation correlated with spiral ligament inflammation.. Meningogenic inflammation of the rat cochlea occurs via the cochlear aqueduct and the spiral ligament capillary bed. The spiral ganglion is infiltrated through the osseous spiral lamina. The degree of inflammation correlates positively with time of death in untreated meningitis, whereas antibiotic treatment leads to subsiding infiltration during recovery.

Topics: Animals; Biopsy, Needle; Ceftriaxone; Cerebrospinal Fluid; Cochlear Diseases; Disease Models, Animal; Immunohistochemistry; Inflammation; Leukocyte Count; Male; Meningitis, Pneumococcal; Microscopy, Electron; Random Allocation; Rats; Rats, Wistar; Sensitivity and Specificity

The pathophysiology of sepsis is due in part to early systemic inflammation. Here we describe molecular and cellular responses, as well as survival, in A 2A adenosine receptor (AR) agonist treated and untreated animals during experimental sepsis.. Sepsis was induced in mice by intraperitoneal inoculation of live bacteria (Escherichia coli or Staphylococcus aureus) or lipopolysaccharide (LPS). Mice inoculated with live bacteria were treated with an A 2A AR agonist (ATL313) or phosphate buffered saline (PBS), with or without the addition of a dose of ceftriaxone. LPS inoculated mice were treated with ATL313 or PBS. Serum cytokines and chemokines were measured sequentially at 1, 2, 4, 8, and 24 hours after LPS was administered. In survival studies, mice were followed until death or for 7 days.. There was a significant survival benefit in mice infected with live E. coli (100% vs. 20%, p = 0.013) or S. aureus (60% vs. 20%, p = 0.02) when treated with ATL313 in conjunction with an antibiotic versus antibiotic alone. ATL313 also improved survival from endotoxic shock when compared to PBS treatment (90% vs. 40%, p = 0.005). The serum concentrations of TNF-alpha, MIP-1 alpha, MCP-1, IFN-gamma, and IL-17 were decreased by ATL313 after LPS injection (p < 0.05). Additionally, ATL313 increased the concentration of IL-10 under the same conditions (p < 0.05). Circulating white blood cell concentrations were higher in ATL313 treated animals (p < 0.01).. Further studies are warranted to determine the clinical utility of ATL313 as a novel treatment for sepsis.

Topics: Animals; Anti-Inflammatory Agents; Ceftriaxone; Cytokines; Disease Models, Animal; Escherichia coli Infections; Female; Inflammation; Leukocytes; Lipopolysaccharides; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Piperidines; Receptor, Adenosine A2A; Sepsis; Staphylococcal Infections; Survival Analysis

Topics: Animals; Anti-Bacterial Agents; Brain Ischemia; Ceftriaxone; Disease Models, Animal; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypothermia, Induced; Rats; Recombinant Proteins; Stroke; Tissue Plasminogen Activator

Ceftriaxone has been reported to reduce neuronal damage in amyotrophic lateral sclerosis and in an in-vitro model of neuronal ischaemia through increased expression and activity of the glutamate transporter, GLT1. We tested the effects of ceftriaxone on mortality, neurological outcome, and infarct size in experimental stroke in rats and looked for underlying mechanisms.. Male normotensive Wistar rats received ceftriaxone (200 mg/kg intraperitoneal) as a single injection 90 min after middle cerebral artery occlusion (90 min with reperfusion). Forty-eight hours after middle cerebral artery occlusion, infarct size (MRI) and neurological deficits were estimated. GLT1 expression was determined by real time RT-PCR, immunoblotting and promoter reporter assay, astrocyte GLT1 activity by measuring glutamate uptake. Bacterial load in various organs was measured by real time RT-PCR, neurotrophins and IL-6 by immunoblotting.. Ceftriaxone dramatically reduced early (24-h) mortality from 34.5% (vehicle treatment, n = 29) to 0% (P < 0.01, n = 19). In a subgroup, followed up for 4 weeks, mortality persisted at 0%. Ceftriaxone strongly tended to reduce infarct size, it significantly improved neuronal survival within the penumbra, reduced neurological deficits (P < 0.001) and led to an upregulation of neurotrophins (P < 0.01) in the peri-infarct zone. Ceftriaxone did not increase GLT1 expression, but increased GLT1 activity (P < 0.05).. Ceftriaxone causes a significant reduction in acute stroke mortality in a poststroke treatment regimen in animal studies. Improved neurological performance and survival may be due to neuroprotection by activation of GLT1 and a stimulation of neurotrophins resulting in an increased number of surviving neurons in the penumbra.

Topics: Animals; Anti-Bacterial Agents; Body Temperature; Brain; Brain Infarction; Ceftriaxone; Cerebrovascular Disorders; Disease Models, Animal; Excitatory Amino Acid Transporter 2; Glutamic Acid; Interleukin-6; Male; Nerve Growth Factors; Rats; Rats, Wistar; Regional Blood Flow; RNA, Messenger; Stroke; Survival Rate

Risk of death may influence the efficacy of anti-inflammatory agents in sepsis. "Physiologic" dose corticosteroids, while improving survival in earlier trials with higher control mortality rates (>50%), were not beneficial in the recent CORTICUS trial with lower control mortality (31%). We investigated whether risk of death altered the effects of hydrocortisone in a mouse pneumonia model.. Mice (n=637) challenged with high, medium or low intratracheal E. coli doses were randomized to receive one of three hydrocortisone doses (5, 25 or 125 mg/kg) or normal saline (NS) only (control) for 4 days. All animals were treated with similar volumes of ceftriaxone and NS support following E. coli and were observed for 168 h.. Decreasing E. coli doses reduced control mortality rates (from 94 to 12%). In similar patterns (not significant) each hydrocortisone dose increased the odds ratio (OR) of survival (95% confidence interval) with each E. coli dose (ORs ranging from 1.2 [0.4, 3.7] to 6.1 [0.6, 61.0]). The effect of hydrocortisone on the OR was not related to control mortality rate (r=-0.13, p=0.29) and overall was highly significant (2.04 [1.37, 3.03], p=0.0004). In randomly selected animals 48 h after the highest E. coli dose, compared with the control, hydrocortisone (125 mg/kg) significantly decreased IL-6, INFgamma, and nitric oxide levels.. In this mouse model the beneficial effects of hydrocortisone were independent of risk of death. These findings suggest that factors other than risk of death may underlie the differing effects of corticosteroids in recent sepsis trials.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Bacteremia; Ceftriaxone; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Escherichia coli; Hydrocortisone; Intubation, Intratracheal; Lung; Male; Mice; Mice, Inbred C57BL; Pneumonia, Bacterial; Severity of Illness Index; Treatment Outcome

The striatum, which processes cortical information for behavioral output, is a key target of Huntington's disease (HD), an autosomal dominant condition characterized by cognitive decline and progressive loss of motor control. Increasing evidence implicates deficient glutamate uptake caused by a down-regulation of GLT1, the primary astroglial glutamate transporter. To test this hypothesis, we administered ceftriaxone, a beta-lactam antibiotic known to elevate GLT1 expression (200 mg/kg, i.p., for 5 days), to symptomatic R6/2 mice, a widely studied transgenic model of HD. Relative to vehicle, ceftriaxone attenuated several HD behavioral signs: paw clasping and twitching were reduced, while motor flexibility, as measured in a plus maze, and open-field climbing were increased. Assessment of GLT1 expression in striatum confirmed a ceftriaxone-induced increase relative to vehicle. To determine if the change in behavior and GLT1 expression represented a change in striatal glutamate handling, separate groups of behaving mice were evaluated with no-net-flux microdialysis. Vehicle treatment revealed a glutamate uptake deficit in R6/2 mice relative to wild-type controls that was reversed by ceftriaxone. Vehicle-treated animals, however, did not differ in GLT1 expression, suggesting that the glutamate uptake deficit in R6/2 mice reflects dysfunctional rather than missing GLT1. Our results indicate that impaired glutamate uptake is a major factor underlying HD pathophysiology and symptomology. The glutamate uptake deficit, moreover, is present in symptomatic HD mice and reversal of this deficit by up-regulating the functional expression of GLT1 with ceftriaxone attenuates the HD phenotype.

Topics: Animals; Ceftriaxone; Corpus Striatum; Disease Models, Animal; Excitatory Amino Acid Transporter 2; Extracellular Fluid; Glutamic Acid; Huntington Disease; Male; Maze Learning; Mice; Mice, Transgenic; Phenotype; Synaptic Transmission; Up-Regulation

The purpose of this study was to develop a rabbit model of rhinogenic chronic rhinosinusitis (CRS).. New Zealand white rabbits were used and divided into two groups. In group A rabbits, a piece of Merocel (Medtronic-Xomed, Jacksonville, FL) was inserted into one nasal cavity and the other was left undisturbed as control. In group B rabbits, 1 microg phorbol 12-myristate 13-acetate (PMA) was injected into bilateral nasal lateral walls and then a piece of Merocel (Medtronic-Xomed) was inserted into one nasal cavity. At week 2, the Merocel (Medtronic-Xomed) was removed, and computed tomography (CT), nasoendoscopy, and cultures were performed. All examinations were repeated at week 12. Rabbits that had purulent discharge in nasal cavities and sinuses opacification shown in CT scans were diagnosed as having rhinosinusitis. Rabbits with CRS were randomly allocated to receive intravenous ceftriaxone (50 mg/kg/day) for 28 days or nothing. All rabbits with CRS received CT scans, nasoendoscopy, and cultures at week 16.. At week 12, CRS had developed in two controlled nasal cavities, six nasal cavities inserted with Merocel (Medtronic-Xomed), six nasal cavities injected with phorbol 12-myristate 13-acetate (PMA), and seven both PMA-injected and Merocel- (Medtronic-Xomed) inserted nasal cavities. Seven of nine treated CRS sides were clear of opacification after treatment. All non-treated CRS sides had persistent diseases at week 16. There was a significant difference in the CRS incidence (P = .00043) and culture rates (P = .027) between treated and non-treated CRS nasal cavities.. Our study developed a rabbit model of rhinogenic CRS. This model is easily performed and is reversible by treatment.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Chronic Disease; Disease Models, Animal; Endoscopy; Female; Male; Nasal Cavity; Nasal Mucosa; Rabbits; Random Allocation; Sinusitis; Surgical Sponges; Tetradecanoylphorbol Acetate; Tomography, X-Ray Computed

Excessive glutamatergic neurotransmission is hypothesized to be associated with depressive-like behaviors and possibly major depressive disorder (MDD). Recent evidence that beta-lactam antibiotic agents stimulate uptake of glutamate suggests that this class of compounds might possess antidepressant-like activity.. Three-month old, male, C57BL/6J mice were administered ceftriaxone (200 mg/kg IP) for 14-18 days, then tested in the tail-suspension, forced swim, and novelty-suppressed feeding tests to determine whether ceftriaxone had similar effects to classical antidepressant compounds in these models.. Ceftriaxone treatment had an antidepressant-like effect across models. Reduced immobility and decreased freezing were observed in the forced swim and tail suspension tests. The same trend was seen in novelty-suppressed feeding, but the effect was not statistically significant.. Ceftriaxone demonstrates antidepressant-like effects in several mouse models. This is consistent with the hypothesis that enhanced uptake of glutamate might have antidepressant-like effects.

Topics: Animals; Antidepressive Agents; Arousal; Ceftriaxone; Depressive Disorder; Disease Models, Animal; Exploratory Behavior; Fear; Feeding Behavior; Glutamic Acid; Male; Mice; Mice, Inbred C57BL; Motivation; Motor Activity; Reaction Time; Stress, Psychological

Astrocytic glutamate transporter protein, GLT-1 (EAAT2), recovers extracellular glutamate and ensures that neurons are protected from excess stimulation. Recently, beta-lactam antibiotics, like ceftriaxone (CTX), were reported to induce the upregulation of GLT-1. Here, we investigated ischemic tolerance induction by CTX in an experimental model of focal cerebral ischemia.. CTX (200 mg/kg per day, IP) was administered for 5 consecutive days before transient focal ischemia, which was induced by intraluminal thread occlusion of the middle cerebral artery for 90 minutes or permanently.. Repeated CTX injections enhanced GLT-1 mRNA and protein expressions after 3 and 5 days of treatment, respectively. CTX-pretreated animals showed a reduction in infarct volume by 58% (reperfusion) and 39% (permanent), compared with the vehicle-pretreated animals at 24 hours postischemia (P<0.01). Lower doses of CTX (20 mg/kg per day and 100 mg/kg per day) reduced infarct volumes to a lesser degree. The injection of GLT-1 inhibitor (dihydrokainate) at 30 minutes before ischemia ameliorated the effect of CTX pretreatment. However, CTX administration at 30 minutes after ischemia produced no significant reduction in infarct volume. CTX reduced the levels of proinflammatory cytokines (tumor necrosis factor-alpha, FasL), matrix metalloproteinase (MMP)-9, and activated caspase-9 (P<0.01). In addition, CTX-pretreated animals showed better functional recovery at day 1 to week 5 after ischemia (P<0.05).. This study presents evidence that CTX induces ischemic tolerance in focal cerebral ischemia and that this is mediated by GLT-1 upregulation.

