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     

Treatment of community-acquired pneumonia in the elderly: the role of cefepime, a fourth-generation cephalosporin.

In a prospective, multicentre double-blind trial, 151 patients over the age of 65 years were randomly assigned to receive either cefepime 2 g every 12 h for a minimum of 3 days and up to 14 days or ceftriaxone 1 g every 12 h for a minimum of 3 days and up to 14 days. Antibiotics were maintained until 48 h after fever had resolved; no other antibiotics were permitted. The average age in each group exceeded 77 years and significant co-morbidity was found in the majority of patients. The mean total duration of therapy was 5.8+/-2.4 days for the cefepime group and 6.7+/-2.7 days for the ceftriaxone group (P = 0.06). The clinical success rate at the end of therapy was 79.1% with cefepime and 75.4% with ceftriaxone (P = 0.62). At the end of follow-up, 91.7% of the cefepime-treated patients and 86.5% of the ceftriaxone patients had a satisfactory clinical response (P = 0.38). In 35 bacteriological evaluable patients, potential pathogens were eradicated in all but one patient receiving cefepime. Seven patients in each group died during the study period but in each case the death was unrelated to study drug. The commonest side-effect was diarrhoea (cefepime, five patients; ceftriaxone, two patients). The clinical and microbiological efficacy of cefepime is similar to that of ceftriaxone in elderly patients with community-acquired pneumonia requiring hospitalization. Cefepime is an appropriate choice for the treatment of community-acquired respiratory tract infections in the elderly.     

Prospective study of empiric monotherapy with ceftazidime for low-risk grade IV febrile neutropenia after cytotoxic chemotherapy in cancer patients

PURPOSE: It was the aim of this study to evaluate the results of a prospective study in a single medical center using ceftazidime monotherapy in cancer patients with chemotherapy-induced grade IV febrile neutropenia and a low risk for gram-negative bacteremia. SUBJECTS AND METHODS: Thirty-eight patients were admitted with low-risk grade IV febrile neutropenia after chemotherapy for solid tumors. The median patient age was 57 years (range 18-74). Sixteen patients (42%) developed febrile neutropenia after the first cycle of current chemotherapy line, 9 patients (24%) received 2-3 cycles and 13 patients (34%) received more than 3 chemotherapy cycles before manifesting febrile neutropenia. Five patients were treated with prophylactic granulocyte colony-stimulating factor commenced 24 h after completion of the chemotherapy cycle. Empiric monotherapy with intravenous ceftazidime was started on admission and administered 2 g every 8 h. RESULTS: The mean polymorphic nuclear cell count on admission was 231 cells/mm(3). Ceftazidime therapy was well tolerated. Twenty-five (66%) patients responded with clinical improvement and complete resolution of fever within 48 h after initiation of ceftazidime therapy. Thirty-two (84%) patients were afebrile after 72 h of therapy. Thirty-three patients (87%) remained on unmodified ceftazidime therapy throughout their hospitalization. Five patients (13%) subsequently required modification of the treatment regimen for various reasons. Mean duration of fever and neutropenia were 2 (1-10) days and 4 (1-11) days, respectively. None of the patients discontinued therapy because of adverse effects. No positive blood cultures were obtained. No events of septic shock were observed. Mean duration of hospitalization was 6 days (range 3-12). CONCLUSION: In our series, monotherapy with intravenous ceftazidime appears safe and effective in cancer patients with low-risk grade IV febrile neutropenia after cytotoxic chemotherapy and may appreciably reduce antibiotics costs.     

A comparative study of cefepime versus ceftazidime as empiric therapy of febrile episodes in neutropenic patients.

