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PubMed1993

International comparative study of cefepime and ceftazidime in the treatment of serious bacterial infections.

In this randomized multicentre study, we compared the safety and efficacy of cefepime, 2.0 g bd i.v., with that of ceftazidime, 2.0 g tid i.v., as initial treatment of adult patients with serious infections of bacterial aetiology. Three hundred and forty-eight patients were entered into the study, 173 received cefepime and 175 ceftazidime. The treatment groups were comparable with respect to demographic characteristics, including the types of infection (cefepime/ceftazidime: urinary tract, 55/72; lower respiratory tract, 83/74; skin and soft tissue, 23/14; septicaemia, 81/81; and others, 15/5). Gram-positive bacteria were identified as pathogens on 86 occasions (cefepime/ceftazidime: 48/41), including 20 Staphylococcus aureus isolates (13/7) and 27 Streptococcus pneumoniae isolates (14/13). Gram-negative bacilli were isolated on 261 occasions (126/135), and included 219 Enterobacteriaceae (cefepime/ceftazidime: 108/111) and 34 strains of Pseudomonas aeruginosa (14/20). An intention-to-treat analysis revealed satisfactory clinical response rates of 80% and 79% for the cefepime and ceftazidime groups, respectively, and bacteriological eradication rates of 85% and 88% for the cefepime and ceftazidime groups, respectively. Of patients with microbiologically documented infections, 86% (84 of 98) treated with cefepime and 87% (94 of 108) treated with ceftazidime responded satisfactorily. Thirty-two patients (19%) treated with cefepime and 26 (15%) treated with ceftazidime died. Thirty-six patients in the cefepime group and 23 in the ceftazidime group experienced adverse events; therapy was discontinued prematurely in four and two patients in the cefepime and ceftazidime groups, respectively. Of the patients experiencing adverse events, 22 (13%) treated with cefepime developed intolerance at the injection site, compared with 11 (6%) treated with ceftazidime (P = 0.045). In conclusion, twice-daily cefepime (2 g bd) is at least as effective as ceftazidime (2 g tid), as initial empirical therapy for serious bacterial infections in non-neutropenic patients.

Adolescent↗
PubMed2002

Cefepime plus amikacin versus piperacillin-tazobactam plus amikacin for initial antibiotic therapy in haematology patients with febrile neutropenia: results of an open, randomized, multicentre trial.

BACKGROUND: Standard therapy for suspected infections in patients with profound neutropenia is the combination of a beta-lactam antibiotic plus an aminoglycoside. Cefepime's broad-spectrum activity makes it an option for initial empirical therapy in neutropenic patients. The aim of this study is to evaluate the efficacy and safety of cefepime plus amikacin compared with piperacillin-tazobactam plus amikacin for initial empirical treatment of fever in adult haematology patients with severe neutropenia. METHODS: In this prospective multicentre trial, 969 patients with 984 febrile neutropenic episodes were randomized to receive iv amikacin (20 mg/kg every 24 h) combined with either cefepime (2 g every 8 h) or piperacillin-tazobactam (4 g/500 mg every 6 h). Clinical response was determined at 72 h and at completion of therapy. RESULTS: Eight hundred and sixty-seven episodes were assessable for efficacy (432 cefepime, 435 piperacillin-tazobactam). The frequency of success without modification of the empirical therapy was nearly identical for cefepime plus amikacin (49%) compared with piperacillin-tazobactam plus amikacin (51%). Similar rates of success were found for microbiologically documented infection: 40% versus 39%, respectively. Antibiotic modification was necessary in 49% of cefepime and 44% of piperacillin-tazobactam patients. The overall response rate, with or without modification of the assigned treatment, was 94% in both groups. Drug-related adverse events were reported in 10% of cefepime plus amikacin versus 11% of piperacillin-tazobactam plus amikacin patients. Mortality due to infection occurred in a total of 10 patients (two cefepime, eight piperacillin-tazobactam). CONCLUSION: The empirical regimen of cefepime plus amikacin is equivalent to piperacillin-tazobactam plus amikacin in febrile adult haematology patients with severe neutropenia. KEYWORDS: cefepime, piperacillin-tazobactam, amikacin, empirical antibiotic therapy, febrile neutropenia, haematological malignancy

Adult↗
PubMed1989

Activity of cefepime against ceftazidime- and cefotaxime-resistant gram-negative bacteria and its relationship to beta-lactamase levels.