Topics: Animals; Anti-Bacterial Agents; Astrocytes; Brain; Brain Ischemia; Ceftriaxone; Cell Communication; Cytoprotection; Disease Models, Animal; Excitatory Amino Acid Transporter 2; Glutamic Acid; Male; Neurons; Neuroprotective Agents; Neurotoxins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Treatment Outcome; Up-Regulation

Astrocytic glutamate transporters are considered an important target for neuroprotective therapies as the function of these transporters is abnormal in stroke and other neurological disorders associated with excitotoxicity. Recently, Rothstein et al., [Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, Jin L, Dykes Hoberg M, Vidensky S, Chung DS, Toan SV, Bruijn LI, Su ZZ, Gupta P, Fisher PB (2005) Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433:73-77] reported that beta-lactam antibiotics (including ceftriaxone, which easily crosses the blood-brain barrier) increase glutamate transporter 1 (GLT-1) expression and reduce cell death resulting from oxygen-glucose deprivation (OGD) in dissociated embryonic cortical cultures. To determine whether a similar neuroprotective mechanism operates in more mature neurons, which show a different pattern of response to ischemia than primary cultures, we exposed acute hippocampal slices obtained from rats treated with ceftriaxone for 5 days (200 mg/kg; i.p.) to OGD. Whole-cell patch clamp recording of glutamate-induced N-methyl-d-aspartate (NMDA) currents from CA1 pyramidal neurons showed a larger potentiation of these currents after application of 15 microM dl-threo-beta-benzyloxyaspartic acid (TBOA; a potent blocker of glutamate transporters) in ceftriaxone-injected animals than in untreated animals, indicating increased glutamate transporter activity. Western blot analysis did not reveal GLT-1 upregulation in the hippocampus. Delay to OGD-induced hypoxic spreading depression (HSD) recorded in slices obtained from ceftriaxone-treated rats was longer (6.3+/-0.2 vs. 5.2+/-0.2 min; P<0.001) than that in the control group, demonstrating a neuroprotective action of the antibiotic in this model. The effect of ceftriaxone was also tested in organotypic hippocampal slices obtained from P7-9 rats (>14 days in vitro). OGD or glutamate (3.5-5.0 mM) damaged CA1 pyramidal neurons as assessed by propidium iodide (PI) fluorescence. Similar damage was observed after pre-treatment with ceftriaxone (10-200 microM; 5 days) and ceftriaxone exposure did not result in GLT-1 upregulation as assayed by Western blot. Treatment of slice cultures with dibutyryl cAMP (100-250 microM; 5 days) increased GLT-1 expression but did not reduce cell damage induced by OGD or glutamate. Thus we confirm the neuroprotective effect of antibiotic exposure on OGD-induced injury, but sugge

Topics: Analysis of Variance; Animals; Animals, Newborn; Anti-Bacterial Agents; Aspartic Acid; Ceftriaxone; Cell Death; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Glutamic Acid; Hippocampus; Hypoxia; Membrane Potentials; Neurons; Neuroprotective Agents; Organ Culture Techniques; Patch-Clamp Techniques; Rats; Stroke; Time Factors

Daptomycin monotherapy was superior to ceftriaxone monotherapy and was highly efficacious in experimental pneumococcal meningitis, sterilizing the cerebrospinal fluid (CSF) of three of three rabbits after 4 to 6 h. With daptomycin therapy only a negligible release of [(3)H]choline as marker of cell wall lysis was detectable in the CSF, peaking around 250 cpm/min after 4 h, compared to a peak of around 2,400 cpm/min after 4 to 6 h for the ceftriaxone-treated rabbits.

Topics: Animals; Anti-Bacterial Agents; Bacteriolysis; Ceftriaxone; Cell Wall; Cerebrospinal Fluid; Choline; Daptomycin; Disease Models, Animal; Humans; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Penicillin Resistance; Rabbits; Streptococcus pneumoniae; Treatment Outcome; Tritium

Bacteriolytic antibiotics cause the release of bacterial components that augment the host inflammatory response, which in turn contributes to the pathophysiology of brain injury in bacterial meningitis. In the present study, antibiotic therapy with nonbacteriolytic daptomycin was compared with that of bacteriolytic ceftriaxone in experimental pneumococcal meningitis, and the treatments were evaluated for their effects on inflammation and brain injury. Eleven-day-old rats were injected intracisternally with 1.3 x 10(4) +/- 0.5 x 10(4) CFU of Streptococcus pneumoniae serotype 3 and randomized to therapy with ceftriaxone (100 mg/kg of body weight subcutaneously [s.c.]; n = 55) or daptomycin (50 mg/kg s.c.; n = 56) starting at 18 h after infection. The cerebrospinal fluid (CSF) was assessed for bacterial counts, matrix metalloproteinase-9 levels, and tumor necrosis factor alpha levels at different time intervals after infection. Cortical brain damage was evaluated at 40 h after infection. Daptomycin cleared the bacteria more efficiently from the CSF than ceftriaxone within 2 h after the initiation of therapy (log(10) 3.6 +/- 1.0 and log(10) 6.3 +/- 1.4 CFU/ml, respectively; P < 0.02); reduced the inflammatory host reaction, as assessed by the matrix metalloproteinase-9 concentration in CSF 40 h after infection (P < 0.005); and prevented the development of cortical injury (cortical injury present in 0/30 and 7/28 animals, respectively; P < 0.004). Compared to ceftriaxone, daptomycin cleared the bacteria from the CSF more rapidly and caused less CSF inflammation. This combined effect provides an explanation for the observation that daptomycin prevented the development of cortical brain injury in experimental pneumococcal meningitis. Further research is needed to investigate whether nonbacteriolytic antibiotic therapy with daptomycin represents an advantageous alternative over current bacteriolytic antibiotic therapies for the treatment of pneumococcal meningitis.

Topics: Animals; Anti-Bacterial Agents; Brain Injuries; Ceftriaxone; Cerebral Cortex; Cerebrospinal Fluid; Daptomycin; Disease Models, Animal; Humans; Inflammation; Meningitis, Pneumococcal; Random Allocation; Rats; Treatment Outcome

The effect of anti-tumor necrosis factor (TNF)-alpha treatment in Borrelia burgdorferi-infected and ceftriaxone-treated C3H/He mice was evaluated.. Mice were infected with B. garinii A218 or B. burgdorferi sensu stricto N40. At 2 weeks of infection, one group was treated simultaneously with ceftriaxone and anti-TNF-alpha, whereas another received ceftriaxone at 2 weeks and anti-TNF-alpha 4 weeks later. One group received ceftriaxone treatment only. Infected and noninfected control groups were sham treated.. At 14 weeks of infection, B. burgdorferi could not be detected by cultivation or by polymerase chain reaction in tissue samples of any mouse treated with ceftriaxone only. However, spirochetes grew from the tissue samples of one-third of the mice treated with anti-TNF-alpha simultaneously or 4 weeks after ceftriaxone. These activated spirochetes showed ceftriaxone sensitivity rates, plasmid profiles, and virulence rates similar to those of bacteria used to infect the mice. All infected control mice and mice given anti-TNF-alpha only were culture positive.. This report shows that, after ceftriaxone treatment for 5 days, a portion of B. burgdorferi-infected mice still have live spirochetes in their body, which are activated by anti-TNF-alpha treatment.

Topics: Animals; Anti-Bacterial Agents; Antibodies; Borrelia burgdorferi; Borrelia burgdorferi Group; Ceftriaxone; Disease Models, Animal; Immunoglobulin G; Joint Diseases; Kinetics; Lyme Disease; Mice; Mice, Inbred C3H; Rats; Spirochaetales; Tumor Necrosis Factor-alpha

Spontaneous bacterial peritonitis (SBP) is a severe complication of cirrhotic patients associated with a high mortality.. To develop an available experimental model of induced bacterial peritonitis in cirrhosis.. Sprague-Dawley rats with carbon-tetrachloride-induced cirrhosis with (N=22) or without (N=101) ascites were randomized to receive an intraperitoneal administration of different concentrations of Escherichia coli (E. coli) diluted in 1 mL of sterile water in ascitic rats and in different volumes in nonascitic rats. A subgroup of nonascitic animals received ceftriaxone 4 h after E. coli inoculation. Mortality of rats was evaluated 24 h after bacterial inoculation.. None of the rats receiving sterile water alone and only one infected with 10(7) cfu of E. coli died. Ascitic rats showed a lower mortality rate than nonascitic rats infected with 10(8) or 10(9) cfu of E. coli (P<0.05). Mortality was higher with 10(9) cfu than with 10(8) cfu of E. coli in ascitic (P NS) and nonascitic (P<0.01) rats. A trend was noted to ward higher mortality in nonascitic rats inoculated with 10(8) cfu with increasing water volumes. A marked peritoneal polymorphonuclear cell response was observed 4 h after E. coli injection in both ascitic and nonascitic rats. Antibiotic therapy significantly reduced the mortality rate of rats infected with 10(8) cfu (P<0.01).. This experimental model of induced bacterial peritonitis in cirrhosis with or without ascites may represent a useful tool for the study of pathogenic events postinfection and for the design of new therapeutic strategies to treat patients with SBP.

Topics: Animals; Anti-Bacterial Agents; Ascites; Bacterial Infections; Carbon Tetrachloride; Ceftriaxone; Disease Models, Animal; Escherichia coli Infections; Liver Cirrhosis, Experimental; Male; Peritonitis; Random Allocation; Rats; Rats, Sprague-Dawley

In this study, we investigated cytokine expression during experimental pneumococcal meningitis. Mice were intracisternally infected with Streptococcus pneumoniae and treated with ceftriaxone starting at 24 h after infection. At different time points before and after antibiotic therapy, the cytokine expression pattern was determined in mouse brains using protein arrays. Underlining the power of this method, the meningitis-relevant cytokines interleukin-1beta (IL-1beta), IL-6, KC, macrophage inflammatory protein-2 (MIP-2), and monocyte chemoattractant protein-1 (MCP-1/CCL2) were markedly elevated in infected animals. Newly identified proteins during the acute stage of the disease (until 30 h after infection) included lymphotactin (XCL-1), MIP-1gamma (CCL9) and MCP-5 (CCL12), cytokine responsive gene- 2 (CRG-2/CXCL10) and CXCL16, and insulin-like growth factor binding protein 3 (IGFBP3). During later stages, an induction of T-cell activation-3 (TCA-3/CCL1), platelet factor-4 (PF-4/CXCL4) and stromal derived factor-1alpha (SDF-1alpha/CXCL13), and IL-4 was observed. The validity of this method was supported by an additional ELISA analysis of the expression profile of CXCL16 and IGFBP3, which was identical to that observed by protein array. In conclusion, the use of protein array technology led to an extension of the current picture of protein expression in pneumococcal meningitis. Most important, new factors that might play a role in pneumococcal meningitis were identified.

Topics: Animals; Anti-Bacterial Agents; Brain; Ceftriaxone; Chemokine CXCL10; Chemokine CXCL13; Chemokines, C; Chemokines, CC; Chemokines, CXC; Cytokines; Disease Models, Animal; Interleukin-4; Macrophage Inflammatory Proteins; Meningitis, Pneumococcal; Mice; Mice, Inbred C57BL; Monocyte Chemoattractant Proteins; Monokines; Platelet Factor 4; Protein Array Analysis; Streptococcus pneumoniae; Time Factors

To study the in vitro and in vivo efficacy of fosfomycin, alone and in combination with ceftriaxone or vancomycin, against two strains of Streptococcus pneumoniae: HUB 2349 (fosfomycin and ceftriaxone, MICs 16 and 2 mg/L) and ATCC 51916 (MICs 4 and 32 mg/L).. Pharmacokinetics/pharmacodynamics data were collected from the study of eight infected animals after a single intravenous dose of 300 mg/kg of fosfomycin. Time-kill curves were plotted using CSF antibiotic concentrations achievable clinically. In the rabbit model, we studied the efficacy and effects on inflammation of treatment with fosfomycin 1200 mg/kg/day, ceftriaxone 100 mg/kg/day and vancomycin 30 mg/kg/day, over 26 h.. Fosfomycin peak level in serum was 324.48 +/- 102.1 mg/L at 0.5 h; CSF penetration was 49.2%. Time-kill curves showed that fosfomycin was bactericidal against the ATCC 51916 strain and that the addition of fosfomycin to ceftriaxone or vancomycin was synergic against the HUB 2349 strain. Resistance to fosfomycin was detected both when fosfomycin was studied alone and in combination. In the rabbit model, fosfomycin showed bactericidal activity only against the ATCC 51916 strain. Combinations of fosfomycin with ceftriaxone or vancomycin were bactericidal against both strains; they improved efficacy and decreased CSF inflammatory parameters over monotherapies, without showing statistical differences in comparison with the combination of ceftriaxone and vancomycin.. Fosfomycin in combination with ceftriaxone or vancomycin appeared to be effective for the treatment of experimental cephalosporin-resistant pneumococcal meningitis. These combinations are possible alternatives in cases of allergy or intolerance to first-line drugs or in rare meningitis caused by highly cephalosporin-resistant pneumococci.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Cephalosporin Resistance; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Female; Fosfomycin; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Rabbits; Streptococcus pneumoniae; Vancomycin

To determine the effects of melatonin combined with antibiotic administration on the suppression of renal scarring in an experimental pyelonephritis model.. The control group underwent a sham operation without infection. In the other groups, treatment began 72 hours after direct bacterial inoculation. In the no-treatment group, rats received daily intraperitoneal injections of saline. In the antibiotic-only group, the rats were treated only with ceftriaxone intramuscularly at a dose of 50 mg/kg once daily for 5 days. In the melatonin-only group, only 20 mg/kg of melatonin once daily was given by intraperitoneal injection for 5 days. In the antibiotic plus melatonin group, melatonin and ceftriaxone were administered at the same dosages and duration as for the single-modality treatment groups. After 6 weeks, the kidneys were removed for malondialdehyde measurements and histopathologic examination (inflammatory response and cicatrization).. Melatonin only (134.25 +/- 13.42) and antibiotic plus melatonin treatment (122.62 +/- 8.91) caused a marked reduction in the mean malondialdehyde values compared with no treatment (214.12 +/- 17.77) and antibiotic-only treatment (161.37 +/- 16.03), with no significant difference compared with that of the control group (120.75 +/- 9.83). Histopathologically, in the no-treatment group, the severity of scarring correlated directly with the severity of inflammation (r = 0.93). No significant differences were found in the renal scarring scores in rats receiving no treatment and those treated only with antibiotic or melatonin. In the antibiotic plus melatonin treatment group, the cicatrization score was not statistically different from that of the control group.. When combined with antibiotics, melatonin causes a significant inhibition of malondialdehyde production and neutrophil infiltration caused by acute pyelonephritis in an experimental rat model, and these are responsible for the protective effect of melatonin against renal damage, preventing renal scarring formation.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Cicatrix; Disease Models, Animal; Drug Therapy, Combination; Kidney Diseases; Male; Melatonin; Pyelonephritis; Rats; Rats, Sprague-Dawley

Topics: Amyotrophic Lateral Sclerosis; Animals; Anti-Bacterial Agents; beta-Lactams; Ceftriaxone; Cephalosporins; Clinical Trials as Topic; Disease Models, Animal; Excitatory Amino Acid Transporter 2; Humans; Mice; Mice, Transgenic

We wanted to study the pathogenesis and the long-term manifestations of Borrelia garinii infection in SJL and C3H/He mice. We report here that B. garinii A218 causes a persisting infection in these mouse strains. Mice infected with intracutaneous inoculation of B. garinii at 4-5 weeks of age developed a disseminated infection and joint swelling within 2 weeks of inoculation and remained infected with joint symptoms until the end of follow-ups of up to 52 weeks. Treatment with ceftriaxone or ampicillin at 18 or 44 weeks of infection did not affect the joint swelling during the follow-ups of 19 and 8 weeks, respectively. However, B. garinii could not be cultured from any of the post mortem tissue samples of the treated mice, whereas the spirochete grew from samples of all untreated infected animals. Borrelia-specific IgG antibodies were detectable after 2 weeks of infection, and in late infection, all mice had high anti-borrelia IgG levels. Antibiotic treatment had no effect on antibody levels. Histology showed only slight changes in the joints of the infected mice with occasional lymphocyte infiltration, synovial proliferation and slight involvement of the Achilles' tendon. No difference was seen in the findings between ceftriaxone-treated and untreated mice. The results suggest that the presence of vegetative spirochetes is no prerequisite for persisting joint symptoms and elevated anti-borrelia IgG levels in these B. garinii-infected mice.

