Synergy between trovafloxacin and ceftriaxone against penicillin-resistant pneumococci in the rabbit meningitis model and in vitro

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.

Relationship between antibiotic concentration in bone and efficacy of treatment of staphylococcal osteomyelitis in rats: azithromycin compared with clindamycin and rifampin

We examined the effect of azithromycin (CP-62,993), a new oral macrolide-like antibiotic, alone and in combination with rifampin, as treatment for experimental staphylococcal osteomyelitis. Clindamycin was used as a comparison drug. Rats (n = 10 to 15 per group) were infected by direct instillation of Staphylococcus aureus into the tibial medullary cavity. After 10 days, 21-day treatments with azithromycin (50 mg/kg of body weight, once daily, by the oral route), rifampin (20 mg/kg, once daily, subcutaneously), or clindamycin (90 mg/kg, three times daily, by the oral route) were started. The drugs were used singly or in combination (azithromycin plus rifampin or clindamycin plus rifampin). Peak azithromycin concentrations in bone were > 30 times higher than levels in serum, but the drug had little effect on final bacterial titers (5.13 +/- 0.46 log10 CFU/g of bone; for controls, 6.54 +/- 0.28 log10 CFU/g). Clindamycin was more active than azithromycin (3.26 +/- 2.14 log10 CFU/g of bone; 20% of sterilized bones), but rifampin was the most active single drug (1.5 +/- 1.92 log10 CFU/g; 53% of sterilized bones). Therapy with rifampin or clindamycin alone was associated with the emergence of resistance. Rifampin plus azithromycin (0.51 +/- 1.08 log10 CFU/g of bone; 80% of sterilized bones) and rifampin plus clindamycin (0.87 +/- 1.34 log10 CFU/g of bone; 66% of sterilized bones) were the most active regimens. Thus, azithromycin is ineffective as a single drug for the treatment of experimental staphylococcal osteomyelitis, despite high levels in bone that markedly exceeded the MIC, but it may be an attractive partner drug for rifampin.

Influence of antibiotic dose, dosing interval, and duration of therapy on outcome in experimental pneumococcal meningitis in rabbits

We examined the influence of several pharmacokinetic parameters on cure rates in rabbits with experimental pneumococcal meningitis. When the duration of treatment was kept constant, cure rates improved as the individual dose of ampicillin was increased. On the other hand, when four doses of ampicillin at 60 mg/kg of body weight, producing peak concentrations in cerebrospinal fluid (CSF) of approximately 40 times the MBC, were administered at intervals of 24 instead of 4 h and the duration of therapy was thus prolonged from 12 to 72 h, cure rates also increased (85 versus 25%; P less than 0.01). These high cure rates were achieved even though bacterial titers in CSF 24 h after the first dose had reached levels similar to those present at the beginning of therapy. Cure in these animals was explained by the fact that the second ampicillin dose reduced bacterial titers in CSF significantly more than did the first dose (5.2 versus 2.5 log10 CFU/ml; P less than 0.02). The clinical relevance of these observations remains to be determined.

New cephalosporins cefotaxime, cefpimizole, BMY 28142, and HR 810 in experimental pneumococcal meningitis in rabbits

Four new cephalosporins, cefotaxime, cefpimizole (U 63196E), BMY 28142, and HR 810 were evaluated in experimental pneumococcal meningitis. Cefotaxime penetrated only moderately into the cerebrospinal fluid of rabbits with meningitis, whereas cefpimizole, BMY 28142, and HR 810 all exhibited unusually good penetration. The bactericidal activity in infected cerebrospinal fluid was comparable for the four drugs.

An old dream revitalised: preconditioning strategies to protect surgical flaps from critical ischaemia and ischaemia-reperfusion injury

