ro13-9904 and Leukopenia

Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne viral disease with a high mortality rate. Infection can also occur through close contact with an infected patient. Scrub typhus is an acute febrile illness caused by

Topics: Aged; Anti-Bacterial Agents; Azithromycin; Bites and Stings; Bunyaviridae Infections; Ceftriaxone; Coinfection; Female; Genotype; Humans; Leukopenia; Molecular Diagnostic Techniques; Orientia tsutsugamushi; Phlebovirus; Phylogeny; Republic of Korea; Scrub Typhus; Thrombocytopenia; Tick-Borne Diseases; Treatment Outcome

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

Streptococcus pneumoniae ( S. pneumoniae ) has been associated with hemolytic uremic syndrome (HUS), which is an unusual but serious disease in childhood. We conducted a retrospective review of children aged less than 18 years with S. pneumoniae -associated HUS in northern Taiwan from January 2000 to June 2005. The demographic characters, clinical courses, and outcomes were analyzed. Seven children (three girls, four boys) with S. pneumoniae -associated HUS were studied. The median age at onset of HUS was 40 months (range: 25-60 months). The median duration of hospital stay was 36 days (range: 15-50 days). The interval between the onset of illness attributable to S. pneumoniae and the development of HUS was around 1-2 weeks. The onset of oliguria developed within 2 weeks after illness. Six patients required dialysis with median duration of 16 days. Three patients had leukopenia as the initial presentation. All seven patients had pneumococcal pneumonia complicating with empyema, and two of them received decortication via video-assisted thoracoscopic surgery. Between patients who needed dialysis or not, there was no significant difference in age, sex, duration of thrombocytopenia, incidence of extra-renal complications, such as hepatitis, pancreatitis, and hypertension, and length of hospital stay. The seven patients survived with normal renal function. HUS is a potentially fatal complication of S. pneumoniae infection. Clinicians managing patients with pneumococcal pneumonia with empyema accompanied by leukopenia should beware of the development of HUS. The long-term prognosis for recovery of renal function appears to be good in these patients in northern Taiwan.

Topics: Anti-Bacterial Agents; Ceftriaxone; Child, Preschool; Empyema, Pleural; Erythrocyte Transfusion; Female; Hemolytic-Uremic Syndrome; Humans; Length of Stay; Leukopenia; Male; Oliguria; Platelet Transfusion; Pneumonia, Pneumococcal; Renal Dialysis; Respiration, Artificial; Retrospective Studies; Taiwan; Thoracostomy; Thrombocytopenia

BAL5788 is a water-soluble prodrug of BAL9141, a new broad-spectrum cephalosporin with high levels of in vitro activity against methicillin- and vancomycin-resistant staphylococci and penicillin-resistant streptococci. In plasma BAL5788 is rapidly converted to BAL9141. We studied the activity of BAL5788 in a mouse model of acute pneumococcal pneumonia. Leukopenic female Swiss albino mice were challenged intratracheally with 10(7) CFU of clinical Streptococcus pneumoniae strains P-52181 (Pen(s) Cro(s) Ctx(s)), P-15986 (Pen(r) Cro(s) Ctx(s)), P-40422 (Pen(r) Cro(r) Ctx(r)), and P-40984 (Pen(r) Cro(r) Ctx(r)). Infected mice received subcutaneous (s.c.) injections of BAL5788 or ceftriaxone starting 3 h after pneumococcal challenge. Uninfected nonleukopenic mice received single s.c. doses of BAL5788 to determine the BAL9141 concentration-time profiles in serum and lungs. Untreated control mice died within 5 days postinfection. Ten-day cumulative survival rates for infected mice receiving BAL5788 (total daily doses of BAL9141 equivalents, 2.1 to 75 mg/kg of body weight) ranged from 57 to 100%, whereas with ceftriaxone (total daily doses, 10 to 400 mg/kg), the survival rates varied between 13 and 100%. In mice infected with P-15986, the survival rates achieved with BAL5788 (BAL9141 equivalent, 8.4 mg/kg) and those achieved with ceftriaxone (50 mg/kg) were significantly different (93 versus 13%; P < 0.0001) in favor of BAL5788; the outcomes of the trials with all other strains were not significantly different between the two antibiotics, but markedly lower doses of BAL5788 than ceftriaxone were required to obtain similar survival rates. Pharmacokinetic data showed that BAL9141 was effective against the four pneumococcal strains tested at very low values of the time above the MIC (T > MIC), which ranged from 9 to 18% of the dosing interval, whereas the values of T > MICs for ceftriaxone ranged from 30 to 50% of the dosing interval.