Topics: Achilles Tendon; Ampicillin; Animals; Anti-Bacterial Agents; Antibodies, Bacterial; Borrelia burgdorferi Group; Ceftriaxone; Disease Models, Animal; Female; Histocytochemistry; Immunoglobulin G; Joint Diseases; Joints; Lyme Disease; Lymphocytes; Mice; Mice, Inbred C3H; Synovial Membrane

Recombinant human osteogenic protein-1 (rhOP-1), combined with a collagen carrier, has been shown to induce new-bone formation in a variety of animal models. The purpose of the present investigation was to test the hypotheses that rhOP-1 would accelerate bone formation in an internally stabilized, chronically infected, critical-size defect in the rat femur and that this effect would be enhanced by the administration of systemic antibiotic.. A 6-mm segmental defect was created surgically, stabilized with a polyacetyl plate and six Kirschner wires, and contaminated with 10(4) colony-forming units of Staphylococcus aureus in one femur in each of 168 Sprague-Dawley rats. After two weeks, these infected defects were débrided surgically and were assigned to one of six treatment groups. The defects in the thirty animals in the first group received lyophilized collagen carrier mixed with 200 microg of rhOP-1 dissolved in buffer, the defects in the thirty animals in the second group received carrier with 20 microg of rhOP-1 in buffer, and the defects in the twenty-four control animals in the third group received carrier mixed with buffer without rhOP-1. The last three groups were treated identically to the first three groups, except that the animals also received the antibiotic ceftriaxone for twenty-eight days after débridement. The animals were killed at two, four, eight, or twelve weeks after débridement. Newly mineralized callus within the defect, and adjacent to and bridging the outside of the defect, was assessed with use of quantitative high-resolution radiography, microcomputed tomography, torsional failure testing, and histological analysis of undecalcified sections.. Bacterial cultures confirmed the presence of a chronic infection during the study period in all animals. At the later time-points, significantly more newly mineralized callus was present within and adjacent to the débrided defects that had been treated with 200 microg of rhOP-1, whereas minimal amounts of callus were present within and adjacent to the defects that had been treated without rhOP-1 and with 20 microg of rhOP-1. At eight and twelve weeks after débridement, there was significantly more newly mineralized callus in the group that had been treated with 200 microg of rhOP-1 with antibiotic than in the group that had been treated with 200 microg of rhOP-1 without antibiotic (p < 0.05). At twelve weeks, the values for torque, energy to failure, and linear stiffness for femora that had been treated with 200 microg of rhOP-1 with antibiotic were not significantly different from the values for intact, contralateral control femora, whereas the values for femora that had been treated with 200 microg of rhOP-1 without antibiotic remained significantly lower than those for the intact, contralateral controls (p < 0.05).. Recombinant human osteogenic protein-1 maintained its osteoinductive capability in the presence of chronic infection, and this property was enhanced by antibiotic therapy. No substantial callus formed in the infected defects without a sufficiently high dose of rhOP-1.. The treatment of an infection at the site of a fracture often necessitates removal of internal fixation. However, internal fixation is needed for fracture stability. This study presents an intervention that may accelerate fracture-healing in the presence of infection and colonized hardware, thereby permitting earlier removal of the hardware and more timely and effective treatment of the infection.

Topics: Animals; Anti-Bacterial Agents; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Bone Regeneration; Ceftriaxone; Chronic Disease; Disease Models, Animal; Drug Therapy, Combination; Femur; Internal Fixators; Male; Prosthesis-Related Infections; Rats; Rats, Sprague-Dawley; Recombinant Proteins

Antibiotics may impair small bowel smooth muscle contractility and contribute to postoperative ileus. The aim of this study was to compare the contractile responses of ileum smooth muscle to different agonists in guinea pigs treated with ceftriaxone (Rocephin; F. Hoffman-La Roche, Kaiseraugst, Switzerland) or ampicillin (Ampisina; Mustafa Nevzat Ilaç Sanayii AS, Istanbul, Turkey).. Twenty-four adult guinea pigs were randomly divided into three groups. Whereas eight of these received ceftriaxone sodium (100 mg/kg per day, i.m.) for 10 days, another eight guinea pigs received ampicillin (50 mg/kg per day, i.m.) for 10 days and the remaining eight served as the control group receiving 1 mL distilled water during 10 days as placebo. By the end of 10 days, the animals were killed and their ilea were excised. Ileum segments were placed in an organ bath; concentration-response relationship for carbachol and histamine were obtained by adding the reagent cumulatively to the bath.. pD(2) values being the same, maximum contractile responses (E(max)) to carbachol and histamine were significantly reduced in the ceftriaxone sodium group compared with the control group. No significant differences in E(max) and pD(2) values to carbachol and histamine were observed between the ampicillin group and the control group.. These data indicate that whereas ceftriaxone may impair small bowel smooth muscle contractility, ampicillin does not. There are implications for the long-term use of parenteral antibiotics in the postoperative period.

Topics: Ampicillin; Animals; Anti-Bacterial Agents; Ceftriaxone; Disease Models, Animal; Follow-Up Studies; Guinea Pigs; Ileum; Ileus; Injections, Intramuscular; Male; Muscle Contraction; Muscle, Smooth; Postoperative Complications; Time Factors

Bacteraemia concomitant with meningitis has been shown to greatly affect outcome. Consequently, the efficacy of serotype-specific anti-pneumococcal antiserum (APAS) was investigated in a rat model of pneumococcal meningitis.. Rats were infected with Streptococcus pneumoniae serotype 3. All rats received ceftriaxone starting 26 h post-infection. APAS was administered either at the time of infection or 26 h post-infection and effects were compared with rats treated with antibiotics only.. A significant clinical benefit was found when APAS was given at the time of infection whereas no effect was found when administered 26 h after infection. This work indicates that the clinical value of using APAS in pneumococcal meningitis may be limited.

Topics: Animals; Anti-Bacterial Agents; Antibodies, Bacterial; Bacterial Capsules; Ceftriaxone; Disease Models, Animal; Drug Therapy, Combination; Immunization, Passive; Meningitis, Pneumococcal; Motor Activity; Rats; Rats, Wistar; Streptococcus pneumoniae; Survival Analysis; Time Factors

Novel rifamycins such as ABI-0043, ABI-0369, and ABI-0699 had comparable in vivo bactericidal activity with ceftriaxone against a penicillin-G-resistant, mefA-positive Streptococcus pneumoniae in a murine pneumonia model. ABI-0043 demonstrated a dose-dependent response with a high correlation to bacterial kill (+0.1 to -3.7 log 10CFU).

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Mice; Mice, Inbred ICR; Penicillin Resistance; Pneumonia, Pneumococcal; Rifamycins

The aim of the study was to determine the efficacy of teicoplanin, alone and in combination with ceftriaxone, in a rabbit model of cephalosporin-resistant pneumococcal meningitis, and to assess the effect of concomitant therapy with dexamethasone.. In vitro killing curves of teicoplanin, with and without ceftriaxone, were performed. Groups of eight animals per treatment were inoculated with a cephalosporin-resistant pneumococcal strain (penicillin MIC, 4 mg/L; ceftriaxone MIC, 2 mg/L; teicoplanin MIC, 0.03 mg/L) and treated over a 26 h period. Teicoplanin was administered at a dose of 15 mg/kg, alone and in combination with ceftriaxone at 100 mg/kg with or without dexamethasone at 0.25 mg/kg. CSF samples were collected at different time-points, and bacterial titres, white blood cell counts, lactate and protein concentrations and bacteriostatic/bactericidal titres were determined. Blood and CSF teicoplanin pharmacokinetic and pharmacodynamic parameters were determined.. Teicoplanin alone promoted a decrease in bacterial counts at 6 h of -2.66 log cfu/mL and was bactericidal at 24 h, without therapeutic failures. Similar good results were obtained when dexamethasone was used simultaneously, in spite of the penetration of teicoplanin into the CSF being significantly reduced, from 2.31% to 0.71%. Teicoplanin and ceftriaxone combinations were synergic in vitro, but not in the meningitis model.. Teicoplanin alone was very effective in this model of cephalosporin-resistant pneumococcal meningitis. The use of concomitant dexamethasone resulted in lower CSF teicoplanin levels, but not in therapeutic failures. The combination of teicoplanin plus ceftriaxone and dexamethasone might be a good alternative for the empirical therapy of pneumococcal meningitis. Additional data should confirm our experiments, in advance of clinical trials to assess efficacy in humans.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Ceftriaxone; Cephalosporin Resistance; Colony Count, Microbial; Dexamethasone; Disease Models, Animal; Drug Therapy, Combination; Humans; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Rabbits; Streptococcus pneumoniae; Teicoplanin

A rat model was used to study the effects of cirrhosis on antibiotic therapy of pneumococcal pneumonia. Cirrhotic and control male Sprague-Dawley rats were infected transtracheally with type 3 Streptococcus pneumoniae. Treatment began 18 h later with phosphate-buffered saline (PBS), azithromycin (50 mg/kg), trovafloxacin (50 mg/kg), or ceftriaxone (100 mg/kg) injected subcutaneously twice daily for 5 days. Antibiotic concentrations were measured by high-performance liquid chromatography. Azithromycin, trovafloxacin, and ceftriaxone were all equally effective at preventing mortality in both cirrhotic and normal rats. Free fraction area under the curve to minimum inhibitory concentration ratio (AUC/MIC) and maximum calculated serum concentration to MIC ratio (C(max)/MIC) and percent time that the serum concentration exceeded the MIC (%T > MIC) were greater for ceftriaxone compared with azithromycin or trovafloxacin. Azithromycin achieved higher concentrations in bronchoalveolar lavage fluid (BALF), epithelial lining fluid (ELF), and BAL white blood cells than ceftriaxone or trovafloxacin in cirrhotic rats. Macrolide, beta-lactam, or fluoroquinolone antibiotic efficacy in a pneumococcal pneumonia model does not appear to be affected by hepatic cirrhosis.

Topics: Animals; Azithromycin; Biological Availability; Blood Chemical Analysis; Bronchoalveolar Lavage Fluid; Ceftriaxone; Disease Models, Animal; Drug Therapy, Combination; Fluoroquinolones; Injections, Subcutaneous; Liver Cirrhosis; Male; Naphthyridines; Pneumonia, Pneumococcal; Random Allocation; Rats; Rats, Sprague-Dawley; Reference Values; Risk Assessment; Sensitivity and Specificity; Survival Rate

Topics: Amyotrophic Lateral Sclerosis; Animals; Anti-Bacterial Agents; Ceftriaxone; Disease Models, Animal; Drug Evaluation, Preclinical; Excitatory Amino Acid Transporter 2; Glutamic Acid; Mice; Neuroprotective Agents

This study was planned to compare the efficacy of ceftriaxone+vancomycin with ceftriaxone+rifampicin in a rabbit model of penicillin and cephalosporin-resistant Streptococcus pneumoniae meningitis. Meningitis was induced by intracisternal inoculation of S. pneumoniae. After 18 h of incubation, Group 1 was given saline solution (control group), whilst Groups 2 and 3 were given ceftriaxone+vancomycin and ceftriaxone+rifampicin, respectively. Cerebrospinal fluid bacterial concentrations were measured at 0, 2, 12, 14 and 24 h after therapy was initiated. In the control group, bacterial growth was present at all time points, whereas no growth was observed in either the ceftriaxone+vancomycin group or the ceftriaxone+rifampicin group after 2 h of therapy. Ceftriaxone+rifampicin was found to be as effective as ceftriaxone+vancomycin in the treatment of penicillin-resistant S. pneumoniae meningitis in experimental rabbit model.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Cephalosporin Resistance; Cerebrospinal Fluid; Disease Models, Animal; Drug Resistance, Bacterial; Drug Therapy, Combination; Meningitis, Meningococcal; Penicillin Resistance; Rabbits; Rifampin; Streptococcus pneumoniae; Vancomycin

Rifampin, a protein synthesis inhibitor, reduced mortality in a mouse model of meningitis compared to bacteriolytic cephalosporin standard therapy. To assess whether moxifloxacin (known to cause a less rapid bacteriolysis than cephalosporins) can similarly reduce mortality, mice infected with Streptococcus pneumoniae by deep intracerebral injection were treated subcutaneously with either 200 mg/kg of moxifloxacin or ceftriaxone every 8 hours for 5 days (n = 49 each). They were then observed for an additional 8 days. Overall mortalities were 35 and 29 in moxifloxacin- and ceftriaxone-treated mice, respectively (p = 0.29). Kaplan-Meier survival analysis also revealed no statistically significant differences (p = 0.32). Moxifloxacin failed to reduce mortality compared to cephalosporin standard therapy.

Topics: Animals; Anti-Bacterial Agents; Aza Compounds; Ceftriaxone; Disease Models, Animal; Drug Administration Schedule; Fluoroquinolones; Injections, Subcutaneous; Male; Meningitis, Pneumococcal; Mice; Mice, Inbred C57BL; Moxifloxacin; Quinolines; Treatment Outcome

The aim of the study was to assess the in vitro and in vivo efficacy of ceftriaxone, vancomycin and rifampicin alone and combined against Streptococcus pneumoniae ATCC 51916 (MIC of ceftriaxone: 32 mg/L).. In vitro killing curves were performed with clinically achievable CSF antibiotic concentrations. In the rabbit model of pneumococcal meningitis, we studied the efficacy of and effects on inflammation of treatment with ceftriaxone 100 mg/kg/day, vancomycin 30 mg/kg/day and rifampicin 15 mg/kg/day, alone and combined, over a 26 h period.. Time-kill curves showed that vancomycin was bactericidal, and ceftriaxone and rifampicin produced a bacteriostatic effect. An additive effect was observed when combinations of ceftriaxone plus vancomycin were studied at subinhibitory concentrations. Emergence of resistance to rifampicin was detected both when rifampicin was studied alone and when combined with ceftriaxone or vancomycin. In the rabbit meningitis model, ceftriaxone was bacteriostatic, whereas rifampicin and vancomycin were bactericidal at 24 h. Although not synergistic, the combinations of ceftriaxone plus vancomycin or rifampicin, and vancomycin plus rifampicin, improved the efficacy of any antibiotic tested alone--all combinations were bactericidal from 6 h--and significantly decreased inflammatory parameters in CSF compared with control and ceftriaxone groups.. Ceftriaxone plus vancomycin, and vancomycin plus rifampicin appeared to be effective in the therapy of experimental pneumococcal meningitis caused by highly cephalosporin-resistant strains such as ATCC 51916. Our results provide an experimental basis for using these combinations as empirical therapy for pneumococcal meningitis, regardless of the degree of cephalosporin resistance of the causative strain.