The prevention of ischaemia and the adequate restitution of blood flow to ischaemic tissue are pivotal to halt the progression of cellular injury associated with decreased oxygen and nutrient supply. Accordingly, the search for novel strategies which aim at preventing ischaemia-reperfusion-induced tissue damage is still of major interest in flap surgery. Preconditioning represents an elegant approach to render the tissue more resistant against deleterious ischaemic insults. For many decades, 'surgical delay' has been the standard method of tissue preconditioning. During the last 10 years, ischaemic preconditioning was added to the repertoire of plastic surgeons to protect flaps from ischaemic necrosis. The invasiveness and expenditure of time of these procedures, however, have always been major drawbacks, hindering a wide distribution in clinical practice. Consequently, the motivation has all along been to further refine and simplify protective strategies. Recent experimental studies have now shown that efficient protection from ischaemic necrosis can also be achieved by remote preconditioning or pretreatment with chemical agents and growth factors, which mimic the action of surgical delay and ischaemic preconditioning. In addition, the local application of unspecific stressors, including both heating and cooling, have been shown to effectively improve flap microcirculation and, thus, tissue survival. In view of successful translational research, it is now time that the efficacy of these novel preconditioning procedures is proven in prospective randomised clinical trials.

[Localised rhabdomyosarcoma of the extremities in children and adolescents: results of the French experience]

PATIENTS AND METHODS: Forty-six patients with localised RMS of the limbs entered the MMT 89 and 95 study in France. We studied potential risk factors that were predictive of relapse and survival to propose a therapeutic approach of surgery and radiotherapy appropriate to the risk of relapse. RESULTS: Median age at diagnosis was 6.5 years [9 months to 15.5 years]. At time of diagnosis, 43% had marginal surgery and only 13% radical intervention. Primary re-excision was performed in 12% of the patients. All patients received chemotherapy, 43% had second look surgery and 37% received radiotherapy. Fifty-four percent of all tumors relapsed: local relapse 36%, nodes l8%, metastatic 40%, local and metastatic 16%. Estimated overall 5-year event-free survival (EFS) and overall survival (OS) were 40 and 57%, respectively. CONCLUSIONS: Prognosis of RMS of the limbs is bad but only 37% of the patients had radiotherapy. We could define patients with very high risk among those with limbs RMS as nodal involvement (5 years overall survival OS 22%), alveolar histology (OS 38%) and site of hand and foot (4 survivors out of 10 patients). In further studies, these patients should be treated even more aggressive with early surgery followed by re-excision if necessary, chemotherapy including alkylating agents and systematic radiotherapy.

Management of infusion reactions in clinical trials and beyond: the US and EU perspectives

Monoclonal antibodies have expanded our cancer-fighting armamentarium in both the United States and Europe. While in general, monoclonal antibodies are well tolerated and do not have significant overlapping side effects with traditional cytotoxic agents, severe infusion reactions (IRs)--sometimes severe enough to be life threatening--have been reported. The pathophysiology of severe infusion reactions associated with monoclonal antibodies is poorly understood, but mechanisms are beginning to be elucidated. Geographic differences in the incidence of IRs have become apparent. Understanding the risk, recognizing the signs and symptoms, and being ready to promptly manage severe IRs are key for the clinician to avoid unnecessarily discontinuing these effective anticancer agents and prevent potentially tragic consequences for their patients. To date, clinical trials have incorporated monoclonal antibodies into combinations with standard cytotoxic regimens; it is expected that in time clinical trials will be testing promising new combinations utilizing multiple targeted agents, resulting in improved toxicity profiles and efficacy for cancer patients.

Neonatal procedural pain exposure and pain management in ventilated preterm infants during the first 14 days of life

OBJECTIVES: Ventilated preterm infants are at high risk for procedural pain exposure. In Switzerland there is a lack of knowledge about the pain management in this highly vulnerable patient population. The aims of this study were to describe the type and frequency of procedures and to determine the amount of analgesia given to this patient group in two Swiss neonatal intensive care units. METHOD: A retrospective cohort study was performed examining procedural exposure and pain management of a convenience sample of 120 ventilated preterm infants (mean age = 29.7 weeks of gestation) during the first 14 days of life after delivery and born between May 1st 2004 and March 31st 2006. RESULTS: The total number of procedures all the infants underwent was 38,626 indicating a mean of 22.9 general procedures performed per child and day. Overall, 75.6% of these procedures are considered to be painful. The most frequently performed procedure is manipulation on the CPAP prongs. Pain measurements were performed four to seven times per day. In all, 99.2% of the infants received either non-pharmacological and/or pharmacological agents and 70.8% received orally administered glucose as pre-emptive analgesia. Morphine was the most commonly used pharmacological agent. DISCUSSION: The number of procedures ventilated preterm infants are exposed to is disconcerting. Iatrogenic pain is a serious problem, particularly in preterm infants of low gestational age. The fact that nurses assessed pain on average four to seven times daily per infant indicates a commitment to exploring a painful state in a highly vulnerable patient population. In general, pharmacological pain management and the administration of oral glucose as a non-pharmacological pain relieving intervention appear to be adequate, but there may be deficiencies, particularly for extremely low birth weight infants born <28 weeks of gestation.

Pharmacokinetics and safety profile of the human anti-Pseudomonas aeruginosa serotype O11 immunoglobulin M monoclonal antibody KBPA-101 in healthy volunteers

KBPA-101 is a human monoclonal antibody of the immunoglobulin M isotype, which is directed against the O-polysaccharide moiety of Pseudomonas aeruginosa serotype O11. This double-blind, dose escalation study evaluated the safety and pharmacokinetics of KBPA-101 in 32 healthy volunteers aged 19 to 46 years. Each subject received a single intravenous infusion of KBPA-101 at a dose of 0.1, 0.4, 1.2, or 4 mg/kg of body weight or placebo infused over 2 h. Plasma samples for pharmacokinetic assessments were taken before infusion as well as 0.25, 0.5, 1, 2, 2.5, 4, 6, 8, 12, 24, 36, and 48 h and 4, 7, 10, and 14 days after start of dosing. Plasma concentrations of KBPA-101 were detected with mean maximum concentrations of drug in plasma of 1,877, 7,571, 24,923, and 83,197 ng/ml following doses of 0.1, 0.4, 1.2, and 4.0 mg/kg body weight, respectively. The mean elimination half-life was between 70 and 95 h. The mean volume of distribution was between 4.76 and 5.47 liters. Clearance ranged between 0.039 and 0.120 liters/h. At the highest dose of 4.0 mg/kg, plasma KBPA-101 levels were greater than 5,000 ng/ml for 14 days. KBPA-101 exhibited linear kinetics across all doses. No anti-KBPA-101 antibodies were detected after dosing in any subject. Overall, the human monoclonal antibody KBPA-101 was well tolerated over the entire dose range in healthy volunteers, and no serious adverse events have been reported.

Harmonised monitoring of antimicrobial resistance in Salmonella and Campylobacter isolates from food animals in the European Union

Many Member States of the European Union (EU) currently monitor antimicrobial resistance in zoonotic agents, including Salmonella and Campylobacter. According to Directive 2003/99/EC, Member States shall ensure that the monitoring provides comparable data on the occurrence of antimicrobial resistance. The European Commission asked the European Food Safety Authority to prepare detailed specifications for harmonised schemes for monitoring antimicrobial resistance. The objective of these specifications is to lay down provisions for a monitoring and reporting scheme for Salmonella in fowl (Gallus gallus), turkeys and pigs, and for Campylobacter jejuni and Campylobacter coli in broiler chickens. The current specifications are considered to be a first step towards a gradual implementation of comprehensive antimicrobial resistance monitoring at the EU level. These specifications propose to test a common set of antimicrobial agents against available cut-off values and a specified concentration range to determine the susceptibility of Salmonella and Campylobacter. Using isolates collected through programmes in which the sampling frame covers all epidemiological units of the national production, the target number of Salmonella isolates to be included in the antimicrobial resistance monitoring per Member State per year is 170 for each study population (i.e., laying hens, broilers, turkeys and slaughter pigs). The target number of Campylobacter isolates to be included in the antimicrobial resistance monitoring per Member State per year is 170 for each study population (i.e., broilers). The results of the antimicrobial resistance monitoring are assessed and reported in the yearly national report on trends and sources of zoonoses, zoonotic agents and antimicrobial resistance.

The effect of monoalkyl phosphates and fluoride on dissolution of hydroxyapatite, and interactions with saliva

The aims were to investigate the effect of monoalkyl phosphates (MAPs) and fluoride on dissolution rate of native and saliva-coated hydroxyapatite (HA). Fluoride at 300 mg/l (as NaF) inhibited dissolution of native HA by 12%, while potassium and sodium dodecyl phosphates (PDP, SDP), at 0.1% or higher, inhibited dissolution by 26-34%. MAPs, but not fluoride, also showed persistence of action. MAPs at 0.5% and fluoride at 300 mg/l were then tested separately against HA pre-treated with human saliva for 2 or 18 h. Agents were applied with brushing to half the specimens, and without brushing to the other half. In control (water-treated) specimens, pre-treatment of HA with human saliva reduced dissolution rate on average by 41% (2 h) and 63% (18 h). Brushing did not have a statistically significant effect on dissolution rate of saliva-coated specimens. In brushed specimens, fluoride significantly increased the inhibition due to 2- or 18-hour saliva pre-treatment. It is hypothesised that brushing partially removes the salivary film and allows KOH-soluble calcium fluoride formation at the surfaces of HA particles. Inhibition was reduced by PDP in 2-hour/non-brushed specimens and in 18-hour/brushed specimens. PDP did not affect dissolution rates in the remaining groups and SDP did not affect dissolution rate in any group. Possible reasons for these variable results are discussed. The experiments show that pre-treatment with saliva can significantly modify results of tests on potential anti-erosive agents and it is recommended that saliva pre-treatment should be a routine part of testing such agents.

Multiplex Liquid Chromatography-Tandem Mass Spectrometry Assay for Simultaneous Therapeutic Drug Monitoring of Ribavirin, Boceprevir, and Telaprevir

New directly acting antivirals (DAAs) that inhibit hepatitis C virus (HCV) replication are increasingly used for the treatment of chronic hepatitis C. A marked pharmacokinetic variability and a high potential for drug-drug interactions between DAAs and numerous drug classes have been identified. In addition, ribavirin (RBV), commonly associated with hemolytic anemia, often requires dose adjustment, advocating for therapeutic drug monitoring (TDM) in patients under combined antiviral therapy. However, an assay for the simultaneous analysis of RBV and DAAs constitutes an analytical challenge because of the large differences in polarity among these drugs, ranging from hydrophilic (RBV) to highly lipophilic (telaprevir [TVR]). Moreover, TVR is characterized by erratic behavior on standard octadecyl-based reversed-phase column chromatography and must be separated from VRT-127394, its inactive C-21 epimer metabolite. We have developed a convenient assay employing simple plasma protein precipitation, followed by high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) for the simultaneous determination of levels of RBV, boceprevir, and TVR, as well as its metabolite VRT-127394, in plasma. This new, simple, rapid, and robust HPLC-MS/MS assay offers an efficient method of real-time TDM aimed at maximizing efficacy while minimizing the toxicity of antiviral therapy.

In vitro effects of novel ruthenium complexes in Neospora caninum and Toxoplasma gondii tachyzoites.

Upon the screening of 16 antiproliferative compounds against Toxoplasma gondii and Neospora caninum, two hydrolytically stable ruthenium complexes (compounds 16 and 18) exhibited 50% inhibitory concentrations of 18.7 and 41.1 nM (T. gondii) and 6.7 and 11.3 nM (N. caninum). To achieve parasiticidal activity with compound 16, long-term treatment (22 to 27 days at 80 to 160 nM) was required. Transmission electron microscopy demonstrated the rapid impact on and ultrastructural alterations in both parasites. These preliminary findings suggest that the potential of ruthenium-based compounds should thus be further exploited.

In vitro and in vivo activities of dicationic diguanidino compounds against Echinococcus multilocularis metacestodes.

Alveolar echinococcosis (AE) is a disease predominantly affecting the liver, with metacestodes (larvae) of the tapeworm Echinococcus multilocularis proliferating and exhibiting tumor-like infiltrative growth. For many years, chemotherapeutical treatment against alveolar echinococcosis has relied on the benzimidazoles albendazole and mebendazole, which require long treatment durations and exhibit parasitostatic rather than parasiticidal efficacy. Although benzimidazoles have been and still are beneficial for the patients, there is clearly a demand for alternative and more efficient treatment options. Aromatic dications, more precisely a small panel of di-N-aryl-diguanidino compounds, were screened for efficacy against E. multilocularis metacestodes in vitro. Only those with a thiophene core group were active against metacestodes, while furans were not. The most active compound, DB1127, was further investigated in terms of in vivo efficacy in mice experimentally infected with E. multilocularis metacestodes. This diguanidino compound was effective against AE when administered intraperitoneally but not when applied orally. Thus, thiophene-diguanidino derivatives with improved bioavailability when administered orally could lead to treatment options against AE.