One hundred clinical isolates resistant to ceftazidime and/or cefotaxime were examined for susceptibility to cefepime. The most frequently encountered ceftazidime-cefotaxime-resistant strains belonged to the genera Enterobacter, Pseudomonas, and Citrobacter. Among these strains, 92% were resistant to cefoperazone, 91% were resistant to cefotaxime, 84% were resistant to ceftazidime, and 6% were resistant to cefepime. Of the members of the family Enterobacteriaceae, 57% were resistant to ceftriaxone. The six strains resistant to cefepime were all Pseudomonas aeruginosa and were resistant to both cefotaxime and ceftazidime. Cefepime-resistant P. aeruginosa strains had exceptionally high levels of beta-lactamase activity, higher than the levels found in strains resistant to ceftazidime but susceptible to cefepime. The beta-lactamases from the cefepime-resistant strains were type I (Richmond-Sykes), were constitutively produced, and did not have increased affinity or hydrolytic activity for cefepime. Thus, cefepime was active against most gram-negative bacteria which have developed resistance to the broad-spectrum cephalosporins, and resistance to cefepime in P. aeruginosa appears to be associated with higher beta-lactamase levels than in cefepime-susceptible strains.

Bacterial Infections↗
PubMed1997

Pharmacokinetics of intravenously and intramuscularly administered cefepime in infants and children.

The pharmacokinetic characteristics of cefepime were determined after first dose (n = 35) and again under steady-state conditions (n = 31) with a group of 37 infants and children. In eight subjects, a cefepime dose given by intramuscular injection was substituted for an intravenous dose, and disposition characteristics were studied again. Study subjects ranged in age from 2.1 months to 16.4 years, and all had normal renal function. Each patient received 50 mg of cefepime/kg of body weight intravenously every 8 h, up to a total maximum individual dose of 2 g. With the exception of one study patient who received a single cefepime dose for surgical prophylaxis, the patients received cefepime for 2 to 13 days. Elimination half-life (t1/2), steady-state volume of distribution, total body clearance, and renal clearance after first dose administration averaged 1.7 h, 0.35 liter/kg, and 3.1 and 1.9 ml/min/kg, respectively. Although cefepime t1/2 and mean residence time (MRT) were slightly longer for subjects <6 months of age than for older subjects, no differences in cefepime disposition characteristics between first dose and steady-state evaluations were observed. t1/2 (1.8 versus 1.9 h) and MRT (2.3 versus 3.2 h) were slightly prolonged after intramuscular administration, reflecting the influence of absorption from the intramuscular injection site on cefepime elimination. Bioavailability after intramuscular administration averaged 82% (range, 61 to 124%). Fifty-seven percent of the first dose and 88.9% of the last dose were recovered as unchanged drug in urine over the 8- and 24-h sampling periods, respectively. These pharmacokinetic data support a single cefepime dosing strategy for patients > or =2 months of age. The integration of the cefepime pharmacokinetic data generated in our study with the MICs for important pathogens responsible for infections in infants and children supports the administration of a dose of 50 mg of cefepime/kg every 12 h for patients > or =2 months of age to treat infections caused by pathogens for which cefepime MICs are < or =8 mg/liter.

Adolescent↗
PubMed2002

A multicenter comparative study of cefepime versus broad-spectrum antibacterial therapy in moderate and severe bacterial infections.

The safety and efficacy of cefepime empiric monotherapy compared with standard broad-spectrum combination therapy for hospitalized adult patients with moderate to severe community-acquired bacterial infections were evaluated. In an open-label, multicenter study, 317 patients with an Acute Physiology and Chronic Health Evaluation (APACHE II) score ranging from >5 to =19 were enrolled with documented pneumonia (n=196), urinary tract infection (n=65), intra-abdominal infection (n=38), or sepsis (n=18). Patients were randomly assigned 1:1 to receive cefepime 1 to 2 g IV twice daily or three times a day or IV ampicillin, cephalothin, or ceftriaxone +/-aminoglycoside therapy for 3 to 21 days. For both treatment groups, metronidazole, vancomycin, or macrolide therapy was added as deemed necessary. The primary efficacy variable was clinical response at the end of therapy. Two hundred ninety-six (93%) patients met evaluation criteria and were included in the efficacy analysis. Diagnoses included the following: 180 pneumonias (90 cefepime, 90 comparator), 62 urinary tract infections (29 cefepime, 33 comparator), 37 intra-abdominal infections (19 cefepime, 18 comparator), and 17 sepses (8 cefepime, 9 comparator). At the end of therapy, overall clinical success rates were 131/146 (90%) for patients treated with cefepime vs 125/150 (83%) for those treated with comparator (95% confidence interval [CI]: -2.6% to 16.3%). The clinical success rate for patients with community-acquired pneumonia, the most frequent infection, was 86% for both treatment groups. Among the patients clinically evaluated, 162 pathogens were isolated and identified before therapy. The most commonly isolated pathogens were Escherichia coli (n=49), Streptococcus pneumoniae (n=29), Haemophilus influenzae (n=14), and Staphylococcus aureus (n=11). Bacteriologic eradication/presumed eradication was 97% for cefepime vs 94% for comparator-treated patients. Drug-related adverse events were reported in 16% of cefepime patients and 19% of comparator patients. In conclusion, cefepime had higher cure rates compared with broad-spectrum combination therapy as an initial empiric treatment for hospitalized patients with moderate to severe community-acquired infections, including urinary tract infections, intra-abdominal infections, and sepsis.