Topics: Animals; Ceftriaxone; Cephalosporin Resistance; Cerebrospinal Fluid; Colony Count, Microbial; Disease Models, Animal; Drug Combinations; Drug Interactions; Drug Resistance, Bacterial; Female; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Rabbits; Rifampin; Streptococcus pneumoniae; Vancomycin

We assessed the efficacy of a new adenosine A2A agonist ATL146e, a potent inhibitor of white blood cell chemotaxis, to reduce cartilage damage in the treatment of septic arthrosis. A live septic arthrosis model was created using Staphylococcus aureus in rabbit knees. Animals were divided into five treatment groups: (1) untreated infected control, (2) antibiotics control, and antibiotics plus ATL146e for (3) 24, (4) 48, or (5) 72 h and assessed at 1, 4, and 7 days. Knees in all ATL146e treated animals exhibited no detectable effusion, and histologic examination revealed near normal cartilage and diminished synovial inflammatory response. Synovial WBC counts decreased with the addition of ATL146e when compared to infected and antibiotic controls. Histologic grading of osteochondral specimens demonstrated improved scores for animals treated with ATL146e compared to infected (p<0.00004) and antibiotics controls (p<0.05). Analysis of glycosaminoglycan content revealed significantly decreased loss of articular cartilage following infection in the ATL146e groups when compared to infected (p<0.03) and antibiotics controls (p<0.05). Addition of an adenosine A2A agonist to antibiotic therapy decreases joint inflammation and articular cartilage destruction without compromising bacterial clearance in rabbit knees following intraarticular bacterial infection. The use of adenosine agonists selective to the A2A receptor to augment conventional treatment of joint sepsis may be chondroprotective and ultimately help prevent arthrosis.

Topics: Adenosine A2 Receptor Antagonists; Animals; Arthritis, Infectious; Cartilage, Articular; Ceftriaxone; Cyclohexanecarboxylic Acids; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Hindlimb; Joints; Leukocyte Count; Leukocytes; Proteoglycans; Purines; Rabbits; Staphylococcus aureus; Synovial Membrane

We compared ceftriaxone and piperacillin-tazobactam at doses ranging from 0.1 to 2 times the human equivalent daily dose (HEDD), to determine their impact on gastrointestinal colonization by ampicillin- and vancomycin-resistant Enterococcus faecium C68 in a mouse model. Ceftriaxone failed to promote colonization at doses up to 0.25 times the HEDD, whereas piperacillin-tazobactam promoted colonization at doses up to 0.5 times the HEDD. Ceftriaxone promoted colonization at doses at least 0.5 times the HEDD, whereas piperacillin-tazobactam inhibited colonization at doses at least 0.75 times the HEDD. Both piperacillin-tazobactam and ceftriaxone inhibited colonization by an enterococcal strain devoid of low-affinity penicillin-binding protein-5 (significantly increasing its susceptibility to these agents), at doses that promoted colonization by E. faecium C68. These results support a model in which the impact that different beta -lactam agents have on colonization by VRE is related to the level of the beta -lactam agent's intrinsic antienterococcal activity against the colonizing strain.

Topics: Animals; Anti-Bacterial Agents; Carrier State; Ceftriaxone; Colony Count, Microbial; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Bacterial; Enterococcus faecium; Feces; Female; Gastrointestinal Tract; Gram-Positive Bacterial Infections; Mice; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination

Encapsulation of ciprofloxacin in sterically stabilized liposomes results in a prolonged circulation time and improved pharmacokinetics. Liposome-encapsulated ciprofloxacin was compared with conventional ciprofloxacin and ceftriaxone in a rat model of pneumococcal pneumonia. Male Sprague-Dawley rats were infected transtracheally with type 3 Streptococcus pneumoniae and then treated with intravenous ceftriaxone (100 mg/kg), ciprofloxacin (40 or 80 mg/kg) or liposomal ciprofloxacin (40 or 80 mg/kg) administered once or twice daily for 3 days. White blood counts, development of bacteraemia and mortality were measured for 10 days. Antibiotic concentrations in serum, lung lavage fluid and white blood cells recovered from lung lavage fluid were determined. Liposomal ciprofloxacin concentrations were significantly higher in serum and lavage fluid compared with conventional ciprofloxacin, resulting in greater area under the serum concentration-time curve and maximum serum concentration. Despite these higher concentrations, survival rates were similar between groups treated with equivalent doses of liposomal ciprofloxacin versus ciprofloxacin. When antibiotics were given once daily, ceftriaxone was more effective than either form of ciprofloxacin.

Topics: Animals; Bronchoalveolar Lavage Fluid; Ceftriaxone; Ciprofloxacin; Colony Count, Microbial; Disease Models, Animal; Leukocyte Count; Liposomes; Male; Neutrophils; Pneumonia, Pneumococcal; Rats; Rats, Sprague-Dawley; Survival Rate

Using a rabbit model of meningitis, we sought to determine the efficacy of LY333328, a semisynthetic glycopeptide, in the treatment of cephalosporin-resistant pneumococcal meningitis. LY333328 was administered at a dose of 10 mg/kg of body weight/day, alone and in combination with ceftriaxone at 100 mg/kg/day with or without dexamethasone at 0.25 mg/kg/day. The therapeutic groups were treated with LY333328 with or without dexamethasone and LY333328-ceftriaxone with or without dexamethasone. Rabbits were inoculated with a cephalosporin-resistant pneumococcal strain (ceftriaxone MIC, 2 microg/ml; penicillin MIC, 4 microg/ml; LY333328 MIC, 0.008 microg/ml) and were treated over a 26-h period beginning 18 h after inoculation. The bacterial counts in cerebrospinal fluid (CSF), the white blood cell count, the lactic acid concentration, the CSF LY333328 concentration, and bactericidal and bacteriostatic activities were determined at different time points. In vitro, LY333328 was highly bactericidal and its use in combination with ceftriaxone at one-half the MIC was synergistic. In the rabbit model, LY333328 alone was an excellent treatment for cephalosporin-resistant pneumococcal meningitis, with a rapid decrease in colony counts and no therapeutic failures. The use of LY333328 in combination with ceftriaxone improved the activity of LY333328, but no synergistic effect was observed. The combination of LY333328 with dexamethasone was also rapidly bactericidal, but two therapeutic failures were observed. The combination of LY333328 with ceftriaxone and dexamethasone was effective, without therapeutic failures.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Ceftriaxone; Cephalosporin Resistance; Colony Count, Microbial; Dexamethasone; Disease Models, Animal; Drug Therapy, Combination; Female; Glycopeptides; Lactic Acid; Leukocyte Count; Lipoglycopeptides; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Rabbits; Streptococcus pneumoniae

The penetration of ertapenem, a new carbapenem with a long half-life, reached 7.1 and 2.4% into inflamed and noninflamed meninges, respectively. Ertapenem had excellent antibacterial activity in the treatment of experimental meningitis due to penicillin-sensitive and -resistant pneumococci, leading to a decrease of 0.69 +/- 0.17 and 0.59 +/- 0.22 log(10) CFU/ml x h, respectively, in the viable cell counts in the cerebrospinal fluid. The efficacy of ertapenem was comparable to that of standard regimens (ceftriaxone monotherapy against the penicillin-sensitive strain and ceftriaxone combined with vancomycin against the penicillin-resistant strain). In vitro, ertapenem in concentrations above the MIC was highly bactericidal against both strains. Even against a penicillin- and quinolone-resistant mutant, ertapenem had similar bactericidal activity in vitro.

Topics: Animals; Anti-Bacterial Agents; beta-Lactams; Ceftriaxone; Disease Models, Animal; Ertapenem; Lactams; Meningitis, Pneumococcal; Penicillin Resistance; Rabbits; Streptococcus pneumoniae; Vancomycin

The effect of optimized maternal therapy by bactericidal agents was evaluated in a reproducible rabbit model of Escherichia coli maternofetal infection simulating human pharmacokinetics. Intravenous antibiotic therapy was begun in the pregnant rabbit 12 h after bacterial intrauterine inoculation, using a computer-controlled pump to simulate human pharmacokinetics of ceftriaxone (1 g/day) associated or not with gentamicin (3 mg/kg of body weight/day). Data were compared for fetal survival, quantitative blood cultures, fetal histology in treated versus untreated groups, and maternal and fetal antibiotic concentrations in plasma in treated animals. Antibiotic therapy led to dramatic improvement in maternal outcome (100% survival versus 100% death in the untreated group in association with maternal septicemia). Fetal survival also improved, with the two-drug combination providing a more potent effect. After 3 days of treatment, 32% of fetuses survived with one-drug therapy and 62% with two-drug therapy (Yates corrected chi(2), P < 0.05). In untreated animals, bacterial counts in blood cultures increased rapidly during the first 24 h up to 8.1 +/- 0.5 log CFU/ml, but remained relatively constant at all times with antibiotic treatment: 4.5 +/- 0.7 log CFU/ml at the start of treatment and 6.2 +/- 0.4 and 5.2 +/- 0.9 log CFU/ml after 72 h for one- and two-drug therapy, respectively (data are means +/- standard deviations). The failure of animals to be cured after 3 days of treatment was not due to an inadequate concentration of ceftriaxone, as the residual level in fetal serum at sacrifice was more than 1000 times the MIC of the microbe. Unexpectedly, inflammation in fetal lung decreased in the treated group after as little as 24 h of antibiotic therapy, despite persistent bacteremia. Although maternal outcome improved and drug concentrations were above the MIC, the treatment did not achieve sterilization of fetuses in utero for this rabbit E. coli maternofetal infection. However, fetal survival showed some improvement, and the histologic features of lung inflammation were reduced.

Topics: Animals; Anti-Bacterial Agents; Bacteremia; Ceftriaxone; Disease Models, Animal; Escherichia coli; Escherichia coli Infections; Female; Fetal Diseases; Infectious Disease Transmission, Vertical; Maternal-Fetal Exchange; Pregnancy; Rabbits

Treatments aimed at inhibition of tumor necrosis factor (TNF) in patients with sepsis have been unsuccessful. Up to 50% of such patients suffer from pneumonia. To determine the effect that treatment with anti-TNF has on pneumococcal pneumonia, mice were intranasally inoculated with Streptococcus pneumoniae and, 25 h later, treated with 1 of the following: (1) control antibody, (2) anti-TNF, (3) ceftriaxone (CEF) with control antibody, or (4) CEF with anti-TNF. In the absence of treatment with CEF, mice displayed high bacterial loads in lungs, and all of these mice died within 5 days after inoculation. Anti-TNF did not influence these outcomes. In contrast, 60% of mice treated with CEF alone survived. Anti-TNF administered together with CEF reduced survival to 40% and was associated with enhanced bacterial outgrowth. These data suggest that treatment with anti-TNF impairs the therapeutic efficacy of CEF during pneumococcal pneumonia.

Topics: Animals; Anti-Bacterial Agents; Antibodies; Ceftriaxone; Disease Models, Animal; Lung; Mice; Pneumonia, Pneumococcal; Streptococcus pneumoniae; Tumor Necrosis Factor-alpha

Current estimates of the mortality associated with brain abscesses range from 0-24%, with neurological sequellae in 30-55% of survivors. Although the incidence of brain abscess appears to be increasing, likely due to an increase in the population of immunosuppressed patients, the condition is still sufficiently uncommon to make human clinical trials of therapy problematic. An animal model to study the efficacy of new treatment regimens, specifically, new antimicrobial agents is therefore necessary. This study uses a well-defined experimental paradigm as an inexpensive method of inducing and studying the efficacy of antibiotics in brain abscess. The rat model of brain abscess/cerebritis developed at this institution was used to determine the relative efficacy of trovafloxacin as compared to ceftriaxone in animals infected with Staphylococcus aureus. S. aureus ( approximately 10(5) CFU in 1 microliter) was injected with a Hamilton syringe, very slowly, over the course of 70 minutes after a two mm burr hole was created with a spherical carbide drill just posterior to the coronal suture and four mm lateral to the midline. Eighteen hours later treatment was begun; every 8 hours the rats were dosed with subcutaneous ceftriaxone (n = 10), trovafloxacin (n = 11) or 0.9% sterile pyogen-free saline (n = 10). After four days of treatment the brains were removed and sectioned with a scalpel. The entire injected hemisphere was homogenized and quantitative cultures performed. The mean +/- SEM log(10) colony forming units/ml S. aureus recovered from homogenized brain were as follows: controls 6.10 +/- 0.28; ceftriaxone 3.43 +/- 0.33; trovafloxacin 3.65 +/- 0.3. There was no significant difference in bacterial clearance between ceftriaxone versus trovafloxacin (p = 0.39). Trovafloxacin or other quinolones may provide a viable alternative to intravenous antibiotics in patients with brain abscess/cerebritis.

Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Area Under Curve; Brain Abscess; Ceftriaxone; Disease Models, Animal; Female; Fluoroquinolones; Half-Life; Injections, Subcutaneous; Microbial Sensitivity Tests; Naphthyridines; Rats; Rats, Wistar; Staphylococcal Infections; Staphylococcus aureus

Hearing loss is the most frequent long-term complication of pneumococcal meningitis, affecting up to 40% of survivors. Unfortunately, adjuvant therapy with dexamethasone has failed to satisfactorily reduce its incidence. Therefore, we evaluated the use of antioxidants for the adjunctive therapy of meningitis-associated deafness. Eighteen hours after intracisternal injection of 7.5 x 10(5) colony-forming units of Streptococcus pneumoniae, rats were treated systemically either with ceftriaxone and the antioxidants and peroxynitrite scavengers Mn(III)tetrakis(4-benzoic acid)-porphyrin (MnTBAP) or N-acetyl-L-cysteine (NAC) or placebo (1 ml phosphate-buffered saline) for 4 days. Hearing was assessed by auditory brainstem response audiometry. Adjunctive antioxidant therapy significantly reduced the long-term hearing loss (14 days after infection) for square wave impulses (mean hearing loss +/- SD: ceftriaxone and placebo, 45+/-26 dB; ceftriaxone and MnTBAP, 9+/-23 dB; ceftriaxone and NAC, 19+/-30 dB) as well as 1 kHz (ceftriaxone and placebo, 28+/-19 dB; ceftriaxone and MnTBAP, 10+/-16 dB; ceftriaxone and NAC, 10+/-17 dB), and 10 kHz tone bursts (ceftriaxone and placebo, 62+/-27 dB; ceftriaxone and MnTBAP, 16+/-13 dB; ceftriaxone and NAC, 25+/-26 dB). Furthermore, both antioxidants attenuated the morphological correlates of meningogenic hearing loss, namely, long-term blood-labyrinth barrier disruption, spiral ganglion neuronal loss, and fibrous obliteration of the perilymphatic spaces. Adjuvant antioxidant therapy is highly otoprotective in meningitis and therefore is a promising future treatment option.

