Administration Of Ceftriaxone Research Articles

Safety and pharmacokinetics of subcutaneous ceftriaxone administered with or without recombinant human hyaluronidase (rHuPH20) versus intravenous ceftriaxone administration in adult volunteers

Objective:To compare pharmacokinetics and safety of recombinant human hyaluronidase (rHuPH20)-facilitated subcutaneous (SC) ceftriaxone administration versus SC ceftriaxone preceded by SC saline placebo or intravenous (IV) ceftriaxone administration.Research design and methods:This Phase I, two-part, placebo-controlled, crossover study was conducted in 54 healthy volunteers. In Part 1 (N = 24), subjects received 1 mL rHuPH20 (150 USP units) or placebo (0.9% sodium chloride) SC, followed by 1 or 2 g ceftriaxone (10–350 mg/mL). In Part 2 (N = 30), subjects received 1 g ceftriaxone at the Part 1 maximum tolerated concentration (MTC) administered either SC – preceded by SC rHuPH20 or placebo – or IV. Subjects were monitored for adverse events (AEs); blood samples were obtained (Part 2 only) during 48 hours post-dosing for ceftriaxone bioanalysis.Main outcome measures:Part 1 primary endpoint was the SC ceftriaxone (with or without rHuPH20) MTC. Pharmacokinetic parameters were determined in Part 2. Bioequivalence was based on maximum concentration (Cmax) and area under plasma concentration–time curve (AUC).Results:The highest SC ceftriaxone concentration tested in Part 1 (350 mg/mL) was selected as the Part 2 MTC. In Part 2, median time to maximum concentration (tmax) was 1 hour earlier (P < 0.0001), and Cmax was 12% higher (P < 0.0001) for ceftriaxone (350 mg/mL) administered via rHuPH20-facilitated SC versus SC preceded by placebo. IV ceftriaxone led to higher Cmax and shorter tmax values than either SC treatment. Ceftriaxone exposure (AUC) was comparable among all three treatments. At least 1 AE was experienced by 100% of subjects after SC ceftriaxone and 76% after IV; most commonly reported AEs were infusion-site reactions.Conclusions:Ceftriaxone AUC did not differ significantly between the three administration routes. Cmax was higher and tmax shorter with rHuPH20-facilitated SC than SC preceded by placebo. rHuPH20-facilitated SC ceftriaxone was generally well tolerated. This study is limited by evaluation of healthy adults and absence of repeated-dose groups.

The pharmacokinetics of ceftriaxone based on population pharmacokinetics and the prediction of efficacy in Japanese adults

By using a population pharmacokinetic analysis method, we predicted the efficacy of Ceftriaxone (CTRX) based on the pharmacokinetics of CTRX in Japanese adults and the sensitivity of infective organisms to CTRX in 2004. In addition, we clarified the difference in efficacy between once-a-day administration and twice-a-day administration. The population pharmacokinetic analysis was based on the serum concentrations of CTRX already published by NONMEM. The possible effect of body weight and age on the pharmacokinetics of CTRX was examined using a model which incorporated the change of a specific protein-binding ratio of CTRX. A Monte Carlo simulation was conducted based on the population pharmacokinetic parameters obtained by this analysis, and thereby the time above MIC (TAM) was determined from the MIC values of CTRX administered once at 0.5, 1, and 2 g and twice at 1 g. The efficacy ratio was predicted from the TAM thus obtained. Because the time course of serum concentration of CTRX in adult subjects was fitted to a 2-compartment model and both body weight and age were not incorporated as the covariate, the dosing method by which a fixed amount of CTRX is administered to patients has been thought to be adequate. Based on the efficacy ratio estimated from the MIC of CTRX, we have predicted that the once-a-day administration of CTRX even at 0.5g is effective on various infecting organisms.

Ceftriaxone-Vancomycin Drug Toxicity Reduction by VRP 1020 in Mus musculus Mice

Drug toxicity is a common cause of liver injury and kidney failure. This study was designed to elucidate whether administration of high doses of Ceftriaxone or Vancomycin induce oxidative stress in liver as well as kidney, and to investigate the protective effects of VRP 1020 with fixed dose combination of ceftriaxone-vancomycin (Immunox-V). Twenty four Mus musculus mice (weighing 30 +/- 5 g) were divided into four groups containing six mice in each group. The activities of antioxidant enzymes such as superoxide dismutase, catalase and the level of malonaldialdehyde, as an marker of lipid per oxidation, were measured to evaluate oxidative stress in homogenates of the liver and renal tissue. Ceftriaxone or vancomycin administration significantly increased malonaldialdehyde levels (p < 0.001) but significant decreased in superoxide dismutase (p<0.01) and catalase (p<0.001) activities. Co-administration of VRP 1020 with FDC of Immunox-V injections caused significantly decreased malonaldialdehyde levels (p< 0.001) and increased superoxide dismutase (p<0.01) and catalase (p<0.001) activities in liver and renal tissue when compared with other treated groups. Similarly, the levels of extracellular antioxidant (Creatinine and Uric acid) were found to be significant lowered in Immunox-V treated group when compared to ceftriaxone or vancomycin alone treated group. These results indicate that chemical mediated technology of VRP 1020 with fixed dose combination of Immunox-V can prevent drug induced nephrotoxicity and oxidative stress which protects liver injury as well as renal tissue damage by reducing reactive oxygen species which improve the activities of free radical scavenging enzymes.

Intravenous Ceftriaxone and Calcium in the Neonate: Assessing the Risk for Cardiopulmonary Adverse Events

Unsolicited reports regarding potentially serious adverse drug reactions in neonates and young infants were reported to the Food and Drug Administration, leading to changes in the package label for ceftriaxone. This report describes and summarizes the reported cases that led to safety concerns regarding the concurrent administration of intravenous ceftriaxone and calcium in this age group. Nine reported cases were assessed. The Food and Drug Administration Adverse Event Reporting System database was searched for potential drug interactions in patients who were receiving concomitant ceftriaxone and calcium therapy. Eight of the reported 9 cases (7 were < or =2 months of age) represented possible or probable adverse drug events. There were 7 deaths. None of the cases were reported from the United States. The dosage of ceftriaxone that was administered to 4 of 6 infants for whom this information was available was between 150 and 200 mg/kg per day. The rate of occurrence of these serious adverse drug reactions cannot be accurately determined from available data. The concurrent use of intravenous ceftriaxone and calcium-containing solutions in the newborn and young infant may result in a life-threatening adverse drug reaction. Contributing factors for infants in this report may include the use of ceftriaxone at dosages higher than those approved by the Food and Drug Administration, intravenous "push" administration, and administration of the total daily dosage as a single infusion.

New approach to the management of Clostridium difficile infection: colonisation with non-toxigenic C. difficile during daily ampicillin or ceftriaxone administration

Non-toxigenic strains of Clostridium difficile are highly effective in preventing toxigenic C. difficile infection in hamsters when given following a single dose of an antimicrobial agent. The goal of this study was to determine the ability of non-toxigenic C. difficile to colonise hamsters during administration of an antibiotic to which the organisms are resistant — ceftriaxone — and an antibiotic to which they are susceptible — ampicillin — and to determine if non-toxigenic colonisation is protective against toxigenic strain challenge. Groups of four or five hamsters were administered daily ceftriaxone 60 mg/kg/d intraperitoneally or ampicillin 60 mg/kg/d orally for 5 days. Three non-toxigenic strains of C. difficile, M3, M23, and T7 (MICs 96–128 mg/L) were each given orally at a dose of 1×10 6 spores to groups of five animals 3h after the first dose of ceftriaxone. All animals were colonised successfully by day 3 of the study and when challenged with 1×10 6 spores of toxigenic strain J9 (MIC >256 mg/L) on day 3 all animals survived, whereas the control animal given ceftriaxone, but not non-toxigenic C. difficile, died within 48h of challenge. When groups of four hamsters were given ampicillin, administration of non-toxigenic strain M3 (MIC 2 mg/L) or toxigenic strain J9 (MIC 0.75 mg/L) at 1×10 6 spores did not result in any colonisation or infection of the animals until day 8, 3 days after the last ampicillin dose. A protection study was designed by giving M3 spores to groups of five animals daily for 5 days beginning on day 1, 3, or 5 of ampicillin. Toxigenic challenge was given with J9 spores on day 3 of each M3 regimen. M3 colonised all animals by day 8 and none became infected with J9. Colonisation by non-toxigenic C. difficile is an effective prevention strategy during antibiotic administration of ceftriaxone or ampicillin, but multiple-day administration is required for ampicillin and colonisation does not occur until several days after the drug is discontinued.

Acute pancreatitis associated with the administration of Ceftriaxone in an adult patient

Acute pancreatitis associated with the administration of Ceftriaxone in an adult patient

Pharmacokinetics of Ceftriaxione, a Third-Generation Cephalosporin, in Pediatric Patients

We monitored the serum concentration of ceftriaxone (CTRX) in order to clarify its pharmacokinetics in pediatric patients. Subjects were 21 patients undergoing CTRX therapy (50 mg/kg/d) for pneumonia from January to September 2007. To determine the serum concentration of CTRX and to obtain other laboratory data, blood samples were drawn just before and after drug administration. To clarify the relationship between protein concentration and the protein binding ratio of CTRX in vitro and in vivo, the effect of human albumin on the binding ratio was investigated. Thereafter, the relationship between the protein binding ratio and the concentration of CTRX in pediatric patients was analyzed. There was no significant correlation between age and the elimination half-life of CTRX. Moreover, no significant differences were observed in the distribution volume and the clearance between pediatric patients and adults. The binding ratios increased with increased CTRX and albumin concentrations in both in vitro and in vivo studies. It was suggested that the CTRX concentration just before administration (i.e., C(trough)) was sufficiently maintained above the mean inhibitory concentration against Streptococcus pneumoniae and Haemophilus influenzae. Therefore, CTRX administration once daily to pediatric patients with pneumonia was shown to be bacteriologically and pharmacokinetically superior in terms of efficacy.