Abdominal Abscess↗
PubMedDate not supplied

Disposition of the cephalosporin cefepime in normal and renally impaired subjects.

The metabolism and disposition of an iv-administered, 1000 mg (100 microCi) single dose of the 14C-labeled cephalosporin cefepime was studied in healthy and renally impaired male volunteers. The 14C-label was located in the methyl group of the N-methyl pyrrolidine (NMP) moiety at the 3'-position of cefepime. Concentrations of cefepime and its metabolites were determined in plasma and urine as a function of time after drug administration. Cefepime comprised 95 and 76% of the total plasma radioactivity in subjects with normal and impaired renal functions, respectively. The elimination half-life of cefepime was 2 hr in normal volunteers and increased to 4 and 12 hr in subjects with moderate and severe renal impairment, respectively. Steady-state volume of distribution was about 18 liters and was independent of the degree of renal impairment. Cefepime was primarily excreted unchanged in the urine of normal subjects, as 87.9% of the total recovered radioactivity. The major cefepime metabolites, NMP N-oxide, the 7-epimer of cefepime and NMP, constituted 6.8, 2.5, and less than 1% of the total radioactivity excreted in urine, respectively. As the severity of renal impairment increased, the proportion of radioactivity recovered in urine as cefepime decreased and that of NMP-N-oxide increased. Our results indicate that cefepime undergoes minimal metabolism and is excreted primarily as unchanged drug in urine in humans with normal kidney functions.

Adult↗
PubMed2003

Cefepime versus imipenem-cilastatin for treatment of nosocomial pneumonia in intensive care unit patients: a multicenter, evaluator-blind, prospective, randomized study.

In a randomized, evaluator-blind, multicenter trial, we compared cefepime (2 g three times a day) with imipenem-cilastatin (500 mg four times a day) for the treatment of nosocomial pneumonia in 281 intensive care unit patients from 13 centers in six European countries. Of 209 patients eligible for per-protocol analysis of efficacy, favorable clinical responses were achieved in 76 of 108 (70%) patients treated with cefepime and 75 of 101 (74%) patients treated with imipenem-cilastatin. The 95% confidence interval (CI) for the difference between these response rates (-16 to 8%) failed to exclude the predefined lower limit for noninferiority of -15%. In addition, therapy of pneumonia caused by an organism producing an extended-spectrum beta-lactamase (ESBL) failed in 4 of 13 patients in the cefepime group but in none of 10 patients in the imipenem group. However, the clinical efficacies of both treatments appeared to be similar in a secondary intent-to-treat analysis (95% CI for difference, -9 to 14%) and a multivariate analysis (95% CI for odds ratio, 0.47 to 1.75). Furthermore, the all-cause 30-day mortality rates were 28 of 108 (26%) patients in the cefepime group and 19 of 101 (19%) patients in the imipenem group (P = 0.25). Rates of documented or presumed microbiological eradication of the causative organism were similar with cefepime (61%) and imipenem-cilastatin (54%) (95% CI, -23 to 8%). Primary or secondary resistance of Pseudomonas aeruginosa was detected in 19% of the patients treated with cefepime and 44% of the patients treated with imipenem-cilastatin (P = 0.05). Adverse events were reported in 71 of 138 (51%) and 62 of 141 (44%) patients eligible for safety analysis in the cefepime and imipenem groups, respectively (P = 0.23). Although the primary end point for this study does not exclude the possibility that cefepime was inferior to imipenem, some secondary analyses showed that the two regimens had comparable clinical and microbiological efficacies. Cefepime appeared to be less active against organisms producing an ESBL, but primary and secondary resistance to imipenem was more common for P. aeruginosa. Selection of a single agent for therapy of nosocomial pneumonia should be guided by local resistance patterns.