Topics: Acetylcysteine; Animals; Anti-Bacterial Agents; Antioxidants; Audiometry; Ceftriaxone; Cell Count; Cochlea; Disease Models, Animal; Drug Interactions; Evans Blue; Evoked Potentials, Auditory, Brain Stem; Hearing Loss; Labyrinthitis; Male; Meningitis, Pneumococcal; Metalloporphyrins; Peroxynitrous Acid; Rats; Rats, Wistar; Spiral Ganglion; Time Factors

The release of proinflammatory components from bacteria depends on the mode of action of the antibacterial therapy used. We studied whether this influences mortality in experimental sepsis.. In a lethal murine model of Staphylococcus aureus sepsis, animals were randomly assigned to receive the protein synthesis inhibitor clindamycin (CLI) or the beta-lactam ceftriaxone (CRO).. Therapy was introduced subcutaneously 5 hrs after intraperitoneal injection of 10 colony forming units of S. aureus American Type Culture Collection 29213 and was continued every 8 hrs for 3 days.. Survival was higher in mice receiving CLI (29/50 animals [58%]) than in mice receiving CRO (16/50 animals [32%]; p =.015). Mice treated with CRO died earlier than mice receiving CLI (p =.002). Eight hours after the first antibiotic dose, the motor performance of mice receiving CRO had deteriorated more than it did for mice receiving CLI (p =.009). Higher levels of tumor necrosis factor-alpha were measured in serum (p =.027) and peritoneal fluid (p =.001) of CRO-treated mice. In vitro, CLI released smaller amounts of staphylococcal enterotoxin A than CRO.. Antibiotic treatment of Gram-positive sepsis with a protein synthesis inhibitor decreases morbidity and mortality compared with a bacteriolytic compound. This may be caused by a reduction of the concentrations of proinflammatory/toxic bacterial components and cytokines.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Cell Wall; Cephalosporins; Clindamycin; Disease Models, Animal; Male; Mice; Mice, Inbred C57BL; Protein Synthesis Inhibitors; Sepsis; Staphylococcal Infections; Treatment Outcome

Toll-like receptor-2 (TLR2) mediates host responses to gram-positive bacterial wall components. TLR2 function was investigated in a murine Streptococcus pneumoniae meningitis model in wild-type (wt) and TLR2-deficient (TLR2(-/-)) mice. TLR2(-/-) mice showed earlier time of death than wt mice (P<.02). Plasma interleukin-6 levels and bacterial numbers in blood and peripheral organs were similar for both strains. With ceftriaxone therapy, none of the wt but 27% of the TLR2(-/-) mice died (P<.04). Beyond 3 hours after infection, TLR2(-/-) mice had higher bacterial loads in brain than did wt mice, as assessed with luciferase-tagged S. pneumoniae by means of a Xenogen-CCD (charge-coupled device) camera. After 24 h, tumor necrosis factor activity was higher in cerebrospinal fluid of TLR2(-/-) than wt mice (P<.05) and was related to increased blood-brain barrier permeability (Evans blue staining, P<.02). In conclusion, the lack of TLR2 was associated with earlier death from meningitis, which was not due to sepsis but to reduced brain bacterial clearing, followed by increased intrathecal inflammation.

Topics: Animals; Ceftriaxone; Cephalosporins; Disease Models, Animal; Disease Susceptibility; Drosophila Proteins; Inflammation; Listeria monocytogenes; Listeriosis; Membrane Glycoproteins; Meningitis, Bacterial; Mice; Mice, Inbred C57BL; Mice, Knockout; Pneumococcal Infections; Receptors, Cell Surface; Streptococcus pneumoniae; Time Factors; Toll-Like Receptor 2; Toll-Like Receptors

Ceftriaxone is highly effective clinically in patients with Lyme disease. We studied a representative invasive human isolate of Borrelia burgdorferi for which the MBC of ceftriaxone was 0.050 microg/ml. A once-per-day dosage regimen of ceftriaxone (50 mg/kg/dose) administered intramuscularly for 5 days was 100% effective in sterilizing tissue samples of C3H mice infected with this strain of B. burgdorferi, regardless of whether the mice were being treated concomitantly with a corticosteroid. Administration of the same five doses of ceftriaxone at 6-h intervals over just 24 h was also 100% effective. These experiments suggest that shorter courses of antibiotics than those currently recommended should be considered for study in patients with early uncomplicated Lyme disease.

Topics: Animals; Borrelia burgdorferi; Ceftriaxone; Cephalosporins; Disease Models, Animal; Female; Lyme Disease; Mice; Mice, Inbred C3H; Treatment Outcome

We compared the efficacy of ceftriaxone combined with gentamicin, both given once a day, with that of cloxacillin given every 4 h plus gentamicin given once a day or in three daily doses (t.i.d.) for the treatment of experimental methicillin-susceptible staphylococcal endocarditis. The antibiotics were administered by using human-like (H-L) pharmacokinetics that simulated the profiles of these drugs in human serum. Animals with catheter-induced endocarditis were infected intravenously with 10(5) CFU of Staphylococcus aureus S5 (MICs and minimal bactericidal concentrations of cloxacillin, ceftriaxone, and gentamicin, 0.5 and 2 microg/ml, 4 and 8 microg/ml, and 0.5 and 1 microg/ml, respectively). The animals were then treated for 24 h with cloxacillin at a dose of 2 g that simulated H-L pharmacokinetics (H-L 2 g) every 4 h alone or combined with gentamicin (administered at doses of H-L 1 mg/kg of body weight every 8 h or H-L 4.5 mg/kg every 24 h) or with ceftriaxone at H-L 2 g every 24 h alone or combined with gentamicin (administered at doses of H-L 1 mg/kg every 8 h or H-L 4.5 mg/kg every 24 h). The results of therapy for experimental endocarditis due to the S5 strain showed that (i) cloxacillin alone is more effective than ceftriaxone alone in reducing the bacterial load (P < 0.01), (ii) the combination of cloxacillin or ceftriaxone with gentamicin is more effective than each of these drugs alone (P < 0.01), and (iii) Ceftriaxone H-L plus gentamicin H-L 4.5 mg/kg, both administered every 24 h, showed efficacy similar to that of the "gold standard," cloxacillin H-L plus gentamicin H-L 1 mg/kg t.i.d. (P > 0.05). An increase in the interval of administration of gentamicin to once daily resulted in a reduction in the numbers of bacteria in the vegetations equivalent to that achieved with the recommended regimen of cloxacillin plus gentamicin t.i.d. in the treatment of experimental endocarditis due to methicillin-susceptible S. aureus. Ceftriaxone plus gentamicin, both administered once a day, may be useful for home-based therapy for selected cases of staphylococcal endocarditis.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Cephalosporins; Disease Models, Animal; Drug Therapy, Combination; Endocarditis, Bacterial; Gentamicins; Microbial Sensitivity Tests; Rabbits; Staphylococcus aureus; Treatment Outcome

The MICs of evernimicin at which 90% of Borrelia burgdorferi patient isolates were inhibited ranged from 0.1 to 0.5 microg/ml. Evernimicin was as effective as ceftriaxone against B. burgdorferi in a murine model of experimental Lyme disease. As assessed by culturing the urinary bladders of infected C3H mice, no live Borrelia isolates were recoverable following antibiotic treatment.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Borrelia burgdorferi Group; Ceftriaxone; Cephalosporins; Disease Models, Animal; Female; Lyme Disease; Mice; Mice, Inbred C3H; Microbial Sensitivity Tests; Treatment Outcome

The efficacy of different antibiotics was compared in an experimental model of aortic valve endocarditis in rabbits, using a serotype 19 strain of Streptococcus pneumoniae resistant to penicillin (MIC 12 mg/L) and ceftriaxone (MIC 12 mg/L). The results were compared with those of a control group, which received no treatment. One hundred and nineteen animals were treated with one of the following antibiotic regimens: im procaine penicillin G at a dosage of 300,000 U/kg weight/12 h (16 animals); iv trovafloxacin, 13.3 mg/kg/12 h (31 animals); iv ceftriaxone, 75 mg/kg/24 h (21 animals); iv vancomycin, 20 mg/kg/12 h (15 animals) and im quinupristin-dalfopristin, 30 mg/kg/8 h (20 animals). All the antibiotics used in this study proved to be efficient in reducing numbers of S. pneumoniae and in increasing the percentage of aortic vegetations that were rendered sterile compared with the control group. Penicillin at the dosage used in our study was capable of achieving serum concentrations two or three times greater than the MIC, thus demonstrating its effectiveness as an antibiotic for this endocarditis model. No significant difference was observed between the effects of vancomycin, quinupristin-dalfopristin and penicillin. Vancomycin proved to be more efficient than trovofloxacin in reducing the bacterial load and increasing the numbers sterilized. There was also a tendency for this antibiotic to be more effective than ceftriaxone in reducing the bacterial load of the vegetations. There was a statistically significant correlation between the weight of the vegetations and their bacterial load. In the light of these results, vancomycin and quinupristin-dalfopristin may be considered suitable alternatives to penicillin for the treatment of penicillin-resistant S. pneumoniae endocarditis.

Topics: Animals; Anti-Infective Agents; Ceftriaxone; Disease Models, Animal; Drug Resistance, Multiple; Endocarditis, Bacterial; Fluoroquinolones; Humans; Male; Naphthyridines; Penicillin Resistance; Penicillins; Pneumococcal Infections; Rabbits; Streptococcus pneumoniae; Vancomycin; Virginiamycin

The course of bacterial titers, meningeal inflammation, behavioral abnormalities, and neuronal damage was studied in a mouse model of Streptococcus pneumoniae meningitis. At 24 h after injection of 10(4) colony-forming units (CFU) S. pneumoniae into the right forebrain, infected mice became severely lethargic. Bacterial titers in cerebrospinal fluid and cerebellum rose to 10(9) CFU/ml, with strong granulocyte invasion into the meninges and neuronal necroses in the neocortex, striatum and hippocampal formation. Meningeal inflammation and neuronal damage in intercellular cell adhesion molecule-1- and macrophage colony-stimulating factor-deficient mice was similar to that in wild-type littermates. Untreated, the infection was fatal. Wild-type mice treated earlier than 24 h after infection with ceftriaxone (2 mg every 12 h for 3 days) survived without apparent behavioral abnormalities. Delay of treatment beyond 30 h led to the death of more than 50% of the infected mice. This mouse model is suitable for therapeutic studies and for the investigation of inflammation in knockout mice. The neuronal damage resembles morphological abnormalities observed in humans.

Topics: Animals; Body Weight; Brain; Ceftriaxone; Cephalosporins; Disease Models, Animal; Glial Fibrillary Acidic Protein; Gliosis; Hyaluronan Receptors; Immunohistochemistry; Intercellular Adhesion Molecule-1; Leukocyte Count; Leukocytes; Macrophage Colony-Stimulating Factor; Macrophage-1 Antigen; Meningitis, Pneumococcal; Mice; Mice, Inbred C57BL; Mice, Knockout; Streptococcus pneumoniae; Survival Rate; Treatment Outcome

Efficacy of panipenem/betamipron (PAPM/BP) against experimental pneumonia caused by penicillin-resistant Streptococcus pneumoniae (PRSP: MIC of benzylpenicillin, > or = 1.56 micrograms/ml) in mice was compared with those of imipenem/cilastatin (IPM/CS), meropenem (MEPM), cefozopran (CZOP), ceftriaxone (CTRX), ampicillin (ABPC), and vancomycin (VCM). The infection was induced by inoculating a PRSP clinical isolate, 9601 (serotype 6) or 10,693 (serotype 19), into ddY male mice intranasally. Drugs were administered subcutaneously at doses of 0.4, 2, and 10 mg/kg, 18, 26, 42, and 50 hours post-infection. Viable cell counts in the lungs were determined 66 hours post-infection. PAPM/BP showed the greatest efficacy against the infections among tested drugs. MICs of PAPM against PRSP 9601 and 10,693 were both 0.125 microgram/ml, which were superior to those of IPM (0.25 and 0.5 microgram/ml, respectively), MEPM (0.5 and 1 microgram/ml, respectively), CZOP (2 and 1 microgram/ml, respectively), CTRX (both 1 microgram/ml), ABPC (both 4 micrograms/ml), and VCM (0.5 and 0.25 microgram/ml, respectively). These results suggest that the potent in vivo activity of PAPM/BP reflects the potent in vitro activity of PAPM. MICs of PAPM, IPM, MEPM, and CZOP against clinical isolates, penicillin-susceptible S. pneumoniae (PSSP: MIC of benzylpenicillin, < or = 0.05 microgram/ml), penicillin-intermediate S. pneumoniae (PISP: MIC of benzylpenicillin, 0.1-0.78 microgram/ml), and PRSP, were tested by an agar dilution method. MIC90s of the drugs against the PSSP, PISP, and PRSP were as follows: PAPM, 0.012, 0.05, and 0.39 microgram/ml; IPM, < or = 0.006, 0.1, and 0.78 microgram/ml; MEPM, 0.05, 0.39, and 1.56 micrograms/ml; and CZOP, 0.2, 0.78, and 6.25 micrograms/ml, respectively. Thus, PAPM showed the most potent activity among tested drugs against clinical isolates of PISP and PRSP.

Topics: Ampicillin; Animals; beta-Alanine; Cefozopran; Ceftriaxone; Cephalosporins; Cilastatin; Cilastatin, Imipenem Drug Combination; Disease Models, Animal; Drug Combinations; Drug Resistance; Imipenem; Male; Meropenem; Mice; Mice, Inbred Strains; Penicillin Resistance; Pneumonia, Pneumococcal; Streptococcus pneumoniae; Thienamycins; Vancomycin

In a rabbit model of Streptococcus pneumoniae meningitis, 5 mg of gemifloxacin mesylate (SB-265805) per kg/h reduced the bacterial titers in cerebrospinal fluid (CSF) almost as rapidly as 10 mg of ceftriaxone per kg/h (Deltalog CFU/ml/h +/- standard deviation [SD], -0.25 +/- 0.09 versus -0.38 +/- 0.11; serum and CSF concentrations of gemifloxacin were 2.1 +/- 1.4 mg/liter and 0.59 +/- 0.38 mg/liter, respectively, at 24 h). Coadministration of 1 mg of dexamethasone per kg did not affect gemifloxacin serum and CSF levels (2.7 +/- 1.4 mg/liter and 0.75 +/- 0.34 mg/liter, respectively, at 24 h) or activity (Deltalog CFU/ml/h +/- SD, -0.26 +/- 0.11).