An open-label, randomized comparative study was conducted to evaluate the efficacy and safety of cefepime (2.0 g q. 8 h) and ceftazidime (2.0 g q. 8 h) in the empiric therapy of febrile neutropenic patients. A total of 45 eligible febrile episodes were randomized (1:1) to be treated with the study regimen. Nineteen febrile episodes treated with cefepime and 22 febrile episodes treated with ceftazidime were evaluable for efficacy. The two groups were comparable in terms of age, sex, height, weight, underlying neoplasm, number of pretherapy neutrophil, duration of neutropenia and types of infections. The overall therapeutic success rate of the cefepime group (53%) was comparable to the ceftazidime group (50%). It did not differ significantly (95% confidence interval: -0.28 to 0. 34, p = 0.85). Eighty-eight percent of pathogens in each group were bacteriologically eradicated. The safety profile was similar in both groups. No patients in either group discontinued the therapy because of adverse events. None (0%) of the cefepime patients and 2 (9%) of the ceftazidime patients died of infection. The results of this study suggest that cefepime is an effective and safe agent in the empiric therapy of febrile episodes in neutropenic patients.     

Comparison of beta-lactam regimens for the treatment of gram-negative pulmonary infections in the intensive care unit based on pharmacokinetics/pharmacodynamics

OBJECTIVES: This study utilized pharmacokinetics/pharmacodynamics to compare beta-lactam regimens for the empirical and definitive treatment of gram-negative pulmonary infections in the ICU. METHODS: Susceptibility data were extracted from the 2002 Intensive Care Unit Surveillance System (ISS) and pharmacokinetic parameters were obtained from published human studies. Monte Carlo simulation was used to model the free percent time above the MIC (free %T > MIC) for 18 beta-lactam regimens against all gram-negative isolates, Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii. The cumulative fraction of response (CFR) was determined for bacteriostatic and bactericidal targets (free %T > MIC): penicillins (> or = 30/50%), cephalosporins/monobactams (> or = 40/70%) and carbapenems (> or = 20/40%). RESULTS: The 2002 ISS database contained MICs for 2408 gram-negative isolates including 1430 Enterobacteriaceae, 799 P. aeruginosa, and 179 A. baumannii. Imipenem had the highest percentage susceptible for all gram-negatives, Enterobacteriaceae and A. baumannii, while piperacillin/tazobactam had the highest percentage susceptible for P. aeruginosa. For empirical therapy, imipenem 0.5 g every 6 h, cefepime 2 g every 8 h and ceftazidime 2 g every 8 h demonstrated the highest CFR. For definitive therapy, imipenem 0.5 g every 6 h, ertapenem 1 g daily and cefepime 2 g every 8 h, cefepime 1 g every 8 h and cefepime 1 g every 12 h had the highest bactericidal CFR against Enterobacteriaceae; ceftazidime 2 g every 8 h, cefepime 2 g every 8 h, piperacillin/tazobactam 3.375 g every 4 h, ceftazidime 1 g every 8 h and aztreonam 1 g every 8 h against P. aeruginosa; and imipenem 0.5 g every 6 h, ticarcillin/clavulanate 3.1 g every 4 h, ceftazidime 2 g every 8 h, cefepime 2 g every 8 h and ticarcillin/clavulanate 3.1 g every 6 h against A. baumannii. CONCLUSIONS: Based on pharmacokinetics/pharmacodynamics, imipenem 0.5 g every 6 h, cefepime 2 g every 8 h and ceftazidime 2 g every 8 h should be the preferred beta-lactam regimens for the empirical treatment of gram-negative pulmonary infections in the ICU. The order of preference varied against Enterobacteriaceae, P. aeruginosa and A. baumannii.     

头孢吡肟或头孢他啶联合阿米卡星治疗白血病化疗后粒细胞缺乏合并感染的疗效比较

目的:比较头孢吡肟或头孢他啶联合阿米卡星在治疗白血病化疗后粒细胞缺乏合并感染中的疗效。方法:回顾分析我科近年收治的白血病患者化疗后粒细胞缺乏合并重症感染者共117例,比较临床经验抗感染治疗方案头孢他啶+阿米卡星与头孢吡肟+阿米卡星的疗效。结果:头孢吡肟+阿米卡星组痊愈率为51.61%,有效率为64.52%;头孢他啶+阿米卡星组痊愈率为49.02%,有效率为62.75%。经统计学分析,两组患者的临床疗效差异无显著性。结论:头孢吡肟+阿米卡星与头孢他啶+阿米卡星在治疗白血病化疗后粒细胞缺乏合并重症感染时疗效相似。     