APACHE↗
PubMed2006

Acute-phase response alters the disposition kinetics of cefepime following intravenous administration to rabbits.

The effect of experimentally induced fever on the pharmacokinetics of cefepime administered intravenously at a dose of 75 mg/kg bw was studied in six healthy rabbits. The study was conducted in two consecutive phases, separated by a washout period of 2 weeks. Infection was induced by the intravenous inoculation of 5 x 10(8) cfu of Escherichia coli 24 h before the pharmacokinetic investigation was carried out. Serial blood samples for cefepime concentration determination were obtained for 48 h following drug administration. The concentrations of cefepime in the plasma were determined by a quantitative microbiological assay using an agar-gel diffusion method employing Bacillus subtilis ATCC 6633 as the test organism, with a level of detectability of approximately 0.10 microg/ml. Cefepime plasma concentrations versus time were evaluated by non-compartmental methods using WinNonLin. Cefepime was well tolerated and no serious adverse events were observed. Rectal temperature increased 1 degree C 24 h post injection in infected animals. Highly significant differences in the blood plasma concentrations of cefepime were observed between febrile and healthy animals at all the sampling times. This could explain the greater area under the plasma level-time curve of the drug in febrile compared with healthy animals. The results from pharmacokinetic calculations showed that both the distribution volume at steady state (V (dss)) and body clearance (CL(tot)) were affected in febrile as compared to healthy animals. The mean values of V (dss) and CL(tot) of cefepime in healthy rabbits were 1.168 L/kg and 0.303 L/kg/h, respectively. As compared with healthy animals, the mean estimates of V (dss) (0.917 L/kg) and CL(tot) (0.205 L/kg per h) of cefepime were significantly lower, whereas t (1/2lambda), MRT and AUMC were significantly higher in febrile rabbits. It is concluded that, although experimental infection had an effect on the disposition kinetics of cefepime in healthy and febrile rabbits, this was not sufficiently pronounced to require alteration of the dosage during disease.

Acute-Phase Reaction↗
PubMed2005

Cefepime and continuous renal replacement therapy (CRRT): in vitro permeability of two CRRT membranes and pharmacokinetics in four critically ill patients.

BACKGROUND: Cefepime is a fourth-generation cephalosporin with a broad spectrum of antimicrobial activity against gram-positive and gram-negative micro-organisms. It is a useful option for treating infections in critically ill patients in intensive care due to its high degree of activity and its tolerability. OBJECTIVE: The aim of this study was to characterize in vitro the permeability to cefepime of 2 membranes frequently used in continuous renal replacement therapies (CRRTs). An in vivo study was also carried out to determine the pharmacokinetics of cefepime in critically ill patients undergoing CRRT. METHODS: In vitro procedures were conducted in 3 different fluids using polyacrylonitrile (AN69) or polysulfone (PS) membranes. Continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodialysis (CVVHD) were simulated. Four male patients undergoing CVVH or continuous venovenous hemodiafiltration, who received 2000 mg of cefepime intravenously every 8 hours, entered the in vivo study. Prefilter and ultrafiltrate samples were collected, and concentrations of cefepime were measured using high-performance liquid chromatography. The sieving coefficient (Sc), defined as the fraction of drug eliminated across the membrane, and the saturation coefficient (Sa), defined as the fraction of drug diffused through the membrane to the dialysate fluid, were analyzed. Pharmacokinetic parameters were determined according to a noncompartmental analysis. RESULTS: The patients ranged in age from 18 to 75 years and weighed from 65 to 80 kg. By analyzing Sc and Sa values in the in vitro procedures, no differences were detected in the permeability of AN69 or PS membranes to cefepime in CVVH or CVVHD. Sc/Sa values were between 0.93 and 1.03 in Ringer's lactate and in bovine albumin-containing Ringer's lactate samples, but Sc/Sa values were lower in plasma samples (0.82-0.95). In the in vivo portion of the study, the patients' mean (SD) Sc/Sa value was 0.76 (0.21) and correlated well with the fraction unbound to proteins (0.79 [0.09]). Clearance by CRRT (mean [SD]) was 29.0 (16.8)% of the total clearance. Serum elimination t(1/2) was 4.6 (0.9) hours, and the volume of distribution at steady state was 0.6 (0.3) L/kg (mean [SD] values). CONCLUSIONS: Cefepime was significantly removed by CRRT. No significant differences were found in the Sc or Sa of cefepime between AN69 and PS membranes used in the CVVH or CVVHD procedures. The clearance of cefepime by CRRT must be considered when dosing critically ill patients.

Acrylic Resins↗
PubMed2005

Potency and spectrum trends for cefepime tested against 65746 clinical bacterial isolates collected in North American medical centers: results from the SENTRY Antimicrobial Surveillance Program (1998-2003).

We evaluated the antimicrobial spectrum and potency of cefepime and selected comparators agents against clinical bacterial strains collected in North America over a 6-year period (1998-2003). Isolates were consecutively collected from bloodstream (44%), respiratory tract (41%), urinary tract (6%), and skin/soft tissue (5%) infections in 48 medical centers. Isolates were susceptibility tested by reference broth microdilution methods in a central laboratory. Oxacillin-resistant staphylococci and enterococci were excluded from the analysis. Imipenem (MIC90 = 1 microg/mL, 99.9% susceptible) was the most active compound tested against Enterobacteriaceae (22860 isolates tested) followed by cefepime (MIC90 = 0.25 microg/mL, 99.5% susceptible) > amikacin (99.4% susceptible) > ceftriaxone (95.6% susceptible) > aztreonam (95.1% susceptible). Among comparators, the lowest susceptibility rate for Enterobacteriaceae was observed with ciprofloxacin (92.8% susceptible). Imipenem was also the most active compound against ESBL-producing Klebsiella spp. and Escherichia coli (99.3% and 100% susceptible, respectively), followed by amikacin (81.4% and 97.2% susceptible, respectively) and cefepime (92.5% and 93.8% susceptible, respectively). Cefepime activity against Pseudomonas aeruginosa (85.2% susceptible) was similar to that of imipenem (86.9% susceptible). Against oxacillin-susceptible Staphylococcus aureus, cefepime (MIC90 = 4 microg/mL, 100.0% susceptible) was 4-fold more active than ceftazidime (MIC90 = 16 microg/mL, 86.4% susceptible) and showed a higher susceptibility rate than ciprofloxacin (93.2% susceptible). Cefepime was the most active compound tested against Streptococcus pneumoniae (MIC90 = 1 microg/mL, 97.4% susceptible), ranked after gatifloxacin and levofloxacin (99.2% susceptible). The activity of cefepime remained stable during the study period evaluated with the susceptibility rates varying from 99.3% to 99.8% among the Enterobacteriaceae and 84.4% to 88.4% among P. aeruginosa isolates. In summary, cefepime has retained broad activity and spectrum against Enterobacteriaceae, P. aeruginosa, and Gram-positive cocci (except oxacillin-resistant staphylococci and enterococci) isolated from North American medical centers in the 1998-2003 period. Continued resistance surveillance is critical to monitor the effectiveness of widely used parenteral antimicrobial agents such as cefepime.

Anti-Bacterial Agents↗
PubMed2003

Serum bactericidal activity of trovafloxacin, in combination with cefepime or amikacin, in healthy volunteers.

OBJECTIVE: To investigate the phamacokinetics and serum bactericidal activities (SBAs) of trovafloxacin, cefepime and amikacin alone and trovafloxacin in combination with cefepime or amikacin, so that the most favorable combination with trovafloxacin can be determined. METHODS: In this open, randomized, crossover study, 12 healthy volunteers (six females, six males; mean age +/- SD, 25.1 +/- 2.6 years) received an infusion of either 300 mg of alatrovafloxacin or 2000 mg of cefepime or 6 mg/kg body weight amikacin alone, or 300 mg of alatrovafloxacin plus 2000 mg of cefepime or plus 6 mg/kg body weight amikacin. The SBAs against Pseudomonas aeruginosa, Staphylococcus aureus (11 strains each), Citrobacter freundii and Acinetobacter spp. (10 strains each) 1, 10 and 24 h after drug administration were measured by a standard microdilution method. Concentrations of trovafloxacin, cefepime and amikacin in serum and urine were analyzed before and up to 10 and 12 h, respectively, after drug infusion. RESULTS: Significant synergistic effects on SBA were observed with the combination of trovafloxacin and cefepime against P. aeruginosa, S. aureus and Acinetobacter spp. 1 h after drug administration, and against Citrobacter freundii 1, 10 and 24 h after drug administration. The combination of trovafloxacin and amikacin showed significant synergistic effects against P. aeruginosa, S. aureus and C. freundii 1 h after drug administration. The combination of trovafloxacin and cefepime was, in general, more active than the combination of trovafloxacin and amikacin. No significant differences in the serum concentrations of trovafloxacin were observed between single and combined administration. However, the maximal concentration of cefepime was significantly lower when it was used in combination with trovafloxacin. CONCLUSION: Our study suggests a favorable interaction between trovafloxacin and cefepime. This combination showed more synergistic bactericidal activity against most of the test strains compared to the combination of trovafloxacin and amikacin. However, for P. aeruginosa, the bactericidal activity of cepefime alone was higher than that of the combination with trovafloxacin.

Adult↗
PubMed1993

In-vitro antibacterial activity of cefepime: a multicentre study.

The antimicrobial activity of cefepime, a new broad-spectrum parenteral cephalosporin, was evaluated in vitro against 1757 recent clinical Gram-positive and Gram-negative isolates. Cefepime was active at low concentrations (MIC50 values < or = 0.06 mg/L and MIC90 values < or = 0.12 mg/L) against non-cephalosporinase-producing Enterobacteriaceae (Escherichia coli, Proteus mirabilis, Salmonella spp. and Shigella spp.). For Klebsiella pneumoniae, MICs were between 0.016 and 16 mg/L; the highest MIC values were observed for extended-spectrum beta-lactamase-producing strains. Against Enterobacteriaceae, such as cephalosporinase producing Enterobacter cloacae, MICs were < or = 0.5 mg/L, but MICs against cephalosporinase hyperproducing strains were generally higher. Ticarcillin-sensitive strains of Pseudomonas aeruginosa were inhibited by cefepime concentrations of 0.5-16 mg/L, while cefepime MICs were 8-64 mg/L for strains resistant to ticarcillin. The cefepime MIC50 value for Haemophilus spp. including many resistant to amoxycillin, was 0.03 mg/L. Against methicillin-sensitive strains of Staphylococcus aureus, cefepime MICs were 0.5-16 mg/L; MICs against methicillin-resistant staphylococci were 16- > 128 mg/L). Against methicillin-sensitive coagulase-negative staphylococci, cefepime MIC values were 0.03-16 mg/L; corresponding values for methicillin-resistant strains were 2-128 mg/L. Streptococci (Groups A, C and G) were sensitive to cefepime with MICs ranging from < or = 0.008-2 mg/L (MIC50, 0.03 mg/L; MIC90, 0.25 mg/L). The activity of cefepime against Group B streptococci and pneumococci were comparable, with MIC50 values of 0.12 and 0.25 mg/L, respectively, and MIC90 values of 0.03 and 0.25 mg/L, respectively. Most enterococci and all Listeria monocytogenes strains had MICs > or = 32 mg/L.(ABSTRACT TRUNCATED AT 250 WORDS)

Bacteria↗
PubMed2003

Cefepime use in a pediatric intensive care unit reduces colonization with resistant bacilli.

BACKGROUND: Cefepime has activity against many hospital-acquired Gram-negative pathogens resistant to earlier beta-lactam antibiotics. This study was designed to test whether preferential use of cefepime in a pediatric intensive care unit could reduce enteric colonization with antibiotic-resistant Gram-negative rods. METHODS: After a 6-month period of uncontrolled antibiotic use, cefepime was preferentially used during 2 years as treatment for nosocomial or serious community-acquired infection. Rectal swab specimens were obtained daily on every patient regardless of antibiotic exposure during the 6 months of uncontrolled antibiotic use and during the first and last 6 months of the 2 years of cefepime preference. The study outcome was rectal colonization with a facultative Gram-negative rod resistant to at least one of four antibiotics: cefepime; ceftazidime; gentamicin; or piperacillin-tazobactam. RESULTS: The incidence of colonization by a resistant organism decreased only slightly during the first 6 months of cefepime use. By contrast, the number of antibiotic-resistant bacilli isolated from rectal swab specimens diminished from 27.6/100 patients during the baseline period to 12.9/100 patients by the last 6 months of the 2 years of cefepime preference (P < 0.01). The proportion of patients harboring at least one resistant organism decreased from 11.6% to 7.4% during the same time period (P < 0.01). A decrease in colonization with resistant organisms occurred for all the tested resistance phenotypes, including cefepime. CONCLUSION: Cefepime may possess a low potential for promoting bacillary resistance in critically ill patients, suggesting that its preferential use might be a key element in limiting the presence of antibiotic resistance in the intensive care unit.

Anti-Bacterial Agents↗
PubMed1992

Pharmacokinetics of cefepime after single and multiple intravenous administrations in healthy subjects.

The pharmacokinetics of cefepime in 31 young, healthy volunteers were assessed after the administration of single and multiple 250-, 500-, 1,000-, or 2,000-mg intravenous doses. Each subject received a single dose of cefepime via a 30-min intravenous infusion on day 1 of the study. Starting from day 2, subjects received multiple doses of cefepime every 8 h for 9 days, and on the morning of day 11, they received the last dose. Serial blood and urine samples were collected after administration of the first dose and on days 1, 6, and 11. Cefepime concentrations in plasma and urine were assayed by using reverse-phase high-performance liquid chromatography with UV detection. Data were evaluated by noncompartmental methods to determine pharmacokinetic parameters. The mean half-life of cefepime was approximately 2 h and did not vary with the dose or duration of dosing. The regression analyses of peak levels (Cmax) in plasma at the end of the 30-min intravenous infusion and the area under the plasma concentration-versus-time curve (AUCo-infinity) showed a dose-proportional response. The steady-state volume of distribution (Vss) was approximately 18 liters and was independent of the administered dose. The multiple-dose pharmacokinetic data are suggestive of a lack of accumulation or change in clearance of cefepime on repeated dosing. Cefepime was excreted primarily unchanged in urine. The recovery of intact cefepime in urine was invariant with respect to the dose and accounted for over 80% of the dose. The values for renal clearance ranged from 99 to 132 ml/min and were suggestive of glomerular filtration as the primary excretion mechanism. It is concluded that cefepime linear pharmacokinetics in healthy subjects.

Adult↗
PubMed1996

Uptake of cefepime by phagocytosing polymorphonuclear neutrophils and subsequent intracellular killing.

Studies of the uptake of beta-lactam antibiotics indicate that they do not accumulate in phagocytic cells. Uptake of beta-lactams is thought to occur through passive diffusion, and this is limited because of their acidic nature. Many studies of antibiotic uptake have utilized either resting phagocytic cells or cells in their postphagocytic phase. We have examined the uptake of cefepime by actively phagocytosing neutrophils under various conditions of neutrophil stimulation in order to determine cefepime intracellular activity against Escherichia coli and Staphylococcus aureus. Exposure of cefepime increased bactericidal activity against E. coli both when bacteria were added during exposure to the antibiotic and when they were added to the neutrophils in the postantibiotic phase. Antibacterial activity was only partially inhibited by phenylbutazone, and an exposure of 4 min to cefepime is sufficient for optimal intracellular activity. Under the same conditions, cefepime-associated killing of S. aureus was not as great as was observed for E. coli. Quantitation of intracellular cefepime showed that neutrophil activation in opsonizing conditions increased the antibiotic concentration by 75 (E. coli) and 55% (S. aureus). The response of neutrophils to the combination of serum, E. coli, and cefepime indicates a significant increase in the chemiluminescence response, compared with the response obtained with bacteria in the absence of cefepime. These data indicate that cefepime rapidly enters phagocytic cells under opsonizing conditions with concomitant increases in oxidative metabolism and intracellular activity against E. coli.

Cefepime↗
PubMed2004

Determination of the in vivo pharmacodynamic profile of cefepime against extended-spectrum-beta-lactamase-producing Escherichia coli at various inocula.