Topics: Animals; Anti-Infective Agents; Ceftriaxone; Cephalosporins; Cerebrospinal Fluid; Disease Models, Animal; Fluoroquinolones; Gemifloxacin; Hippocampus; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Naphthyridines; Neurons; Rabbits; Streptococcus pneumoniae

Beta-lactamase enzymes are the most common cause of bacterial resistance to Beta-lactam antibiotics. They hydrolyze the amide bound in the Beta-lactam ring and produce acidic derivatives that have no antibacterial properties. The aim of this study was to evaluate a combination of clavulanic acid with cephalosporins against Beta-lactamase-producing and nonproducing strains of Staphylococcus aureus using in vitro tests and a rat animal model. In vitro tests (MIC) of the drug combination were done using standard methods. In an animal model, rats were submitted to surgical implantation of polyurethane sponges in their backs to induce granulomatous tissue. After seven days, the animals received cephalexin, cephalexin with clavulanic acid, ceftriaxone, ceftriaxone with clavulanic acid or clavulanic acid alone. One hour after the drug administration, granulomatous tissue was removed and placed in Petri dishes previously inoculated with 10(8) cfu of producing or non-producing Beta-lactamase Staphylococcus aureus. After 24h at 37 degrees C, the inhibition zones formed by granulomatous tissue was measured and scored for statistical analysis. Both tests (ex vivo ¿animal model¿ and in vitro) showed that the cephalexin was more active than ceftriaxone against non-producing Beta-lactamase S.aureus (p<0.01). Against Beta-lactamase producing S.aureus, ceftriaxone was more active than cephalexin, which was inactive. Combinations of clavulanic acid with cephalexin or ceftriaxone had similar antimicrobial activity against non-producing Beta-lactamase S.aureus compared to the cephalosporins used alone. When tested using Beta-lactamase producing strains, the combination of clavulanic acid with cephalosporins showed synergism. We conclude that the combination of cephalosporins with clavulanic acid could be useful in staphylococcal infections caused by Beta-lactamase producing strains.

Topics: Animals; Anti-Bacterial Agents; beta-Lactam Resistance; beta-Lactamase Inhibitors; Ceftriaxone; Cephalexin; Cephalosporin Resistance; Cephalosporins; Clavulanic Acid; Disease Models, Animal; Drug Therapy, Combination; Male; Microbial Sensitivity Tests; Rats; Rats, Wistar; Staphylococcus aureus

To determine the degree to which bioactive penicillin, metronidazole, ceftriaxone, clindamycin, vancomycin, and gentamicin penetrate into empyemic pleural fluid using our new rabbit model of empyema.. An empyema was created via the intrapleural injection of 10(8)()Pasteurella multocida bacteria into the pleural space of New Zealand white rabbits. After an empyema was verified by thoracentesis and pleural fluid analysis, penicillin, 24,000 U/kg; metronidazole, 37 mg/kg; ceftriaxone, 30 mg/kg; clindamycin, 9 mg/kg; vancomycin, 15 mg/kg; or gentamicin, 1 mg/kg, were administered IV. Antibiotic levels in samples of pleural fluid and serum, collected serially for up to 480 min, were then determined using a bioassay.. The degree to which the different antibiotics penetrated into the infected pleural space was highly variable. Penicillin penetrated most easily, followed by metronidazole, ceftriaxone, clindamycin, vancomycin, and gentamicin. Of the antibiotics tested, penicillin and metronidazole equilibrated the most rapidly with the infected pleural fluid. Penicillin levels remained elevated in pleural fluid even after serum levels had decreased.. Using this rabbit model of empyema, there was marked variation in the penetration of antibiotics into the empyemic fluid. Although there are species differences between rabbit and human pleura, the variance in degree of penetration of antibiotics into the pleural space should be considered when antibiotics are selected for the treatment of patients with empyema.

Topics: Animals; Anti-Bacterial Agents; Biological Availability; Ceftriaxone; Clindamycin; Disease Models, Animal; Empyema, Pleural; Gentamicins; Humans; Infusions, Intravenous; Metronidazole; Pasteurella Infections; Pasteurella multocida; Penicillins; Rabbits; Vancomycin

The bactericidal activities of monotherapy with trovafloxacin (-0.37 +/- 0.15 Delta log(10) CFU/ml. h), vancomycin (-0.32 +/- 0.12 Delta log(10) CFU/ml. h), and ceftriaxone (-0.36 +/- 0.19 Delta log(10) CFU/ml. h) for the treatment of experimental meningitis in rabbits due to a clinical penicillin-resistant pneumococcal strain (MIC, 4 mg/liter) were similar. The combination of ceftriaxone with trovafloxacin considerably improved the killing rates (-0.67 +/- 0.16 Delta log(10) CFU/ml. h) and was slightly superior to ceftriaxone with vancomycin (killing rate, -0.53 +/- 0. 22 Delta log(10) CFU/ml. h), the regimen most commonly used in clinical practice. In vitro, synergy was demonstrated between ceftriaxone and trovafloxacin by the checkerboard method (fractional inhibitory concentration index, 0.5) and by time-killing assays over 8 h.

Topics: Animals; Anti-Infective Agents; Ceftriaxone; Cephalosporins; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Fluoroquinolones; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Naphthyridines; Penicillin Resistance; Pneumococcal Infections; Rabbits; Streptococcus pneumoniae

A rat model of ethanol feeding was used to study the effects of ethanol on antibiotic therapy of pneumococcal pneumonia. Male Sprague-Dawley rats (150 g) received a liquid diet containing 36% of total calories as ethanol. Controls were pair-fed a liquid diet without ethanol or received rat chow. Diets began 7 days pre- and continued postinfection. Rats were infected transtracheally with type 3 Streptococcus pneumoniae and then treated with azithromycin (50 mg/kg), trovafloxacin (50 mg/kg), or ceftriaxone (100 mg/kg) injected subcutaneously twice daily for 5 days. Antibiotic levels in serum, lung cells, and lavage fluid were measured by HPLC. Ethanol- and pair-fed rats had depressed baseline peripheral neutrophil counts but were able to generate adequate numbers of peripheral and pulmonary polymorphonuclear leukocytes early in the course of their infection. Ethanol feeding did not alter the pharmacokinetics of azithromycin, trovafloxacin, or ceftriaxone. All three antibiotics were equally effective in curing experimental pneumococcal pneumonia, and survival rates were similar in treated ethanol-fed and control rats.

Topics: Animals; Anti-Infective Agents; Azithromycin; Bronchoalveolar Lavage Fluid; Ceftriaxone; Disease Models, Animal; Ethanol; Feeding Behavior; Fluoroquinolones; Leukocyte Count; Male; Naphthyridines; Neutrophils; Pneumonia, Pneumococcal; Rats; Rats, Sprague-Dawley

A simple LC method was developed and validated for the analysis of ceftriaxone in aqueous and biological samples. Chromatographic separation was achieved on a reversed-phase C18 microbore column (Hypersil 5 microm, 200x2.1 mm) with UV detection at 270 nm. This isocratic system was operated at ambient temperature and required less than 10 min of chromatographic time. The flow-rate was maintained at 0.5 ml min(-1). Cetyltrimethylammonium bromide (0.01 M) was utilized as the ion-pairing agent. For the analysis of the drug in the aqueous system, the mobile phase consisted of methanol-acetonitrile-phosphate buffer, pH 7.4 (20:20:60, v/v/v). The plasma and CSF systems used the same mobile phase constituents in a slightly different ratio (30:40:30, v/v/v). Lidocaine was used as an internal standard and the peak height ratios of the drug to that of the internal standard were linear over the concentration range of 0.0 to 16 microg ml(-1) only in the case of aqueous systems. Within-day and day-to-day relative standard deviations ranged from 0.3 to 2.2% and 1.1 to 5.9%, respectively. This method was used to: (1) quantify ceftriaxone in an aqueous system, in rabbit plasma using a simple protein precipitation procedure, and in the CSF; (2) evaluate the permeability characteristics of ceftriaxone across the blood-brain barrier through quantification of ceftriaxone in the CSF using a microdialysis sampling technique; and (3) analyze the effects of dexamethasone (a synthetic fluorinated corticosteroid used for the relief of cerebral edema) on the permeability of ceftriaxone across the blood brain barrier through quantification of ceftriaxone in the dexamethasone-treated animals with meningitis.

Topics: Animals; Blood-Brain Barrier; Ceftriaxone; Chromatography, High Pressure Liquid; Dexamethasone; Disease Models, Animal; Meningitis, Bacterial; Microdialysis; Rabbits; Reference Standards; Reproducibility of Results; Sensitivity and Specificity; Spectrophotometry, Ultraviolet

The inflammatory response following initiation of antibiotic therapy and parameters of neuronal damage were compared during intravenous treatment with quinupristin/dalfopristin (100 mg/kg as either a short or a continuous infusion) and ceftriaxone (10 mg/kg/h) in a rabbit model of Streptococcus pneumoniae meningitis. With both modes of administration, quinupristin/dalfopristin was less bactericidal than ceftriaxone. However, the concentration of proinflammatory cell wall components (lipoteichoic acid (LTA) and teichoic acid (TA)) and the activity of tumour necrosis factor (TNF) in cerebrospinal fluid (CSF) were significantly lower in the two quinupristin/dalfopristin groups than in ceftriaxone-treated rabbits. The median LTA/TA concentrations (25th/75th percentiles) were as follows: (i) 14 h after infection: 133 (72/155) ng/mL for continuous infusion of quinupristin/dalfopristin and 193 (91/308) ng/mL for short duration infusion, compared with 455 (274/2042) ng/mL for ceftriaxone (P = 0.002 and 0.02 respectively); (ii) 17 h after infection: 116 (60/368) ng/mL for continuous infusion of quinupristin/dalfopristin and 117 (41/247) ng/mL for short duration infusion, compared with 694 (156/2173) ng/mL for ceftriaxone (P = 0.04 and 0.03 respectively). Fourteen hours after infection the median TNF activity (25th/75th percentiles) was 0.2 (0.1/1.9) U/mL for continuous infusion of quinupristin/dalfopristin and 0.1 (0.01/3.5) U/mL for short duration infusion, compared with 30 (4.6/180) U/mL for ceftriaxone (P = 0.02 for each comparison); 17 h after infection the TNF activity was 2.8 (0.2/11) U/mL (continuous infusion of quinupristin/dalfopristin) and 0.1 (0.04/6.1) U/mL (short duration infusion), compared with 48.6 (18/169) U/mL for ceftriaxone (P = 0.002 and 0.001). The concentration of neuron-specific enolase (NSE) 24 h after infection was significantly lower in animals treated with quinupristin/dalfopristin: 4.6 (3.3/5.7) microg/L (continuous infusion) and 3.6 (2.9/4.7) microg/L (short duration infusion) than in those treated with ceftriaxone (17.7 (8.8/78.2) microg/L) (P = 0.03 and 0.009 respectively). In conclusion, antibiotic treatment with quinupristin/dalfopristin attenuated the inflammatory response within the subarachnoid space after initiation of antibiotic therapy. The concentration of NSE in the CSF, taken as a measure of neuronal damage, was lower in quinupristin/dalfopristin-treated rabbits than in ceftriaxone-treated rabbits.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Cerebrospinal Fluid Proteins; Disease Models, Animal; Inflammation; Lactic Acid; Lipopolysaccharides; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Neurons; Phosphopyruvate Hydratase; Rabbits; Streptococcus pneumoniae; Subarachnoid Space; Teichoic Acids; Tumor Necrosis Factor-alpha; Virginiamycin

In the rabbit model of Streptococcus pneumoniae meningitis, treatment with rifabutin, quinupristin-dalfopristin, moxifloxacin and trovafloxacin led to smaller increases of the CSF concentrations of the pro-inflammatory cell wall components lipoteichoic and teichoic acids (LTA and TA) than did treatment with ceftriaxone. Low doses of moxifloxacin were associated with higher LTA and TA concentrations in CSF than were high doses.

Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Aza Compounds; Ceftriaxone; Cephalosporins; Disease Models, Animal; Fluoroquinolones; Immunoenzyme Techniques; Lipopolysaccharides; Meningitis, Pneumococcal; Moxifloxacin; Naphthyridines; Polysaccharides, Bacterial; Quinolines; Rabbits; Reference Values; Rifabutin; Teichoic Acids; Virginiamycin

In a rabbit model of meningitis caused by a pneumococcus highly resistant to penicillin (MIC, 4 microg/ml), meropenem, a broad-spectrum carbapenem, was bactericidal (-0.48+/-0.14 deltalog10 cfu/ml h) and slightly superior to ceftriaxone (-0.34+/-0.23 deltalog10 cfu/ml x h) and vancomycin (-0.39+/-0.19 deltalog10 cfu/ml x h). Although the combination of vancomycin with ceftriaxone was significantly more active than ceftriaxone alone (-0.55+/-0.19 deltalog10 cfu/ml x h), only an insignificant gain was observed by the addition of vancomycin to meropenem (-0.55+/-0.28 deltalog10 cfu/ml x h).

Topics: Animals; Ceftriaxone; Cephalosporins; Colony Count, Microbial; Disease Models, Animal; Drug Therapy, Combination; Meningitis, Pneumococcal; Meropenem; Microbial Sensitivity Tests; Penicillin Resistance; Rabbits; Streptococcus pneumoniae; Thienamycins; Vancomycin

Gelatinolytic activity of matrix metalloproteinases (MMPs), particularly MMP-9 and MMP-2, was studied by quantitative zymography in a rabbit model of bacterial meningitis during 24 h after inoculation with Streptococcus pneumoniae. In cerebrospinal fluid (CSF), MMP-2 was constitutively present and its level did not change during the experiment. In contrast, MMP-9, hardly detectable in CSF of healthy animals, increased dramatically. The increase of MMP-9 was correlated with both, an increase of CSF cell count and of total protein concentration. Intrathecal production of MMP-9 and MMP-2 was demonstrated by zymography of equal amounts of total protein from CSF and serum. Homogenates, prepared from various cortical regions of infected rabbits did not show increase of MMP activities. On the other hand, leucocytes isolated from CSF expressed high levels of MMP-9 suggesting a significant contribution of these cells to the elevation of MMP-9 activity in this body fluid.

Topics: Animals; Ceftriaxone; Cerebral Cortex; Cerebrospinal Fluid; Cerebrospinal Fluid Proteins; Collagenases; Colony Count, Microbial; Disease Models, Animal; Electrophoresis, Polyacrylamide Gel; Gelatinases; Leukocytes; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Meningitis, Pneumococcal; Metalloendopeptidases; Rabbits; Time Factors

To compare a recombinant bactericidal/permeability-increasing protein variant and a recombinant endotoxin-neutralizing protein.. Randomized, blinded, controlled study, using a rat model of sepsis.. Animal research facility.. Male Wistar rats.. An inoculum of 1.5 x 10(7) to 1.8 x 10(8) Escherichia coli O18ac K1, implanted in the peritoneum, produced bacteremia in 95% of animals after 1 hr. One hour after E. coli challenge, animals received recombinant bactericidal/permeability-increasing protein variant, recombinant endotoxin-neutralizing protein, or saline intravenously, followed by ceftriaxone and gentamicin intramuscularly.. Twenty-four (85.7%) of 28 animals receiving recombinant endotoxin-neutralizing protein (p < .001 vs. control) survived 7 days compared with nine (33.3%) of 27 recombinant bactericidal/permeability-increasing protein variant-treated (p < .001 vs. control) and two (6.5%) of 31 control animals.. Both recombinant endotoxin-neutralizing protein and recombinant bactericidal/permeability-increasing protein variant improved survival. Recombinant endotoxin-neutralizing protein was superior to recombinant bactericidal/permeability-increasing protein variant in its protective effect at the doses tested. Our results suggest that both proteins may be useful in the treatment of human Gram-negative sepsis.

