hr-810 and Sepsis

Topics: Adult; Cefpirome; Ceftazidime; Cephalosporins; Chi-Square Distribution; Female; Humans; Infusions, Intravenous; Male; Prognosis; Sepsis; Severity of Illness Index; Treatment Outcome

Cefpirome is a fourth-generation cephalosporin with good in-vitro activity against both Gram-positive and Gram-negative aerobes, including Pseudomonas spp. A multicentre, randomized trial was performed to compare cefpirome at a dose of 2 g bd iv with ceftazidime (2 g tds iv) in the empirical treatment of suspected bacteraemia in patients with severe sepsis but not septic shock. The majority of the patients had community-acquired infections. Patients were stratified into high- and low-risk groups using a Simplified Sepsis Score. Metronidazole, an aminoglycoside or a glycopeptide could be added to the treatment as required. In patients with a positive blood culture treated for > or = 48 h, the clinical success rates were 37/48 (77%) for cefpirome and 35/52 (67%) for ceftazidime with no significant difference between the two. In patients with bacteriologically proven infection, 92 (89%) of 103 patients treated with cefpirome were assessed as cured and 94 (89%) of 106 patients with treated ceftazidime. More Gram-positive pathogens, enterococci and staphylococci were resistant in vitro to ceftazidime than to cefpirome (15/90 (17%) and 5/92 (5%) respectively; chi2 = 4.8, P < 0.05) but the bacteriological response was not significantly different between the two groups (cefpirome, 54/60 (90%); ceftazidime, 54/63 (86%)). Cefpirome showed equivalent efficacy and safety to ceftazidime in the empirical treatment of suspected bacteraemia or sepsis. Regarding safety, there were no statistically significant differences between the two treatments, with adverse events thought to be possibly related to the study drug occurring in 55/187 and 40/184 patients on cefpirome and ceftazidime, respectively.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; APACHE; Bacteremia; Cefpirome; Ceftazidime; Cephalosporins; Female; Humans; Male; Middle Aged; Sepsis

The objective of the present study was to evaluate whether cefpirome, a member of the latest class of broad-spectrum cephalosporins, sufficiently penetrates subcutaneous adipose tissue in septic patients. After the administration of the drug at 2 g, tissue cefpirome concentrations in septic patients (n = 11) and healthy controls (n = 7) were determined over a period of 4 h by means of microdialysis. To assess the antibacterial effect of cefpirome at the target site, the measured pharmacokinetic profiles were simulated in vitro with select strains of Staphylococcus aureus and Pseudomonas aeruginosa. The tissue penetration of cefpirome was significantly impaired in septic patients compared with that in healthy subjects. For subcutaneous adipose tissue, the area under the concentration-versus-time curve values from 0 to 240 min were 13.11 +/- 5.20 g . min/liter in healthy subjects and 6.90 +/- 2.56 g . min/liter in septic patients (P < 0.05). Effective bacterial growth inhibition was observed in all in vitro simulations. This was attributed to the significantly prolonged half-life in tissue (P < 0.05), which kept the tissue cefpirome levels above the MICs for relevant pathogens for extended periods in the septic group. By consideration of a dosing interval of 8 h, the values for the time above MIC (T > MIC) in tissue were greater than 60% for pathogens for which the MIC was

Topics: Adipose Tissue; Adult; Area Under Curve; Cefpirome; Cephalosporins; Chromatography, Micellar Electrokinetic Capillary; Colony Count, Microbial; Female; Humans; Male; Microbial Sensitivity Tests; Microdialysis; Pseudomonas aeruginosa; Sepsis; Staphylococcus aureus

Broad initial antibiotic treatment is crucial for patients experiencing septic shock or severe sepsis. Fourth-generation beta-lactam antibiotics, such as cefpirome, are frequently favored in these conditions because of their low toxicity and wide antimicrobial coverage. From recent data, however, there is circumstantial evidence that one reason for the high mortality rate of patients with sepsis might be an impaired penetration of antimicrobial agents from the central compartment to the infectious focus. Thus, the present study aimed at describing penetration properties of cefpirome to the target site of many bacterial infections, which is the extracellular space fluid of soft tissues.. Prospective comparative study of two groups.. An intensive care unit and research ward in a university hospital.. The study population included 12 patients with septic shock or severe sepsis and a control group of six overall age-matched healthy volunteers.. To measure cefpirome penetration into the interstitial space fluid of skeletal muscle, we employed microdialysis after single intravenous administration of 2.0 g of cefpirome to patients and healthy volunteers.. Maximum concentration and area under the concentration vs. time values in interstitium were significantly lower in patients compared with the control group (p <.004). Cefpirome area under the concentration time values for plasma were 16.0 +/- 1.1 mg.min/mL (mean +/- sem) and 18.8 +/- 1.1 mg.min/mL in patients and healthy volunteers, respectively (p =.075, not significant). In both study groups, mean cefpirome concentrations in interstitium and plasma exceeded 28 microg/mL throughout the observation period of 240 mins and covered completely minimal inhibitory concentration values for a range of clinically relevant pathogens.. Cefpirome concentrations reached in tissue interstitium and plasma exceeded minimal inhibitory concentrations of most clinically relevant pathogens in patients with sepsis. Thus, cefpirome exhibits a tissue pharmacokinetic profile, which seems to be particularly valuable for the empirical therapy of patients with sepsis.

Topics: Aged; Aged, 80 and over; Cefpirome; Cephalosporins; Female; Humans; Male; Middle Aged; Prospective Studies; Sepsis; Tissue Distribution

To measure plasma levels and pharmacokinetics of cefpirome in critically ill septic patients with normal renal function. To use the pharmacokinetic model to simulate alternate dosing regimens and identify those that predict sustained levels.. A prospective, open-label, descriptive study in a 22-bed, multidisciplinary, adult ICU in a university-affiliated, tertiary referral hospital.. Twelve adults with normal renal function on enrollment and with suspected or documented sepsis in whom cefpirome was judged to be the appropriate therapy by the managing clinician.. Cefpirome 2 g was infused intravenously over 3 min every 12 h. Timed blood samples were taken prior to and during two dosing intervals. Urine was collected for creatinine clearance determination.. Two patients were non-evaluable due to renal dysfunction post-enrollment. The median cefpirome trough level was 1.1 mg/l (range 0.5-8.1 mg/l) after the initial dose and 1.4 mg/l (range < 0.5-15.9 mg/l) at 'steady state'. The volumes of distribution and elimination half-lives were greater and more variable than in healthy volunteers. Pharmacokinetic simulation predicted that more frequent bolus dosing, increased doses and continuous infusions would result in concentrations greater than 4 mg/l for over 60% of the dosing interval for all patients.. Cefpirome 2 g twice daily produced low plasma troughs in a number of patients. Our data suggest that this drug regimen may be inadequate for successful treatment of difficult-to-treat infections in critically ill patients with normal renal function.

Topics: Adult; Aged; APACHE; Area Under Curve; Cefpirome; Cephalosporins; Critical Illness; Female; Half-Life; Humans; Infusions, Intravenous; Intensive Care Units; Male; Middle Aged; Prospective Studies; Sepsis; Treatment Outcome

To study the cefpirome pharmacokinetics of patients with sepsis and multiple organ failure treated with CVVH.. Measurements of serum and ultrafiltrate (UF) concentrations and in vitro sensitivity testing of isolated micro-organisms.. University hospital-based, single ICU.. Six critically ill CVVH-dependent patients with sepsis and multiple organ dysfunction syndrome in need of antimicrobial therapy. Age range: 60-75 years; APACHE II score for severity of illness on admission: 19-30. One patient survived.. Cefpirome i.v. was started at 2 g in 30 min, then continued 1 g i.v.b.i.d.. The UF rate was 27 +/- 7 ml/min on day 1 and 34 +/- 2 ml/min on day 2. Serum and ultrafiltrate samples were measured by a validated high performance liquid chromatography assay. Volume of distribution: 23 x 5(SD +/- 4 x 6) l. Total cefpirome clearance was 32 +/- 6 x 3 ml/min; cefpirome CVVH clearance (ClCVVH): 17 +/- 4.2 ml/min; mean serum half-life (t1/2): 8.8 +/- 2.3 h; mass transfer on day 1: 660 +/- 123 mg/12 h (33 +/- 6% of administered dose) and day 2: 642 +/- 66 mg/12 h (64 +/- 7%). Estimated sieving coefficient (ClCVVH/UF rate): 64 +/- 11%. In vitro sensitivity of isolated microbes was excellent except for two non-sensitive enterococci and Candida spp.. The sieving coefficient (64%) indicates that a substantial fraction of the drug is not filtered; clearance by pathways other than CVVH mounted to 50% of the total clearance and increased on day 2, indicating that the dosing schedule used is appropriate for this setting. Cefpirome appeared to be safe in these patients and effective for most of the nosocomial microbial isolates. During more than 90% of the time, serum levels were maintained above killing concentrations for susceptible micro-organisms.

Topics: Aged; APACHE; Cefpirome; Cephalosporins; Critical Care; Female; Hemofiltration; Humans; Infusions, Intravenous; Male; Middle Aged; Multiple Organ Failure; Renal Insufficiency; Sepsis; Serum Bactericidal Test

In systemic and local infections, the therapeutic efficacy of cefpirome was compared to that of imipenem and cefotaxime. Murine septicemia induced with methicillin-sensitive and methicillin-resistant Staphylococcus aureus strains responded well to cefpirome and imipenem therapy, the ED50 values ranged from 0.8 to 28.40 mg/kg and 0.5 to 15.58 mg/kg, respectively. The carbapenem also displayed high efficacy against Enterococci and was more potent than cefpirome. Cefotaxime, however, exhibited lower activity or proved to be inactive against these strains. With ED50 values of 0.03 to 31.33 mg/kg, cefpirome was the most active of the three antibiotics in protecting mice challenged with Enterobacteriaceae. The corresponding ED50 values of imipenem and cefotaxime ranged from 0.72 to 70.95 mg/kg and 0.06 to 66.30 mg/kg, respectively. Despite distinctly lower in vitro activity against the infecting organism, cefpirome showed efficacy similar to imipenem in the treatment of subcutaneous S. aureus abscesses in mice. It was more effective than imipenem and cefotaxime against experimental Klebsiella pneumonia in mice and the Escherichia coli infected granuloma pouch in rats.

Topics: Abscess; Animals; Bacterial Infections; Cefotaxime; Cefpirome; Cephalosporins; Enterobacteriaceae Infections; Escherichia coli Infections; Female; Granuloma; Imipenem; Male; Mice; Mice, Hairless; Mice, Inbred C3H; Pneumonia; Rats; Rats, Inbred Strains; Sepsis; Staphylococcal Skin Infections; Staphylococcus aureus; Streptococcal Infections