Cefepime was evaluated in vivo against two inoculum sizes of four strains of Escherichia coli that produced extended-spectrum beta-lactamases (ESBLs) in a murine neutropenic thigh infection model to characterize the pharmacodynamic activity of cefepime in the presence of ESBL-producing bacteria and to evaluate if differences in lengths of cefepime exposure are required with various inocula. Three strains possessed a single enzyme each: TEM-10, TEM-12, and TEM-26. The fourth strain possessed two TEM-derived ESBLs and a third uncharacterized enzyme. Two non-ESBL-producing E. coli strains were included for comparison. Mice received various doses of cefepime to achieve a spectrum of percentages of time the drug was above the MIC (%T>MICs) for each isolate at both inocula. No significant difference in cefepime exposure was required to achieve similar bactericidal effects for ESBL- and non-ESBL-producing isolates when the starting inoculum was 10(5) CFU of E. coli per thigh. The increased MICs observed in vitro for the ESBL-producing strains at 10(7) CFU/ml did not predict the amount of exposure required to achieve a comparable level of bactericidal activity in vivo at the corresponding starting inoculum of 10(7) CFU/thigh. Compared to the cefepime exposure in tests with the lower inoculum (10(5) CFU/thigh), less exposure was required when the starting inoculum was 10(7) CFU/thigh (%T>MIC, 6% versus 26%), such that similar doses (in milligrams per kilogram of body weight) produced similar bactericidal effects with both inocula of ESBL-producing isolates. Equivalent exposures of cefepime produced similar effects against the microorganisms regardless of the presence of ESBL production. Pharmacodynamic profiling undertaken with conventional cefepime MIC determinations predicted in vivo microbial outcomes at both inoculum sizes for the ESBL-producing isolates evaluated in this study. These data support the use of conventional MIC determinations in the pharmacodynamic assessment of cefepime.

Animals↗
PubMedDate not supplied

Intravitreal penetration of cefepime after systemic administration to humans.

PURPOSE: To investigate the penetration of cefepime (a fourth-generation cephalosporin) into the vitreous after single-dose intravenous administration to human subjects. METHODS: Thirty phakic patients about to undergo vitreous surgery received 1 g (group 1, 15 patients) or 2 g cefepime (group 2, 15 patients) in a single intravenous injection before surgery. The indications for vitreous surgery were retinal detachment with proliferative vitreoretinopathy (24 patients), retinal detachment associated with giant retinal tear (4 patients), macular hole (1 patient) and intraocular foreign body (1 patient). Samples of vitreous and serum were obtained at 0.5, 1, 2, 4 and 12 h after injection. Three patients were used for each sampling time and for 1 g and 2 g of cefepime. Samples were assayed for cefepime concentrations with high-performance liquid chromatography (HPLC). RESULTS: All the patients had detectable cefepime in their vitreous and serum measurable by HPLC. The level of cefepime in the vitreous peaked at 2 h and reached a minimum at 12 h after intravenous injection in both groups. A mean peak vitreous level of cefepime was 1.91 +/- 0.13 microg/ml in group 1 and 2.86 +/- 0.37 microg/ml in group 2. The level of cefepime in the vitreous at 12 h after injection was 0.89 +/- 0.14 microg/ml in group 1 and 0.97 +/- 0.30 microg/ml in group 2. CONCLUSION: The vitreous level of cefepime after intravenous injection was below the minimum inhibitory concentration (MIC(90)) against Staphylococcus aureus, Staphylococcus epidermidis and Pseudomonas aeruginosa, but was over the MIC(90) against Proteus mirabilis, Klebsiella spp., Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus pyogenes and Enterobacter spp.

Adult↗
PubMed2004

Comparison of 99mTc-DTPA and urea for measuring cefepime concentrations in epithelial lining fluid.

The efficacy of antimicrobial agents against pulmonary infections depends on their local concentrations in the lung. The aims of the present study were to: 1) compare technetium-99m diethylenetriaminepenta-acetic acid (99mTc-DTPA) and urea as markers of epithelial lining fluid (ELF) dilution for measuring ELF concentrations of pharmaceuticals; 2) quantify ELF cefepime concentrations in normal and injured lung; and 3) measure the increase in permeability to cefepime following oleic acid-induced acute lung injury. A modified bronchoalveolar lavage technique, based on equilibration of infused 99mTc-DTPA, was used to measure ELF volume. Cefepime was administered intravenously at steady plasma levels. Six serial bronchoalveolar lavages were performed 5 h after the beginning of infusion. ELF to plasma cefepime concentration ratios were 95 +/- 17 and 100 +/- 14.5% in normal and injured lung respectively. When urea was used as marker, cefepime concentration ratios were underestimated at 16.4 +/- 2.7 and 73.9 +/- 8.4% respectively. Cefepime blood/ airspace clearance increased from 3.8 +/- 0.7 micro x min(-1) in controls to 39.8 +/- 4.9 microL x min(-1) in acute lung injury. It was concluded that: 1) cefepime concentrations in epithelial lining fluid were in equilibrium with those in plasma in both normal and injured lung after 5 h at steady plasma concentrations; 2) epithelial lining fluid cefepime concentration by the urea method was much less underestimated in injured versus normal lung; and 3) acute lung injury induces a 10-fold elevation of cefepime blood/airspace clearance.

Analysis of Variance↗