Topics: Animals; Anti-Infective Agents; Ceftriaxone; Disease Models, Animal; Drug Therapy, Combination; Escherichia coli Infections; Gentamicins; Gram-Negative Bacterial Infections; Male; Rats; Rats, Wistar; Recombinant Proteins; Sepsis; Survival Analysis

The gram negative bacteria, nontypable Haemophilus influenzae (NTHi) was used to induce otitis media in a total of 18 chinchillas. Three days post-inoculation, three cohorts of 6 chinchillas each were treated daily for four days with either ceftriaxone, chloramphenicol, or diluent without antibiotics. Middle ear fluid (MEF) was obtained daily, assayed for endotoxin content by means of the chromogenic limulus amebocyte lysate assay, and concentration of the NTHi/mL MEF determined by standard plate count. The endotoxin concentration per mL MEF from both the antibiotic treated cohorts decreased during the observation period, but increased in the MEF of the untreated control group. The data indicate that, unlike the dramatic increase in endotoxin concentration, after antibiotic treatment in the cerebrospinal fluid (CSF) during experimental Haemophilus influenzae-induced meningitis, there is no demonstrable sustained release of endotoxin in the middle ear subsequent to antibiotic treatment during experimental otitis media.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Chinchilla; Chloramphenicol; Disease Models, Animal; Endotoxins; Haemophilus influenzae; In Vitro Techniques; Otitis Media; Protein Synthesis Inhibitors

This study evaluates the ability of the new fluoroquinolone trovafloxacin to attenuate the inflammatory burst known to occur after initiation of antibiotic treatment in pneumococcal meningitis. After exposure to trovafloxacin or ceftriaxone for 3 h in vitro, Streptococcus pneumoniae was injected intracisternally (i.c.) into rabbits every 3 h over 9 h (n = 6 for each antibiotic). Ceftriaxone-treated S. pneumoniae induced consistently higher CSF leucocyte counts (median 2568/microL versus 543/microL at 6 h; P = 0.03; 4560/microL versus 2207/microL at 18 h; P = 0.03) than trovafloxacin-treated bacteria. Meningitis induced in rabbits by i.c. injection of live S. pneumoniae was treated with equal doses of trovafloxacin or ceftriaxone i.v. (ten per group). The bactericidal rates of both antibacterial agents in CSF were almost identical. In comparison with ceftriaxone, trovafloxacin resulted in lower tumour necrosis factor (TNF) and interleukin 1beta (IL-1beta) CSF levels 2 h after the initiation of treatment (TNF levels, median 26 U/mL versus 141 U/mL; P = 0.02; IL-1beta levels 455 pg/mL versus 1399 pg/mL; P = 0.02). Twelve hours after initiation of therapy, however, TNF and IL-1beta were higher in trovafloxacin-treated animals (TNF, 61 U/mL versus 7 U/mL; P = 0.001; IL-1beta, 4320 pg/mL versus 427 pg/mL; P = 0.006). The increase in CSF lactate was less during trovafloxacin therapy than with ceftriaxone (median: 2.0 mmol/L versus 4.0 mmol/L; P = 0.03). In conclusion, S. pneumoniae treated in vitro with trovafloxacin induced less CSF leucocytosis than ceftriaxone-treated S. pneumoniae. After i.c. inoculation of live S. pneumoniae, trovafloxacin therapy delayed, but did not inhibit, the release of the proinflammatory cytokines TNF and IL-1beta, probably by slowing the liberation of bacterial cell wall components into the subarachnoid space.

Topics: Adult; Animals; Anti-Infective Agents; Ceftriaxone; Cephalosporins; Disease Models, Animal; Fluoroquinolones; Humans; Injections, Intravenous; Interleukin-1; Lactic Acid; Meningitis, Pneumococcal; Naphthyridines; Rabbits; Streptococcus pneumoniae; Tumor Necrosis Factor-alpha

Topics: Animals; Antibodies, Monoclonal; Bacteremia; Ceftriaxone; Cephalosporins; Cytokines; Disease Models, Animal; Female; Humans; Lymphotoxin-alpha; Male; Papio; Streptococcal Infections; Streptococcus pyogenes

This study evaluated the effects of combining antibiotic therapy with the application of a nonsteroidal anti-inflammatory drug on the degradation of articular cartilage for an animal model of Staphylococcal septic arthritis. Rabbits were infected intra-articularly with Staphylococcus aureus. Antibiotic treatment started 18 hours after infection and continued for 7 days. Treatment with the nonsteroidal anti-inflammatory drug naproxen sodium started 24 hours before infection and continued for either 3 or 7 weeks. The cartilage matrix of uninfected and infected knees was quantified by analysis of glycosaminoglycan and collagen content. Three weeks after infection, the combined treatment of the nonsteroidal anti-inflammatory drug and antibiotics reduced the loss of glycosaminoglycan and collagen from the cartilage of the infected knee by 15 and 30%, respectively, compared with antibiotic treatment alone. Continuing treatment with naproxen sodium for 7 weeks reduced the loss of collagen by 50% when compared with antibiotic treatment alone. The longer period of treatment with naproxen sodium showed little further effect on the loss of glycosaminoglycan than that observed for the 3-week treatment. Treatment with this drug and antibiotics reduced swelling of the knee and levels of prostaglandin E2 in the synovial fluid. The data support the hypothesis that decreasing post-infectious inflammation by adding the drug to a standard antibiotic regimen reduces cartilage damage from Staphylococcal septic arthritis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Infectious; Cartilage, Articular; Ceftriaxone; Cephalosporins; Dinoprostone; Disease Models, Animal; Drug Therapy, Combination; Female; Glycosaminoglycans; Hydroxyproline; Knee Joint; Naproxen; Rabbits; Staphylococcal Infections; Staphylococcus aureus; Synovial Fluid; Synovitis

Typical features of pneumococcal meningitis have been demonstrated in rats inoculated with Streptococcus pneumoniae. HU-211, a novel noncompetitive N-methyl-D-aspartate antagonist recently demonstrated to inhibit tumor necrosis factor-alpha production under various conditions, improves recovery in some experimental models of brain injury. The present study tested the efficacy of HU-211 in combination with antimicrobial therapy in reducing brain damage in experimental pneumococcal meningitis. S. pneumoniae-infected rats were treated with saline alone, ceftriaxone alone, or with combination of ceftriaxone and HU-211 18 h after inoculation of the bacteria. Brain edema and blood-brain barrier impairment 48 h after infection were significantly (P<.05) reduced suggest that HU-211 when given concomitantly with antibiotics attenuates brain damage in the rat model of pneumococcal meningitis.

Topics: Animals; Blood-Brain Barrier; Brain Edema; Ceftriaxone; Disease Models, Animal; Dronabinol; Drug Therapy, Combination; Male; Meningitis, Pneumococcal; Neuroprotective Agents; Rats; Tumor Necrosis Factor-alpha

The miniature pig exhibits physiological and anatomical similarities to man. In addition, its reduced size and its docility make it appropriate for laboratory use. Curiously, this model remains seldom used in experimental pharmacokinetics. We present here in a chronic model of catheterized micropig allowing long term investigations of antiinfective agents. We work with Yucatan adult female micropigs weighing between 20 and 40kg. A catheter (60 cm x 2 mm) is placed in the external jugular vein under general anaesthesia and exits in the midline dorsal neck. The catheter is flushed every two days with heparinized saline to retain its potency. At the time of kinetic studies, the antiinfective agent is injected in an ear vein. Blood samples are obtained using the jugular catheter. The mean time of viability of the device is 13 weeks (SD: 10 weeks). Thrombosis was the main cause of arrest of the model. In conclusion, this chronic model of catheterized micropig is suitable for long term pharmacokinetic and pharmacodynamic investigations of antiinfective agents.

Topics: Adult; Animals; Antibiotics, Antitubercular; Antifungal Agents; Catheterization, Peripheral; Cefepime; Cefpirome; Ceftriaxone; Cephalosporins; Disease Models, Animal; Female; Humans; Injections, Intravenous; Meropenem; Swine; Thienamycins

We previously demonstrated the efficacy of ceftriaxone (CRO), at 50 mg/kg of body weight every 12 h, against a highly penicillin-resistant (MIC, 4 micrograms/ml) Streptococcus pneumoniae strain with low-level resistance to CRO (MIC, 0.5 microgram/ml) in a leukopenic-mouse pneumonia model (P. Moine, E. Vallée, E. Azoulay-Dupuis, P. Bourget, J.-P. Bédos, J. Bauchet, and J.-J. Pocidalo, Antimicrob. Agents Chemother. 38:1953-1958, 1994). In the present study, we assessed the activity of CRO versus those of cefotaxime (CTX) and amoxicillin (AMO) against two highly penicillin- and cephalosporin-resistant S. pneumoniae strains (P40422 and P40984) (MICs of 2 and 8 for penicillin, 2 and 4 for AMO, and 4 and 8 for CRO or CTX, respectively). Against both strains, a greater than an 80% cumulative survival rate was observed with CRO at a dose of 100 or 200 mg/kg every 12 h (dose/MIC ratio, 25). With CTX, a high dosage of 400 mg/kg (dose/MIC ratio, 100 or 50) administered every 8 h (TID) was needed to protect 66 and 75% of the animals, respectively, with no statistically significant differences versus CRO. Against the P40422 strain, CRO (100 mg/kg) produced the greatest bactericidal effect, from the 8th to the 24th hour after a single injection (1.8-log-unit reduction over 24 h), and the fastest bacterial pulmonary clearance during treatment; with CTX, only multiple injections at a high dosage, i.e., 400 mg/kg TID, demonstrated a significant bactericidal effect. AMO in a high dosage, 400 mg/kg (dose/MIC ratio, 200) TID, showed good activity only against the P40422 strain. Despite the identical MICs of CTX and CRO, the longer time (3.6 to 4.6 h) that serum CRO concentrations remained above the MICs for the pathogens at a dose of 100 mg/kg resulted in greater efficacy versus CTX against highly penicillin- and cephalosporin-resistant S. pneumoniae strains.

Topics: Amoxicillin; Animals; Cefotaxime; Ceftriaxone; Cephalosporin Resistance; Cephalosporins; Disease Models, Animal; Female; Lung; Mice; Microbial Sensitivity Tests; Penicillin Resistance; Penicillins; Pneumonia, Pneumococcal; Streptococcus pneumoniae

Bacterial meningitis, particularly that resulting from Streptococcus pneumoniae, is a common cause of acquired profound sensorineural deafness in children. The pathogenesis of meningogenic hearing loss has been investigated in an experimental rabbit model. In this study significant deafness was documented within the first 15 hours of infection. Initiation of antibiotic therapy at this time diminished the severity of hearing loss in most animals. The addition of dexamethasone to antibiotic therapy prevented the development of profound deafness. These results suggest this model will be useful in developing antiinflammatory strategies to improve the outcome of bacterial meningitis.

Topics: Animals; Ceftriaxone; Dexamethasone; Disease Models, Animal; Drug Therapy, Combination; Evoked Potentials, Auditory; Female; Hearing Loss, Sensorineural; Linear Models; Meningitis, Pneumococcal; Rabbits

Monoclonal antibodies (MAbs) specific for O polysaccharide or core oligosaccharide/lipid A of Escherichia coli O111:B4 lipopolysaccharide (LPS) were compared in canine septic shock. Animals received O-specific, core-specific, or control murine IgG2a MAbs (or saline) before intraperitoneal implantation of an E. coli O111:B4-infected clot. Animals were further randomized to ceftriaxone or saline. O-specific MAb significantly reduced bacteremia and endotoxemia but not serum tumor necrosis factor. Core-specific MAb significantly increased mean arterial pressure from day 4 to 28 (P = .02). In dogs not receiving ceftriaxone, survival was enhanced by O-specific MAb (4/5) compared with core-specific MAb (0/5) and control (1/8) (P = .03). Survival rates were similar (P = .22) but survival was prolonged in antibiotic-treated animals also receiving O-specific MAb (P = .02 vs. core-specific MAb and controls) or core-specific MAb (P = .08 vs. controls). These data support the complex role of LPS in sepsis and the discrete functional effects of MAbs specific for different elements of LPS.

Topics: Animals; Antibodies, Monoclonal; Bacteremia; Body Temperature; Body Weight; Ceftriaxone; Disease Models, Animal; Dogs; Endotoxins; Escherichia coli; Hemodynamics; Lipopolysaccharides; O Antigens; Polysaccharides, Bacterial; Shock, Septic; Tumor Necrosis Factor-alpha

The increasing emergence of penicillin-resistant (Pr) strains of Streptococcus pneumoniae could pose a therapeutic problem in the next few years. Ceftriaxone (CRO), a broad-spectrum cephalosporin, exhibits a smaller increase in MICs against Pr S. pneumoniae strains than amoxicillin (AMO) (usually referred as to the "gold standard" therapy for pneumococcal infections). Therefore, we compared their respective efficacies in a leukopenic Swiss mouse model of pneumococcal pneumonia. Infection was induced with two serotype 19 strains: a penicillin-susceptible (Ps) strain (MICs of < 0.01 for penicillin, 0.03 for AMO, and 0.03 for CRO) and a Pr strain (MICs of 4 for penicillin, 2 for AMO, and 0.5 for CRO). Untreated mice died within 2 or 3 days. Against the Ps strain, the minimal protective dose (two subcutaneous injections at 12-h intervals for 3 days) for both CRO and AMO was 5 mg/kg of body weight (87% survivors). Ten-fold-increased doses of CRO (50 mg/kg) gave similar protection (75% survivors) against the Pr strain, whereas 20- and 40-fold-increased doses of AMO protected 0 and 34% of the animals, respectively, against the Ps strain. CRO had a marked and prolonged antibacterial effect in the lungs (2.7-log-unit reduction of CFU in 24 h after a single 50-mg/kg injection) against the Pr strain in comparison with AMO. A standard dosage of 50 mg of CRO per kg in mice resulted in peak levels in serum and protein binding comparable to those observed with 1 g given intravenously in humans. This dosage remained effective against a highly Pr S. pneumoniae strain in this model. The microbiological activity and pharmacodynamic and pharmacokinetic properties of CRO (time during which concentrations exceed the MIC for the test pathogen [delta t MIC], > or less than 8 h; and peak/MIC ratio, >90 for free active drug) accounted for its efficacy relative to AMO (50 mg/kg: delta t MIC, <2; peak/MIC ratio, <25) against the highly Pr S. pneumoniae strain used in this study.

Topics: Amoxicillin; Animals; Ceftriaxone; Disease Models, Animal; Female; Injections, Subcutaneous; Lung; Mice; Microbial Sensitivity Tests; Penicillin Resistance; Pneumococcal Infections; Pneumonia, Pneumococcal; Streptococcus pneumoniae

The effect of cytostatic treatment on the cellular defence and the efficacy of treatment with ceftriaxone in Klebsiella pneumoniae pneumonia was studied. Mice, made monocytopenic and granulocytopenic by cyclophosphamide or monocytopenic by etoposide, were infected intratracheally with K. pneumoniae (approximately 10(4) CFU) and then treated with ceftriaxone. At various intervals, the numbers of bacteria in the broncho-alveolar lavage (BAL) fluid and in lungs homogenised after lavage were determined. Cyclophosphamide reduced the numbers of granulocytes in the BAL fluid significantly but reduced only slightly the number of alveolar macrophages at the time of inoculation, 12 and 15 h later. The number of CFU in cyclophosphamide-treated mice was higher than that in controls, being significant in the homogenised lungs at 15 h after infection. In etoposide-treated mice, the numbers of alveolar phagocytes in BAL did not differ from those in control mice, whereas the number of bacteria was lower (only significantly in BAL fluid at 15 h after infection) than that in the controls. In this short experimental infection cytostatic treatment did not affect the outgrowth of Klebsiella pneumoniae substantially or the efficacy of treatment with ceftriaxone.

Topics: Animals; Antineoplastic Agents; Bronchoalveolar Lavage Fluid; Ceftriaxone; Cyclophosphamide; Disease Models, Animal; Etoposide; Granulocytes; Immunosuppressive Agents; Klebsiella Infections; Klebsiella pneumoniae; Leukopenia; Lung Diseases; Macrophages, Alveolar; Male; Mice; Phagocytosis; Specific Pathogen-Free Organisms

The most appropriate therapy for meningitis caused by Streptococcus pneumoniae strains resistant to the extended-spectrum cephalosporins is unknown. We evaluated ceftriaxone, vancomycin, and rifampin alone and in different combinations and meropenem, cefpirome, and clinafloxacin alone in the rabbit meningitis model. Meningitis was induced in rabbits by intracisternal inoculation of one of two pneumococcal strains isolated from infants with meningitis (ceftriaxone MICs, 4 and 1 microgram/ml, respectively). Two doses, 5 h apart, of each antibiotic were given intravenously (except that ceftriaxone was given as one dose). Cerebrospinal fluid bacterial concentrations were measured at 0, 5, 10, and 24 h after therapy was started. Clinafloxacin was the most active single agent against both strains. Against the more resistant strain, ceftriaxone or meropenem alone was ineffective. The combination of vancomycin and ceftriaxone was synergistic, suggesting that this combination might be effective for initial empiric therapy of pneumococcal meningitis until results of susceptibility studies are available.

Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Cefpirome; Ceftriaxone; Cephalosporins; Disease Models, Animal; Drug Resistance, Microbial; Drug Synergism; Drug Therapy, Combination; Fluoroquinolones; Male; Meningitis, Pneumococcal; Meropenem; Microbial Sensitivity Tests; Penicillin Resistance; Quinolones; Rabbits; Rifampin; Thienamycins; Vancomycin

Using a rat model of intraperitoneal abscess due to Bacteroides fragilis, we evaluated therapy with the combination of ceftriaxone plus the beta-lactamase inhibitor tazobactam in comparison with ceftriaxone or cefotaxime alone. When treatment was begun five hours after bacterial challenge, final bacterial counts within abscesses at 3.5 days of treatment were as follows (mean +/- S.D., log10 cfu/g): ceftriaxone plus tazobactam, 4.15 +/- 1.25; cefotaxime, 4.77 +/- 1.80; ceftriaxone alone, 5.68 +/- 1.04; untreated controls, 9.14 +/- 1.13. In spite of pharmacokinetic differences between the two drugs, coadministration of tazobactam significantly enhanced activity of ceftriaxone in this model.

Topics: Abdomen; Abscess; Animals; Bacteroides fragilis; Bacteroides Infections; Ceftriaxone; Disease Models, Animal; Drug Therapy, Combination; Male; Penicillanic Acid; Peritoneal Diseases; Rats; Rats, Sprague-Dawley; Tazobactam

Escherichia coli and Staphylococcus aureus are the most common pathogens encountered in septic shock. This is a descriptive study in which the pathophysiologic response to infusions of LD100 concentrations of E. coli and S. aureus are staged and compared. Equivalent concentrations of both organisms were infused over a 2 hr period into antibiotic-treated and untreated animals with the following results: 1) The apparent clearance of E. coli was less than that of S. aureus over the 2-hr infusion period, but far greater during the next 8 hr in both antibiotic-treated and untreated animals. Thus the clearance of E. coli fits a one-compartment (intravascular), and that of S. aureus fits a two-compartment (intra- and extravascular) model. 2) The intensity of the cardiovascular, temperature, and metabolic response to E. coli was greater, whereas that of the disseminated intravascular coagulant (DIC) response to S. aureus was greater. We conclude, therefore, that the response to E. coli consists of four stages with no invasion and colonization of tissues, whereas the response to S. aureus consists of two stages with invasion and colonization of tissues.

Topics: Animals; Ceftriaxone; Disease Models, Animal; Escherichia coli Infections; Gentamicins; Hemodynamics; Hemostasis; Kidney; Lung; Papio; Shock, Septic; Staphylococcal Infections

Pharmacologic considerations suggest that third-generation cephalosporins might penetrate the vitreous humor better after periocular injection and might be eliminated less readily after intravitreous injection than older agents. We studied the sodium salts of ceftizoxime, ceftriaxone, and ceftazidime, and of an investigational cephalosporin, cefepime, in rabbits. After a single subconjunctival injection in animals with normal eyes, vitreous levels ranged from 3 to 13 mg/L. After five subconjunctival injections in rabbits with infected eyes, vitreous concentrations ranged from 12 to 34 mg/L. These concentrations are not appreciably greater than those found with older beta-lactams. The vitreous half-life of the four drugs after intravitreous injection varied from 5.7 to 20 hours in rabbits with uninflamed eyes and from 9.4 to 21.5 hours in rabbits with infected eyes. Except for ceftizoxime, the half-lives were substantially longer than those for older beta-lactams and suggest predominantly anterior route elimination. Vitreous penetration of these new agents after subconjunctival injection does not appear to be sufficient to overcome the need for intravitreous injections in the treatment of endophthalmitis. However, the longer vitreous half-lives of some of the newer agents may be useful if the drugs are to be given intravitreally.

Topics: Animals; Cefepime; Ceftazidime; Ceftizoxime; Ceftriaxone; Cephalosporins; Colony Count, Microbial; Conjunctiva; Disease Models, Animal; Endophthalmitis; Eye Infections, Bacterial; Half-Life; Rabbits; Staphylococcal Infections; Vitreous Body

The incidence of gram-negative bacteremia is significantly increasing in recent years by the wide-spread use of cytotoxic and immunosuppressive drugs. Although, the effective antimicrobial drugs are being used in treatment, the mortality rate is still high. In this study, we searched for the histopathological changes occurring on lung tissue in E. coli sepsis, and their severity in different models. Microscopically, all the specimens were examined by the presence of interstitial and peribronchiolar inflammation, congestive atelectasis, and emphysema. The differences between the ratios of histopathological changes in treatment subgroups were not statistically significant. However, the ratio of interstitial and peribronchiolar inflammation and emphysema was significantly decreased in mice received cyclophosphamide, when compared with control group. Besides, the ratio of peribronchiolar inflammation was significantly increased in mice received steroid when compared with control group.

Topics: Animals; Bacteremia; Ceftriaxone; Cyclophosphamide; Disease Models, Animal; Escherichia coli Infections; Immunosuppression Therapy; Lung; Methylprednisolone; Mice; Steroids

Mice made monocytopenic and granulocytopenic by cyclophosphamide or monocytopenic by etoposide were infected by exposure to an aerosol containing Klebsiella pneumoniae. Eighteen hours later ceftriaxone was administered and three hours after that the experiment was ended. At the time of infection and at 18 and 21 h the numbers of alveolar macrophages and granulocytes in bronchoalveolar lavage (BAL) fluid were significantly lower in the cyclophosphamide-pretreated animals than in the controls. Furthermore, outgrowth of K. pneumoniae in the lungs was significantly stronger in cyclophosphamide-pretreated mice and a fourfold higher dose of ceftriaxone was needed to obtain the same antibacterial effect as in the controls. In the etoposide-pretreated mice the number of alveolar macrophages in BAL was not significantly lower than that in the controls, but the number of granulocytes was. Compared with the controls, there was no significant difference in the number of K. pneumoniae in the lungs, and the efficacy of ceftriaxone did not differ either.

Topics: Animals; Bronchoalveolar Lavage Fluid; Ceftriaxone; Cell Count; Cyclophosphamide; Disease Models, Animal; Dose-Response Relationship, Drug; Etoposide; Klebsiella Infections; Klebsiella pneumoniae; Lung Diseases; Male; Mice; Phagocytes; Pulmonary Alveoli

The in vitro activity of four cephalosporins was compared with their effects in an experimental thigh infection (cefuroxime and cefamandole against Escherichia coli and cefamandole, ceftriaxone, and ceftazidime against Klebsiella pneumoniae) in granulocytopenic mice. The effect in vitro (ER) was defined as the difference between the growth rate without antibiotic and the growth rate at the steepest part of a 3-h growth curve in the presence of an antibiotic. The relation between concentration and ER was described with the Hill equation. Using pharmacokinetic parameters of the plasma concentrations in vivo and those of the Hill equation the corresponding time course of ER was calculated and by integration with respect to time (0tERdt), an estimate was obtained of the effect on bacteria. For all four antibiotics this estimate was significantly correlated with the actual values of the effect in vivo (EN), defined as the difference in numbers of bacteria between controls and antibiotic-treated animals at 4 h.

Topics: Agranulocytosis; Animals; Cefamandole; Ceftazidime; Ceftriaxone; Cefuroxime; Cephalosporins; Disease Models, Animal; Escherichia coli; Escherichia coli Infections; Klebsiella Infections; Klebsiella pneumoniae; Mice; Protein Binding; Specific Pathogen-Free Organisms

Bacterial interstrain variation for cochlear invasion was studied by intraperitoneal inoculation of infant rats with Haemophilus influenzae type b. Eight pairs of CSF isolates from children with or without deafness due to meningitis were injected into half of each litter in separate experiments. At 48 h, quantitative CSF culture results and CSF white blood cell counts were equivalent for the two groups. Organisms within the cochlea were detected in four of eight animals in each group. There was no difference between the deaf and nondeaf isolates in the degree or frequency of inner ear inflammation in formalin-fixed sections. In separate experiments, animals were inoculated with H. influenzae type b and 24 h later treated with ampicillin, or ampicillin plus dexamethasone. At 48 h, although CSF white blood cell counts were significantly reduced in the steroid group, no difference was noted in the degree of cochlear inflammation between the two groups. The ability of H. influenzae type b to invade the inner ear of infant rats does not correlate with the development of sensorineural deafness in children following H. influenzae type b meningitis. Steroid administration does not appear to diminish the inflammatory reaction within the cochlea more than antibiotics alone in this model, but may delay CSF sterilization by ampicillin.

Topics: Ampicillin; Animals; Animals, Newborn; Ceftriaxone; Cochlea; Dexamethasone; Disease Models, Animal; Drug Therapy, Combination; Haemophilus influenzae; Labyrinth Diseases; Labyrinthitis; Meningitis, Haemophilus; Rats; Specific Pathogen-Free Organisms

Experience with the use of first-generation cephalosporins in bacterial meningitis has been disappointing; low concentrations were obtained in the cerebrospinal fluid, and therapeutic failures were encountered. Of the second-generation cephalosporins cefamandole, cefuroxime, and cefoxitin, only cefuroxime has proved efficacy in meningitis caused by meningococci, pneumococci, or Hemophilus influenzae. The third-generation cephalosporins offer new advantages in the treatment of meningitis because they are active at the cerebrospinal fluid concentrations obtainable. Cefotaxime has produced high cure rates in patients with meningitis caused by meningococci, pneumococci, or H. influenzae. Several controlled comparative studies indicate that ceftriaxone is as effective as conventional treatment in therapy for neonatal or childhood meningitis caused by Streptococcus agalactiae, Escherichia coli, or H. influenzae. Moxalactam has been found in uncontrolled studies to be effective when the cause was enteric gram-negative bacilli. Ceftazidime is a new cephalosporin with a high degree of beta-lactamase stability and a broad antibacterial spectrum, which includes Pseudomonas aeruginosa that enters the cerebrospinal fluid. Data from 29 patients who received ceftazidime as monotherapy for bacterial meningitis showed an overall cure or improvement rate of 75.9 percent. Therapy failed in three patients with meningitis caused by gram-positive organisms (Staphylococcus aureus, S. epidermidis, S. agalactiae), and in three with gram-negative organisms. Of 14 patients with Pseudomonas meningitis, 11 showed a cure, as did six of six patients with meningitis caused by Enterobacter, Serratia, or Acinetobacter. More, preferably controlled, studies of the efficacy of ceftazidime in the treatment of meningitis should be undertaken.

Topics: Adult; Animals; Bacterial Infections; Cefoperazone; Cefotaxime; Ceftazidime; Ceftriaxone; Cephalosporins; Disease Models, Animal; Humans; Meningitis

The therapeutic efficacy of ceftriaxone and gentamicin was investigated in a foreign body induced abscess model in the rat by implanting a dialysis tube contaminated with Klebsiella pneumoniae into the subcutaneous tissue. Animals were treated for four days with ceftriaxone, gentamicin, and their combination starting immediately following or 48 h after the implantation. Peak free ceftriaxone and gentamicin abscess fluid levels were 4.3 and 2.6 mcg/ml, which were 7.3% and 37.5% of peak blood levels respectively. Both agents persisted longer in abscess fluid than in blood. Ceftriaxone inhibited the development of abscess formation when administered shortly after the implantation of the contaminated foreign body whereas gentamicin alone was without beneficial effect. When administered after 48 h ceftriaxone was less effective than immediately after implantation and gentamicin was again without any therapeutic effect. The effect of the combination of ceftriaxone and gentamicin was slightly better than ceftriaxone alone. Low oxygen tension may be an explanation for the lack of bactericidal effect of gentamicin. Ceftriaxone may be more suitable for the therapy of closed space infections caused by susceptible microorganisms than gentamicin.

Topics: Abscess; Animals; Cefotaxime; Ceftriaxone; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Therapy, Combination; Female; Gentamicins; Kinetics; Klebsiella Infections; Klebsiella pneumoniae; Male; Rats; Rats, Inbred Strains