Sphingomonas mucosissimaBacteremia in Patient with Sickle Cell Disease

To the Editor: The genus Sphingomonas was proposed by Yabuuchi et al. in 1990 (1) and amended by Takeuchi et al. in 1993 (2). It now has been subdivided into 4 separate genera: Sphingomonas sensu stricto, Sphingobium, Novosphingobium, and Sphingopyxis. The bacteria of the genus Sphingomonas are yellow-pigmented, nonfermenting, gram-negative bacilli with a single polar flagellum; they are widely distributed in the natural environment, especially in water and soil (3). These bacteria are characterized by the presence of a unique sphingoglycolipid with the long-chain base—dihydrosphingosin, ubiquinone 10 (Q-10), and 2-hydroxymyristic acid (2-OH C14:0)—and the absence of 3-hydroxy fatty acids (4). S. mucosissima was isolated and identified in 2007 by Reddy and Garcia-Pichel from biologic soil crust samples collected from sandy arid soil in the US Colorado Plateau (5). Sphingomonas spp. are opportunistic pathogens and have recently been implicated in a variety of community-acquired and nosocomial infections, considered to originate from contaminated hospital equipment or manipulation of some medical devices (3). The survival of Sphingomonas spp. in indoor dust particles as aerosols and their resistance to many disinfecting and toxic chemicals may explain their ability to colonize medical devices such as mechanical ventilators, catheters, and bronchofiberoscopes (6). In the past few years, these organisms, in particular S. paucimobilis, have been implicated in a variety of community-acquired and nosocomial infections. We report a case of S. mucosissima bacteremia in a patient with sickle cell disease. In February 2008, a 17-year-old woman with homozygous sickle cell anemia was hospitalized when her condition suddenly became worse. The patient had undergone a splenectomy in 1992 and a cholecystectomy in February 2007. Four days after admission, she had a fever of 38.7°C. Two aerobic blood specimens, drawn on the fifth day of her hospitalization, yielded gram-negative bacilli after a 24-hour incubation. The gram-negative bacilli were positive for catalase and oxidase but remained unidentified by API 20NE strip (bioMerieux, Marcy l’Etoile, France). MICs of antimicrobial drugs were determined for the gram-negative bacilli by using an Etest assay (AB BIODISK, Solna, Sweden) on Mueller-Hinton medium. MICs were 1 μg/mL for cefotaxime, 1 μg/mL for amoxicillin–clavulanic acid, 2–3 μg/mL for vancomycin, 0.064 μg/mL for imipenem, 4–5 μg/mL for ceftazidime, 1 μg/mL for amikacin, 3 μg/mL for ciprofloxacin, and 0.047 μg/mL for trimethoprim-sulfamethoxazole. DNA was extracted from 1 colony by using a QIAamp Tissue kit (QIAGEN, Hilden, Germany) as described by the manufacturer. A 16S rDNA sequence was obtained (1,410 bp) by using the fD1 (5′-AGAGTTTGATCCTGGCTCAG-3′) and rP2 (5′-ACGGCTACCTTGTTACGACTT-3′) primer pair (7,8). Using BLAST version 2.2.9 software (www.ncbi.nlm.nig.gov/BLAST), we determined that this sequence showed 98% similarity with the 16S rDNA sequence of S. mucosissima (GenBank accession no. {type:entrez-nucleotide,attrs:{text:AM229669,term_id:87080454,term_text:AM229669}}AM229669). A phylogenetic neighbor-joining tree resulting from comparison of sequences of the 16S rDNA genes of Sphingomonas spp. was made with the MEGA 3.1 software (www.megasoftware.net). This analysis confirmed that the isolate belonged to S. mucosissima. Initial treatment of intravenous administration of ceftriaxone was begun. The fever resolved after 1 day and the patient’s condition improved. Treatment was stopped after 5 days, and the patient remained apyretic. Two S. mucosissima isolates were recovered from 2 different blood-culture samples drawn 24 hours apart, which suggests that S. mucosissima was not just a transient organism but indeed was responsible for the patient’s septicemia. Phenotypic identification of the gram-negative bacilli failed because the definite bacterial species S. mucosissima was not included in the API database (http://industry.biomerieux-usa.com/industry/food/api/apiweb.htm) used for the phenotypic identification. However, the isolates’ biochemical characteristics were consistent with those previously reported for S. mucosissima (5) (Table). Final identification was achieved by comparing the almost complete 16S rDNA sequence with homologous sequences deposited in GenBank. Table Biochemical characteristics of the previously reported Sphingomonas mucosissima isolate ({type:entrez-nucleotide,attrs:{text:AM229669,term_id:87080454,term_text:AM229669}}AM229669) and the isolate from this study We believe that the patient’s intravenous catheter was the source of the infection because she did not have wound infections and cultures of her urine were negative for infectious agents. Antimicrobial drug treatment, selected on the basis of an in vitro S. mucosissima susceptibility profile, facilitated the patient’s recovery. This case report illustrates that the pathogenic potential of S. mucosissima should be considered in diagnosis in such cases because the organism can cause bacteremia in patients, primarily in those with underlying debilitating conditions and those who have undergone medical interventions.