Topics: Animals; Ceftriaxone; Cephalosporin Resistance; Cephalosporins; Female; Injections, Subcutaneous; Leukopenia; Lung; Mice; Microbial Sensitivity Tests; Pneumonia, Pneumococcal; Prodrugs; Streptococcus pneumoniae; Survival Analysis

The effectiveness of ziracin (SCH27899), a novel everninomicin, was at first investigated against lethal pneumonia caused by a penicillin-susceptible Streptococcus pneumoniae strain. A single intravenous injection of ziracin at a dose of 60 mg/kg of body weight given at 18 h postinfection protected 100% mice and led to the complete clearance of bacteria from their lungs. The activity of ziracin was observed to be the same as that of ceftriaxone: the 50% protective doses (PD(50)s) of ziracin and ceftriaxone were 24.8 and 24.6 mg/kg, respectively. Evaluation of this therapy with leukopenic mice showed that a single injection of ziracin protected 75% of these mice. A delay in therapy with ziracin, which was initiated at 48 h postinfection with 30 mg/kg given once daily for 3 days, resulted in an 83% survival rate of immunocompetent mice. The efficacy of ziracin was further compared to that of vancomycin against lethal pneumonia caused by a penicillin-resistant S. pneumoniae strain in leukopenic mice. The PD(50)s of ziracin and vancomycin were 40.5 and 44.2 mg/kg, respectively. Treatment with ziracin at 30 mg/kg once daily for 2 days (initiated 18 h postinfection) yielded an 83% survival rate and achieved complete eradication of the bacteria. The results were the same as those obtained with vancomycin administered at 15 mg/kg twice daily for 2 days. It is notable that the high survival rates for mice treated with ziracin were associated with effective eradication of the bacteria and rapid recovery of pulmonary tissues from pneumonia. The pharmacokinetic properties of ziracin, ceftriaxone, and vancomycin were estimated following intravenous administration of a single dose of 30 mg/kg to immunocompetent mice. The half-life of ziracin was observed to be longer than those of ceftriaxone and vancomycin (2.3 h versus 1.0 and 0.36 h in the bloodstream and 3 h versus 1.9 and 0. 45 h in lung tissues). The areas under the concentration-time curves (AUCs) in lung tissue for ziracin versus those for ceftriaxone and vancomycin were 36 microg. h/g versus 20 and 9.5 microg. h/g. The prolonged half-life and high AUC for ziracin in tissue contributed to its excellent in vivo activities.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Ceftriaxone; Cephalosporins; Female; Leukopenia; Lung; Mice; Microbial Sensitivity Tests; Penicillin Resistance; Pneumonia, Pneumococcal; Serum Bactericidal Test; Streptococcus pneumoniae; Survival Analysis; Vancomycin

Forty five positive blood culture acute typhoid cases were studied during a 2 years period (1997-1999) in Abbassia Fever hospital, Cairo, Egypt. Their ages ranged between 4-23 (12 +/- 2.5) years. Male: Female ratio was 1:1. Three of the 4 classical signs namely: toxic look (84%), bronchitic chest (47%), tumid tympanitic abdomen (84%) and just palpable receding spleen (69%) were found in almost all cases and offer a good bed side clinical diagnostic test. Blood picture revealed anaemia, within normal white blood count and thrombocytopenia. Liver function tests showed within normal total serum bilirubin, two or more folds increase of ALT and within normal serum alkaline phosphatase. Comparing the 3 tests, namely significant Widal titre (56%), modified Widal test (89%) and bright spleen (78%), it was found that modified Widal test is the most sensitive serological test. Ultrasonographic finding of bright spleen is an easy, safe, noninvasive and sensitive technique which is relatively cheap. Each of the 3 drugs in our study namely chloramphenicol, quinolones and ceftriaxone resulted in improvement of general condition, drop of fever, increase in haemoglobin, white blood count and platelet count. Also, there was a significant improvement of liver function tests by either of the 3 drugs. Ceftriaxone is the best drug from the clinical and laboratory points of view followed by quinolones in multidrug resistant (MDR) acute typhoid cases. Chloramphenicol is still the drug of choice in chloramphenicol sensitive salmonellae.

Topics: Acute Disease; Adolescent; Adult; Agglutination Tests; Anti-Bacterial Agents; Case-Control Studies; Ceftriaxone; Child; Child, Preschool; Chloramphenicol; Drug Resistance, Bacterial; Egypt; Female; Humans; Leukopenia; Liver Function Tests; Male; Quinolones; Sensitivity and Specificity; Treatment Outcome; Typhoid Fever; Urban Health

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 antibacterial interaction between ceftriaxone and the aminoglycosides tobramycin, gentamicin and amikacin against pseudomonas aeruginosa was investigated in vitro and in experimental systemic infections of the mouse. In vitro synergy was observed in 70% of the strains with tobramycin, 67.5% with gentamicin, and 77.5% with amikacin. Synergistic bactericidal activity was demonstrated with all three aminoglycosides in combination with ceftriaxone. In line with these in vitro results, synergism against most isolates also occurred in mice. In leukopenic mice, the addition of ceftriaxone resulted in a more than 2.5-fold reduction of the aminoglycoside dose necessary for antiinfective protection, although ceftriaxone alone was only marginally active against the pathogen used in immunocompromised animals.

Topics: Amikacin; Animals; Cefotaxime; Ceftriaxone; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Gentamicins; Kanamycin; Leukopenia; Mice; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin