Daptomycin for the treatment of osteomyelitis and orthopaedic device infections: real-world clinical experience from a European registry.

Osteomyelitis is a serious infection predominantly caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Orthopaedic device-related infections are complex and require a careful combination of surgical intervention and antimicrobial therapy. Daptomycin, a cyclic lipopeptide, effectively penetrates soft tissue and bone and demonstrates rapid concentration-dependent bactericidal activity against Gram-positive pathogens. This retrospective, non-interventional study evaluated clinical outcomes in patients with osteomyelitis or orthopaedic device infections treated with daptomycin from the European Cubicin® Outcomes Registry and Experience (EU-CORE(SM)) study. Patients were treated between January 2006 and April 2012, with follow-up to 2014. Clinical outcomes were assessed as success (cured or improved), failure or non-evaluable. Of 6,075 patients enrolled, 638 (median age, 63.5 years) had primary infections of osteomyelitis or orthopaedic device infections, 224 had non-prosthetic osteomyelitis, 208 had osteomyelitis related to a permanent or temporary prosthetic device, and 206 had orthopaedic device infections. The most commonly isolated pathogen was S. aureus (214 [49.1 %]; 24.8 % were MRSA). Overall, 455 (71.3 %) patients had received previous antibiotic therapy. Patients underwent surgical interventions, including tissue (225 [35.3 %]) and bone (196 [30.7 %]) debridement, as part of their treatment. Clinical success rates were 82.7 % and 81.7 % in S. aureus and coagulase-negative staphylococcal infections. Adverse events (AEs) and serious AEs assessed as possibly related to daptomycin were observed in 6.7 % and 1.9 % of patients, respectively. Daptomycin was discontinued by 5.5 % of patients due to AEs and 10 (1.6 %) deaths were reported. In conclusion, daptomycin was effective and safe in patients with osteomyelitis or orthopaedic device infections.

Open-label, multicentre, emergency-use study of clinafloxacin (CI-960) in the treatment of patients with serious life-threatening infections.

In an open-label emergency-use study, 23 patients with bacterial infections caused by multiply drug resistant pathogens were treated with clinafloxacin. Efficacy and safety were evaluated by tabulating investigators' assessments at the end of treatment, treatment discontinuations and adverse event data. Most of the patients were seriously ill and had multi-organ infections, primarily respiratory tract infections such as nosocomial pneumonia and gastrointestinal infections. Eleven patients were successfully treated, two had treatment failure and 10 were not evaluable because the patients died of their underlying disease. Considering that most of the patients had several infections caused by multiply resistant pathogens, clinafloxacin may be useful for the treatment of such life-threatening episodes.

Clinafloxacin monotherapy (CI-960) versus ceftazidime plus amikacin for empirical treatment of febrile neutropenic cancer patients.

OBJECTIVE: To assess the efficacy and safety of clinafloxacin as a single agent for the empirical treatment of febrile episodes and bacterial infections in neutropenic cancer patients. METHODS: An open label, active-controlled, randomized, parallel treatment, multicenter study was conducted where clinafloxacin monotherapy was compared to the combination of ceftazidime plus amikacin (plus optional vancomycin or teicoplanin). Four hundred and nineteen patients were randomized to receive either intravenous clinafloxacin 200 mg every 12 h or intravenous ceftazidime (2 g) iv every 8 h plus intravenous amikacin (15 mg/kg) per day in divided doses. All randomized patients were to receive a minimum of 48 h of primary study drug treatment, after which the primary treatment could be modified. Clinical and microbiological responses were evaluated at 7-21 days post-treatment after study treatment and long term (maximum 28 days), in intent-to-treat and modified intent-to-treat populations. RESULTS: Clinafloxacin and ceftazidime-amikacin were statistically equivalent for the 72-h defervescence rate, overall defervescence rate, time to defervescence, clinical success rate, by-pathogen microbiological eradication rate, and survival rate. Clinical cure was achieved in 84% (59/70) of patients who received clinafloxacin monotherapy. There were no significant differences between treatments in rates of adverse events or treatment discontinuation rates due to adverse events. CONCLUSIONS: Clinafloxacin appears to be an appropriate agent for empirical treatment in febrile neutropenic cancer patients.

A prospective, randomized, multicenter comparative study of clinafloxacin versus a ceftriaxone-based regimen in the treatment of hospitalized patients with community-acquired pneumonia.

In an open-label, phase 3, randomized, multicenter study, clinafloxacin (200 mg/d) was compared to ceftriaxone (2 g/d; with or without erythromycin) in 527 patients with acute community-acquired bacterial pneumonia (CAP). Primary efficacy parameters were clinical cure rate and microbiologic eradication rates (by pathogen and by patient) determined 5-9 d post-therapy (test of cure; TOC). Clinical cure rates at TOC for the 2 treatment groups were equivalent in the intention-to-treat (clinafloxacin 79.3, ceftriaxone 78.6%), clinically evaluable (clinafloxacin 88.1, ceftriaxone 85.0%), modified intention-to-treat (clinafloxacin 82.6, ceftriaxone 86.9%) and microbiologically evaluable populations (clinafloxacin 86.2, ceftriaxone 86.2%). Microbiologic eradication rates were similar in the 2 treatment groups. Both drugs were tolerated. Treatment of hospitalized CAP patients with clinafloxacin is a reasonable choice, especially when a resistant pathogen is anticipated.

Cefdinir vs. amoxicillin/clavulanic acid in the treatment of suppurative acute otitis media in children.

An investigator-blinded, randomized, multicenter study was conducted to compare the efficacy and safety of cefdinir and amoxicillin/ clavulanate (amoxicillin/CA) in the treatment of pediatric patients with acute suppurative otitis media. Patients 6 months to 12 years of age were randomized in a 1:1:1 ratio to receive cefdinir 14 mg/kg once-daily, cefdinir 7 mg/kg b.i.d., or amoxicillin/CA 13.3 mg/kg t.i.d. Test-of-cure was determined 11 to 16 days posttherapy. Of the 752 patients who entered the study, 665 (88%) completed treatment and 595 (79%) were evaluable. Response rates in the three treatment groups were similar. Overall rates of adverse events were statistically lower in the cefdinir once-daily group than in the amoxicillin/CA group. Diarrhea was the most common adverse event in all treatment groups. Cefdinir given either once-daily or twice-daily is a safe and effective treatment for pediatric patients with acute suppurative otitis media.

Cefdinir versus amoxicillin/clavulanic acid in the treatment of suppurative acute otitis media in children.

An investigator-blinded, randomized, multicenter study was conducted to compare the efficacy and safety of cefdinir and amoxicillin/clavulanate (amoxicillin/CA) in the treatment of pediatric patients with acute suppurative otitis media. Patients 6 months to 12 years of age were randomized in a 1:1:1 ratio to receive cefdinir 14 mg/kg once-daily, cefdinir 7 mg/kg b.i.d., or amoxicillin/CA 13.3 mg/kg t.i.d. Test-of-cure was determined 11 to 16 days post therapy. Of the 752 patients who entered the study, 665 (88%) completed treatment and 595 (79%) were evaluable. Response rates in the three treatment groups were similar. Overall rates of adverse events were statistically lower in the cefdinir once-daily group than in the amoxicillin/CA group. Diarrhea was the most common adverse event in all treatment groups. Cefdinir given either once-daily or twice-daily is a safe and effective treatment for pediatric patients with acute suppurative otitis media.

Magnesium, zinc, and copper status of US Navy SEAL trainees.

Magnesium, zinc, and copper status of 270 US Navy Sea, Air, and Land (SEAL) trainees was determined from dietary intakes and biochemical profiles. Although mean intakes exceeded the Recommended Dietary Allowances or the Estimated Safe and Adequate Intake range, intakes of 34%, 44%, and 37% of the trainees were below the recommendations for Mg, Zn, and Cu, respectively. Mean plasma concentrations were 0.85 +/- 0.004 mmol/L, 13.4 +/- 0.2 mumol/L, and 16.5 +/- 0.2 mumol/L for Mg, Zn, and Cu respectively. Mean 24-h urinary excretions were 5.7 +/- 0.2 mmol, 11.1 +/- 0.3 mumol, and 0.05 +/- 0.003 mumol, for Mg, Zn, and Cu, respectively. The data provided by the present study should be useful for comparing other physically active male populations.

Hormonal and metabolic responses of untrained, moderately trained, and highly trained men to three exercise intensities.

Untrained, moderately trained (runners, 15 to 25 mi/wk), and highly trained (runners, greater than 45 mi/wk) men participated in graded treadmill exercise at 50%, 70%, and 90% of their maximal oxygen consumption to quantify the relation between intensity of exercise and sympathetic nervous system and metabolic responses. Sympathetic system activation was noted at all intensities tested and was proportional to the relative exercise intensity. The magnitudes of the norepinephrine (NE) and epinephrine (E) responses were similar in all three groups of men at each relative exercise intensity and correlated with the magnitudes of change in levels of circulating plasma adrenocorticotropin hormone, cortisol, lactate (La), phosphate (Pi), and glucose (GI). The magnitudes of change in concentrations of La, Pi, and GI were also similar for the three groups at each relative exercise intensity. In contrast, a lower degree of sympathetic system activation in response to a given absolute workload was noted in the moderately and highly trained men as compared to that of the untrained men. Sympathetic and metabolic responses to exercise are similar under conditions of comparable relative exercise intensities, regardless of conditioning level. The sympathetic-adrenal medullary system is more sensitive to exercise than the hypothalamic-pituitary-adrenal axis. For a given absolute workload, the degree of activation significantly lower in trained individuals.

Alterations in magnesium and zinc metabolism in thyroid disease.

Magnesium (Mg) and zinc (Zn) status was assessed in subjects to evaluate the effects of thyroid diseases on Mg and Zn metabolism. Plasma and red blood cell (RBC) concentration and peripheral blood mononuclear cell (MNC) content of Mg and Zn, and 24-hour urinary excretion of Mg, Zn, creatinine (Cr), calcium (Ca), sodium (Na), and potassium (K) were measured in 11 thyrotoxic, 29 hypothyroid, and 25 euthyroid control subjects. Serum albumin, alpha 2-macroglobulin, and the binding of Zn to albumin were also determined. Plasma and RBC Mg concentrations were low in half of the hyperthyroid subjects, but mean values were not significantly different from controls. Urinary excretion and clearance of Mg were lower in hypothyroid subjects, but differences were removed when expressed relative to Cr excretion and clearance. Similar patterns were noted for urinary Ca, Na, and K, suggesting that their reduced excretion reflects alterations in renal hemodynamics. Plasma Zn was lower in hypothyroid subjects and correlated with serum albumin; MNC Zn and urinary Zn were also low. Plasma Zn concentration was normal and serum albumin significantly lower in the hyperthyroid group than in the control group. Further, RBC Zn content was significantly lower in hyperthyroid subjects, and inversely related to plasma thyroxine concentration. The hyperthyroid group also excreted significantly greater amounts of Zn than controls, indicative of a catabolic process. This increased urinary loss may reflect a shift in the distribution of plasma Zn between ultrafilterable and Zn-albumin complexes. In summary, this study provides evidence for marked alterations in Zn homeostasis in persons with thyroid disease. Whether the observations indicate deficiency states and have clinical implications will require further investigation.

Magnesium and zinc status during the menstrual cycle.

The effect of menstrual cycle phases on the indexes of magnesium and zinc status was assessed in five normally menstruating women. Plasma concentrations of magnesium and zinc and the magnesium and zinc content of red blood cells and peripheral blood mononuclear cells were measured for 3 or 5 days per week during three menstrual cycles. The cycles were divided into four phases: menses, follicular, ovulatory, and luteal. Plasma magnesium concentrations were highest during menses and then gradually declined, reaching the lowest point during the ovulatory phase. This was followed by a rise during the luteal phase. Plasma zinc concentrations were higher during menses and the follicular phase and then dropped during the ovulatory and luteal phases. Both the magnesium and zinc content of red blood cells and mononuclear cells remained constant over the course of the study and did not change significantly as a function of cycle phase. This study provides evidence that plasma magnesium and zinc concentrations fluctuate during the menstrual cycle in a phase-related fashion in normally menstruating women. Whether these changes are hormonally mediated or reflect metabolic changes will require further study.

Indirect vs direct measurement of magnesium and zinc in erythrocytes.

We evaluated three methods (two indirect and one direct) for determining the magnesium (Mg) and zinc (Zn) content of erythrocytes, to compare methodologic differences and to establish a method suitable for use in field studies. For the indirect methods, erythrocytes in whole blood were lysed by adding either de-ionized water (I) or nitric acid, 2 mol/L (II). For the direct method (III), erythrocytes were isolated by density centrifugation, washed, then digested in concentrated HNO3. Mg and Zn concentrations were measured by atomic absorption spectrophotometry in plasma and whole blood for the indirect methods, and in the pellet for the direct method. Hematocrit and hemoglobin were measured, and erythrocytes were sized and counted on all samples. Within-run CVs for the three methods ranged from 2.2% with method III for Mg to 5.4% with method I for Zn. CVs for reproducibility of the analytical procedures ranged from 2.6% with method II for Zn to 4.2% with method I for the two cations. Analytical recoveries of added Mg and Zn ranged from 93.8 to 104.7%. When values for the three methods were compared, those by method I were significantly (p less than 0.05) lower than those by methods II and III. Values obtained by method II were 100.1% for Mg and 102.4% for Zn of those by the direct method. Thus, the indirect method with 2 mol/L HNO3 lysing solution provides a reproducible, reliable, accurate, and simple technique for measuring Mg and Zn in erythrocytes.

Development of the photosynthetic apparatus during light-dependent greening of a mutant of Chlorella fusca.

The formation of chlorophyll, cytochrome f, P-700, ribulose bisphosphate carboxylase as well as photosynthesis and Hill reaction activities were tested during the light-dependent greening process of the Chlorella fusca mutant G 10. Neither chlorophyll nor protochlorophyllide was detected in the darkgrown cells. When transferred to light the mutant cells developed chlorophyll and established its photosynthetic capacity after a short lag phase. In the in vivo absorption spectra a spectral shift of the red absorption peak position from 674 to 680 nm was indicated during the first 3 h of greening. Cytochrome f was already present in the dark-grown cells, but during the greening phase a threefold increase in the cytochrome f content could be seen. At the early stages of greening a characteristic primary oscillation in the content of cytochrome f was observed. P-700 was lacking in the dark and during the first 30 min of illumination. From the first to the second h of light a forced synthesis of P-700 took place and the time-course curve for the ratios of P-700/chlorophyll rose to a sharp maximum. The synthesis of P-700 started together with photosystem I activity and showed similar kinetics. We found the simultaneous appearance of photosystem II, photosystem I, and photosynthetic activities 30 min after the beginning of the illumination. Based on chlorophyll content they attained maximum activity after 2 h of light, but at this time photosystem I capacity proved to be remarkably higher than photosynthetic and photosystem II activities. Highest carboxylase activity existed in darkgrown cells. During the greening process the activity of the enzyme decreased continuously. After 2 h of illumination chlorophyll synthesis partially served to increase the size of the photosynthetic unit, which consequently led to a decrease in the light energy needed to saturate photosynthesis and also to a decrease of photosynthetic rate based on chlorophyll content.