生魚の喫食後に発症した&lt;i&gt;Shewanella algae &lt;/i&gt;菌血症/化膿性 椎体椎間板炎の1 例

Shewanella algae is an aquatic gram-negative bacterium, rarely recovered from human clinical samples. Case reports of human Shewanella infection are, however, slowly increasing, and a Shewanella infection outbreak was reported at a South Korean hospital. We report the case of an 89-year-old man admitted for back pain and fever after eating raw marine fish. Sulbactam/cefoperazone was started under a tentative diagnosis of gall bladder inflammation with gallstones based on ultrasonographic findings. His persistent back pain, however, necessitated vertebral magnetic resonance imaging (MRI), which showed thoracic vertebral osteomyelitis and discitis. Two sets of blood culture on admission yielded a gram-negative bacillus identified as "Shewanella putrefaciens" by automated identification. Ceftriaxone administration for 3 weeks followed by oral levofloxcin for 5 weeks cured the vertebral osteomyelitis and discitis. 16S rRNA sequence analysis showed that "S. putrefacien" was, in fact, S. algae-incorrectly detected because semi-automated and automated identification did not include S. algae in their database. It should thus be kept in mind that consuming raw-fish may cause Shewanella bacteremia and osteomyelitis in patients with hepatobiliary disease and that genetic analysis is required to precisely determine the occurrence of Shewanella spp.

Procalcitonin implication in renal cell apoptosis induced by acute pyelonephritis in children

The aim of this biomedical trial was to clarify the physiological role of procalcitonin (PCT) in renal parenchyma apoptosis and fibrosis caused by acute childhood pyelonephritis. This prospective study enrolled 183 children. All children were treated with bi-therapy according to the French consensus on acute pyelonephritis treatment dated November 16, 1990: intra-vascular administration of ceftriaxone 50 mg/kg/day and netromicine 7 mg/kg/day during the first 48 hours, followed by specific antibiotherapy suited to antibiogram. On admission, PCT, C-reactive protein, and phospholipase A2 were quantified in serum. Scintigraphy monitoring with (99m)Tc-DMSA was performed on day 4 and 9 months later, in the presence of persistent abnormalities. On day 4, 78% presented renal parenchyma alterations and 30% renal fibrosis 9 months after admission. Paradoxically, PCT level was significantly lower in the presence of renal fibrosis due to cell apoptosis (4.19 vs 7.59 μgL(-1)). A significant increase in PCT indicated favorable progress (recovery 7.55 vs aggravation 3.34) and no difference between recovery and improvement. This result suggests the protective effect of PCT against apoptosis by nitric oxide down-regulation.

Toxic epidermal necrolysis managed with immunoglobulin

We thank the reader for critical appraisal of our report and kind remarks. The reply to queries raised by him is as follows; Our patient had presented with fever and was receiving antibiotics at the time of presentation which was the reason of negative cultures. Sepsis is the most debilitating complication in TEN and is one of the leading causes of mortality [1]. Patient had onset of TEN following therapy for fever, cough and sore throat and was continuing antibiotics till consultation in the emergency at our centre. In presence of >80% body surface area involvement with purulent mucositis of the oral and urethra and urinalysis full of pus cells, infection was very much evident which prompted us to continue with changed antibiotics despite culture reports being negative. Lastly, offering antibiotic therapy after obtaining culture positive reports and or signs of septic shock seems purely academic and sometimes dangerous in day to day practice. IgE mediated hypersensitivities are well known to be cross reactive between cephalosporins and penicillins, however, non IgE mediated hypersensitivities usually are not cross reactive. Patients with a prior immediate hypersensitivity reaction to penicillin should generally not be treated with cephalosporin unless: Penicillin or cephalosporin skin testing, if available, is negative or a graded challenge with the cephalosporin can be given under careful observation by an allergist. A history of a rash or unclear reaction to penicillin does not necessarily preclude administration of cephalosporins [2]. Moreover, there is not a single report of TEN attributable to piperacillin till date on medline search. Only single case report putatively linking cephalosporin hypersensitivity to Meropenem induced TEN has been reported [3]. This does not preclude the use of other beta lactam antibiotics, it just merits caution. Compared to sulfonamides antibiotics, other sulfonamides like sulfonylurea, thiazides etc do not show cross sensitivity just because of the structural similarities. It may be other metabolites of the drugs that can induce TEN or individuals with metabolic defects or polymorphisms in cytochrome metabolizing enzymes are predisposed to TEN. It will be too hasty to generalize and blame beta lactam structure as the cause of TEN. Our patient did not have immediate hypersensitivity reaction to cephalosporins hence Tazobactum Piperacillin was continued under supervision. Regarding IgE mediated allergic reaction to piperacillin in a case of ceftriaxone induced TEN, the reason is evident in the case report itself, if the reader would have cared to read the paper carefully. This patient had received piperacillin before ceftriaxone administration that could have sensitized him and led to IgE mediated Type I hypersensitivity reaction, subsequently. Moreover TEN is mediated by T cells and macrophages/monocytes, and is unrelated to B cell mediated effects. Lastly, the SCORTEN score of 3 was arrived at based on following criteria, age >40 years, tachycardia (>120) and BSA >80% involvement. Regarding the biopsy confirmation of the diagnosis, the clinical presentation was so characteristic and therefore it was needless to subject already critical patient to an invasive procedure which would have been purely academic without any additional advantage. On the basis of experience in one case, we are not advocating IVIg as panacea for all the cases of TEN, rather since there are not many reports of similar experience from our country we thought it prudent to share our experience with medical fraternity to increase the awareness. Moreover, after the index case, we have treated three more cases of TEN with IVIg and one patient died. This patient had presented with severe neutropenia (absolute neutrophil count <200/µl) and respiratory tract infection. We encourage other centers from our country to share their experience with therapy of TEN. As far as the rationale of IVIg is concerned, there is ample evidence both in vitro [4] and clinical to recommend its use in such a life threatening condition [1, 5]. The numbers of studies that question the efficacy of IVIg are small with small patient population as compared to numbers of studies that report benefit with large number of patients. Since randomized placebo controlled trial is virtually impossible for such a rare and sporadic adverse event, it's up to readers to decide which school of thought to follow. Regarding the discontinuation of the offending agent and intensive supportive therapy, it cannot be over emphasized and we agree with the reader but since the aim of our case report was to highlight the beneficial effect of IVIg in addition to these measures, we discussed more about IVIg. However, we never intend to sideline the significance of these measures.

A Case of Canine Streptococcal Meningoencephalitis Diagnosed Using Universal Bacterial Polymerase Chain Reaction Assay

A 3-year-old, spayed female, mixed-breed dog was evaluated for acute, progressive neurological disease. Analysis of cerebrospinal fluid (CSF) showed neutrophilic pleocytosis. The dog later developed liver disease, thrombocytopenia, and anemia that were presumably secondary to ceftriaxone administration. Bacterial cultures of blood, urine, and CSF were negative. However, a universal bacterial polymerase chain reaction assay of CSF identified deoxyribonucleic acid from Streptococcus spp. The dog recovered with therapy for streptococcal encephalitis.

Ceftriaxone rescues hippocampal neurons from excitotoxicity and enhances memory retrieval in chronic hypobaric hypoxia

Exposure to high altitude is known to cause impairment in cognitive functions in sojourners. The molecular events leading to this behavioral manifestation, however, still remain an enigma. The present study aims at exploring the nature of memory impairment occurring on chronic exposure to hypobaric hypoxia and the possible role of glutamate in mediating it. Increased ionotropic receptor stimulation by glutamate under hypobaric hypoxic conditions could lead to calcium mediated excitotoxic cell death resulting in impaired cognitive functions. Since glutamate is cleared from the synapse by the Glial Glutamate Transporter, upregulation of the transporter can be a good strategy in preventing excitotoxic cell death. Considering previous reports on upregulation of the expression of Glial Glutamate Transporter on ceftriaxone administration, the therapeutic potential of ceftriaxone in ameliorating hypobaric hypoxia induced memory impairment was investigated in male Sprague Dawley rats. Exposure to hypobaric hypoxia equivalent to an altitude of 7600 m for 14 days lead to oxidative stress, chromatin condensation and neuronal degeneration in the hippocampus. This was accompanied by delayed memory retrieval as evident from increased latency and pathlength in Morris Water Maze. Administration of ceftriaxone at a dose of 200 mg/kg for 7 days and 14 days during the exposure on the other hand improved the performance of rats in the water maze along with decreased oxidative stress and enhanced neuronal survival when compared to hypoxic group without drug administration. An increased expression of Glial Glutamate Transporter was also observed following drug administration indicating faster clearance of glutamate from the synapse. The present study not only brings to light the effect of longer duration of exposure to hypobaric hypoxia on the memory functions, but also indicates the pivotal role played by glutamate in mediating excitotoxic neuronal degeneration at high altitude. The therapeutic potential of ceftriaxone in providing neuroprotection in excitotoxic conditions by increasing Glial Glutamate Transporter expression and thereby enhancing glutamate uptake from the synapse has also been explored.

Thoracic Spinal Epidural Abscess Caused by Salmonella Typhi -Case Report-

A 56-year-old man presented with a rare spinal epidural abscess manifesting as attacks of back pain associated with fever, weight loss, generalized weakness and fatigability, and constipation. He had multiple skin pustules in the last 4 months treated with oral amoxicillin. He had suffered diabetes mellitus for the last 5 years and was insulin dependent. Physical examination found slight paraparesis with sensory loss around the nipple and sphincteric urgency, and diabetic retinopathy. Magnetic resonance imaging showed edematous T2, T3, and T4 vertebral bodies, and narrow enhanced T3-4 disk space with a soft tissue enhanced mass mostly anterior to the spinal cord and indenting the cord. T3-4 costotransversectomy was performed to remove the extradural mass and evacuate the intradiscal material. Histological examination of the bone found osteomyelitis, and culture of the soft tissue showed Salmonella typhi sensitive to ceftriaxone and ciprofloxacin. Intravenous ceftriaxone administration was started, and the patient was discharged after 6 days in good condition. The outcome of spinal epidural abscess is devastating unless recognized and treated early. The present case of spinal epidural abscess in the thoracic spine caused by Salmonella typhi infection illustrates the importance of cultures to assess the drug sensitivity of the specific strain detected and adjusting the treatment accordingly.

Corticosteroids for Bacterial Meningitis in Adults in Sub-Saharan Africa

In sub-Saharan Africa, bacterial meningitis is common and is associated with a high mortality. Adjuvant therapy with corticosteroids reduces mortality among adults in the developed world, but it has not been adequately tested in developing countries or in the context of advanced human immunodeficiency virus (HIV) infection. We conducted a randomized, double-blind, placebo-controlled trial of dexamethasone (16 mg twice daily for 4 days) and an open-label trial of intramuscular versus intravenous ceftriaxone (2 g twice daily for 10 days) in adults with an admission diagnosis of bacterial meningitis in Blantyre, Malawi. The primary outcome was death at 40 days after randomization. A total of 465 patients, 90% of whom were HIV-positive, were randomly assigned to receive dexamethasone (233 patients) or placebo (232 patients) plus intramuscular ceftriaxone (230 patients) or intravenous ceftriaxone (235 patients). There was no significant difference in mortality at 40 days in the corticosteroid group (129 of 231 patients) as compared with the placebo group (120 of 228 patients) by intention-to-treat analysis (odds ratio, 1.14; 95% confidence interval [CI], 0.79 to 1.64) or when the analysis was restricted to patients with proven pneumococcal meningitis (68 of 129 patients receiving corticosteroids vs. 72 of 143 patients receiving placebo) (odds ratio, 1.10; 95% CI, 0.68 to 1.77). There were no significant differences between groups in the outcomes of disability and death combined, hearing impairment, and adverse events. There was no difference in mortality with intravenous ceftriaxone (121 of 230 patients) as compared with intramuscular ceftriaxone (128 of 229 patients) (odds ratio, 0.88; 95% CI, 0.61 to 1.27). Adjuvant therapy with dexamethasone for bacterial meningitis in adults from an area with a high prevalence of HIV did not reduce mortality or morbidity. In this setting, intramuscular administration was not inferior to intravenous administration of ceftriaxone for bacterial meningitis. (Current Controlled Trials number, ISRCTN31371499 [controlled-trials.com].).

Adjuvant Glycerol and/or Dexamethasone to Improve the Outcomes of Childhood Bacterial Meningitis: A Prospective, Randomized, Double-Blind, Placebo-Controlled Trial

Despite favorable meta-analyses, no study involving third-generation cephalosporins for the treatment of childhood bacterial meningitis has documented a benefit of adjuvant dexamethasone therapy if the outcomes are examined individually. We conducted a prospective, randomized, double-blind trial comparing adjuvant dexamethasone or glycerol with placebo in children aged from 2 months through 16 years in Latin America. Ceftriaxone was administered to all children; children were randomized to also receive dexamethasone intravenously, glycerol orally, both agents, or neither agent. Primary end points were death, severe neurological sequelae, or deafness, with the first 2 end points forming a composite end point. A subgroup analysis for Haemophilus influenzae type b meningitis was undertaken. Intention-to-treat analysis was performed using binary logistic regression models. H. influenzae type b, pneumococci, and meningococci were the main agents found among 654 patients; dexamethasone was given to 166, dexamethasone and glycerol were given to 159, glycerol was given to 166, and placebo was given to 163. No adjuvant therapy significantly affected death or deafness. In contrast, glycerol and dexamethasone plus glycerol reduced severe neurological sequelae, compared with placebo; the odds ratios were 0.31 (95% confidence interval [95% CI], 0.13-0.76; P=.010) and 0.39 (95% CI, 0.17-0.93; P=.033), respectively. For neurological sequelae and death, the odds ratios were 0.44 (95% CI, 0.25-0.76; P=.003) and 0.55 (95% CI, 0.32-0.93; P=.027), respectively. Dexamethasone therapy prevented deafness in patients with H. influenzae type b meningitis only if patients were divided grossly into dexamethasone recipients and nonrecipients and if timing between dexamethasone and ceftriaxone administration was not taken into account (odds ratio, 0.27; 95% CI, 0.09-0.77; P=.014). Oral glycerol therapy prevents severe neurological sequelae in patients with childhood meningitis. Safety, availability, low cost, and oral administration also add to its usefulness, especially in resource-limited settings.

Intraosseous Drug Administration in Children and Adults During Cardiopulmonary Resuscitation

To review and assess the available literature on the use of intraosseous (IO) drug administration during cardiopulmonary resuscitation, addressing the benefits and risks of using this method of drug delivery in children and adults. The MEDLINE (1950-July 2007) database was searched for pertinent abstracts, using the key term intraosseous infusions. Additional references were obtained from the bibliographies of the articles reviewed. Manufacturer Web sites were used to obtain information about IO insertion devices. All available English-language clinical trials, retrospective studies, and review articles describing IO drug administration were reviewed. Studies conducted in animal models to evaluate the effectiveness and safety of IO drug administration were also included. IO access uses the highly vascularized bone marrow to deliver fluids and medications during cardiopulmonary resuscitation. This route, developed in the 1940s, has been revived in the past decade as a means of achieving rapid vascular access when intravenous access cannot be obtained. The primary advantage of IO access is the high success rate (approximately 80%). Most trained providers can place an IO line within 1-2 minutes. A number of small-scale studies and retrospective reviews have established the usefulness of this route for the delivery of many commonly used resuscitation drugs. In addition, animal models have demonstrated rapid drug delivery to the systemic circulation. While all resuscitation drugs can be given by the IO route, administration of ceftriaxone, chloramphenicol, phenytoin, tobramycin, and vancomycin may result in lower peak serum concentrations. The most common adverse effect seen with IO use, extravasation, has been reported in 12% of patients. Compartment syndrome, osteomyelitis, and tibial fracture are rare, but have also been reported. IO administration is a safe and effective method for delivering drugs during cardiopulmonary resuscitation. It should be considered whenever intravenous access cannot be rapidly obtained.

Acute Interstitial Nephritis Associated with Coadministration of Vancomycin and Ceftriaxone: Case Series and Review of the Literature

We report what we believe to be the first two cases of acute interstitial nephritis associated with vancomycin and ceftriaxone therapy in adults. A 40-year-old man with a medical history of traumatic brain injury and tonic-clonic seizure disorder was admitted to the hospital with a seizure episode and temperature of 103 degrees F. He was administered ceftriaxone, vancomycin, and acyclovir for suspected bacterial and/or viral meningitis. On day 4, the patient was noted to have diffuse erythematous plaques on the neck, chest, arms, abdomen, and back, as well as an elevated serum creatinine level of 3.1 mg/dl (baseline 0.9 mg/dl) and an elevated eosinophil count (6%). Dermatology and renal consultations were obtained, and a diagnosis of suspected acute interstitial nephritis was made. After a 3-day course of antibiotic treatment (day 4 of hospitalization), all antibiotics were discontinued and topical triamcinolone 0.1% ointment and hydrocortisone 2.5% cream were begun for the rash. The patient was discharged 5 days later with improvement in the rash, serum creatinine level (1.0 mg/dl), and eosinophil count (0.9%). A 59-year-old woman with a medical history of diabetes mellitus was admitted to the hospital with a serum creatinine level of 3.7 mg/dl, eosinophil count of 8.4%, and fractional excretion of sodium of 2.94%. The patient had been receiving treatment with vancomycin and ceftriaxone for osteomyelitis for 28 days before this hospital admission. Her baseline serum creatinine level (before antibiotic therapy) was 1.0 mg/dl. Renal consultation was obtained, and a diagnosis of probable acute interstitial nephritis was made. Ceftriaxone and vancomycin were discontinued, and her serum creatinine level gradually decreased to 3.3 mg/dl and then further to 1.5 mg/dl over the next 3 months. Use of the Naranjo adverse drug reaction probability scale revealed that the adverse reaction was possible in the first case and probable in the second case. Health care professionals need to be cognizant that drug-induced acute interstitial nephritis can be associated with concomitant administration of ceftriaxone and vancomycin therapy. Early detection of this rare adverse reaction is paramount in order to prevent acute renal insufficiency.

Antioxidant administration with the initiation of fever prevents renal scarring in the rat model of acute pyelonephritis

Purpose To evaluate the efficacy of antioxidant administration starting at the onset of fever detection in reducing renal scars in an animal model of acute pyelonephritis (APN), and comparing the effectiveness of Allopurinol and vitamin E in the prevention of renal scaring. Material and methods Twenty male Wister rats divided to 4 groups. Group 1 to 3 underwent direct inoculation of 0.1 ml of E-coli suspension into the parenchyma of the right kidney. Group 4 received 0.1 ml of saline. Group I were treated with ceftriaxone for 5 days, starting 3 days after bacterial inoculation; group II & III received Allopurinol and vitamin E as soon as animal's body temperature rose above 37°C. followed by the administration of daily ceftriaxone 3 says after inoculation for five days. Six weeks later all rats were sacrificed; both kidneys examined histopathologically for scarring. Renal cell apoptosis index was determined in paraffin embedded kidneys (using TUNEL assay). Results The fever started 4.6±1.3 hours (measured by continues digital rectal thermometer) after inoculation in all rats. Histopathologically, subsequent scar formation had occurred in all rats of the group 1 which didn't receive antioxidant agents. The inflammation and fibrosis was mildest in group 2 and 3 (Allopurinol and Vitamin E); whereas it was significantly lower in group 3 than in group 2 (p Conclusions Initiation of the antioxidant agents following detection of fever can be effective in reducing the severity of scarring in APN. Comparing the total scar scores in experimental groups, vitamin E has more protective effect against renal damage due to APN than Allopurinol.

Hepatic gas gangrene following liver transplantation

A 45-year-old man presented with a 2-day history of diarrhea, fever, and progressing fatigue. The patient had undergone a liver transplantation for cryptogenic cirrhosis with Roux-en-Y hepaticojejunostomy 9 years earlier. No vascular complications had emerged in the posttransplant period. Immunosuppression was achieved initially with prednisolone and cyclosporine A, and was later switched to mycophenolate mofetil and prednisolone. Upon admission, the patient's blood pressure was 100/70 mm Hg, and his pulse was 115 beats per minute, with an oxygen saturation of 93% while breathing 6 liters of oxygen per minute through nasal cannula. Upon examination, the patient appeared somnolent, but his chest and abdomen were unremarkable. Laboratory investigations revealed procalcitonin of 56.8 μg/L, creatinine of 487 μmol/L, and aspartate aminotransferase of 1,502 U/L. Escherichia coli in the first blood culture prompted the administration of ceftriaxone plus metronidazole. A computed tomography scan of the abdomen revealed massive aerobilia (Fig. 1) and gas-filled cavity of the right hepatic lobe. During the next hours, the patient became anuric, and the hemodynamic situation deteriorated rapidly despite maximal treatment. Surgical debridement that might have ended up in hepatectomy was not regarded to be an option in the face of advanced multiorgan failure. The patient died shortly thereafter. A computed tomography scan of the abdomen revealing massive aerobilia (black arrow) and gas-filled cavity of the right hepatic lobe (white arrows). The postmortem examination revealed a large abscess formation within the right lobe of the liver, and portal-vein thrombosis. The necrotic hepatic parenchyma was infiltrated by gram-positive rods. Blood cultures tested positive for Clostridium perfringens shortly thereafter. C. perfringens is a member of the normal colonic flora. Spores in soil or food can enter the organism and cause food poisoning or gas gangrene with a high mortality rate.1C. perfringens appears as a short, plump, strongly gram-positive rod (2 to 4 μm long and 1 to 1.5 μm wide) that possesses a central or subterminal spore.2 Alpha toxin (phospholipase C) is one of at least 12 antigenic protein toxins of C. perfringens and induces hemolysis, platelet destruction, cardiogenic shock, and multiple organ failure.3 Spontaneous C. perfringens bacteremia has been associated with neoplastic diseases (mortality rate of 58% in a case series of 136 episodes) and liver cirrhosis (mortality rate of 30% in a case series of 73 episodes).4, 5 Hepatic involvement of C. perfringens infection can lead to pylephlebitis, which carries a bad prognosis and may come to attention by floating high amplitude ultrasound echoes within the extrahepatic and intrahepatic portal veins.6 In the current case, the cause of portal vein thrombosis, which was recognized post mortem but not seen on the initial computed tomography scan, remains unclear. The patient had not received vascular grafts during the transplantation. Moreover, the hepatic artery as well as the hepatic veins were patent on computed tomography imaging. Five cases of Clostridium infections following liver transplantation have recently been described in the literature.7-11 At least 2 patients died, another underwent immediate retransplantation. Although this strain of C. perfringens was sensitive to metronidazole, the antibiotic therapy was probably initiated too late to be effective. Broad-spectrum coverage with concomitant administration of penicillin G, aminoglycoside, and clindamycin is now recommended for C. perfringens infections.2, 12 Surgical debridement of all necrotic tissue should be performed immediately, and liver retransplantation has been suggested as a salvage therapy.10 The current case reminds us, however, that C. perfringens infections in transplant patients may come to attention too late to be effectively treated.