Piperacillin/tazobactam plus tobramycin versus ceftazidime plus tobramycin for the treatment of patients with nosocomial lower respiratory tract infection. Piperacillin/tazobactam Nosocomial Pneumonia Study Group

An open-label, randomized, comparative, multi-centre study was conducted at 25 centres in the USA and Canada to compare the safety and efficacy of piperacillin/tazobactam plus tobramycin with ceftazidime plus tobramycin in patients with lower respiratory tract infections. Piperacillin/tazobactam (3 g/375 mg) every 4 h or ceftazidime (2 g) every 8 h were administered i.v. for a minimum of 5 days. Tobramycin (5 mg/kg/day) given in divided doses every 8 h was administered to all patients. Patients with Pseudomonas aeruginosa isolated from respiratory secretions at baseline were to continue tobramycin for the duration of the study. Tobramycin could be discontinued in other patients after the baseline culture results were known. A total of 300 patients was randomized, 155 into the piperacillin/tazobactam group and 145 into the ceftazidime group. Of these, 136 patients (78 in the piperacillin/tazobactam group and 58 in the ceftazidime group) were considered clinically evaluable. Both groups were comparable for age, sex, duration of treatment and other demographic features. The clinical success rate in evaluable patients was significantly greater (P = 0.006) in the piperacillin/tazobactam treatment group (58/78; 74%) than in the ceftazidime group (29/58; 50%). Eradication of the baseline pathogen was significantly greater (P = 0.003) in the piperacillin/tazobactam group (66%) than in the ceftazidime group (38%). The clinical and bacteriological responses of those patients with nosocomial pneumonia were similar to the overall results. Twelve (7.7%) piperacillin/tazobactam-treated patients and 24 (17%) ceftazidime-treated patients died during the study (P = 0.03). Seven of the 24 deaths in the ceftazidime treatment group but only one of the 12 deaths in the piperacillin/tazobactam treatment group were directly related to failure to control infection. The majority of adverse events were thought by the investigator to be attributable to the patients' underlying disease and not drug related. In this study, piperacillin/tazobactam plus tobramycin was shown to be more effective and as safe as ceftazidime plus tobramycin in the treatment of patients with nosocomial LRTI.     

Pharmacodynamics of antimicrobials for the empirical treatment of nosocomial pneumonia: a report from the OPTAMA Program

OBJECTIVE: To compare the probability of achieving specific pharmacodynamic exposures of commonly used intravenous antibiotics for the empirical treatment of nosocomial pneumonia against those pathogens most commonly implicated in the disease. DESIGN: Ten thousand-subject Monte Carlo simulation. SETTING: Research center. SUBJECT: None. INTERVENTIONS: Pharmacodynamic analysis was conducted for the following antimicrobials at standard doses: meropenem, imipenem-cilastatin, ceftazidime, cefepime, piperacillin/tazobactam, and ciprofloxacin. Prevalence of causative pathogens was based on the 2000 SENTRY Antimicrobial Surveillance Study, and minimum inhibitory concentration (MIC) values were obtained using the 2003 US MYSTIC database. The probabilities of each drug and dosing regimen in achieving pharmacodynamic targets were calculated. Bactericidal targets were defined as 40% T>MIC for the carbapenems, 50% T>MIC for other beta-lactams, and an area under the curve (AUC)/MIC ratio of 125 for ciprofloxacin. A sensitivity analysis was performed using two alternate models to determine the impact of varying pathogen prevalence on target attainment. MEASUREMENTS AND MAIN RESULTS: Meropenem and imipenem provided high probabilities of achieving their bactericidal target of 40% T>MIC, with target attainments of 98% for all regimens. At the bactericidal end point of 50% T>MIC, cefepime 2 g every 8 hrs displayed the highest target attainment at 99.9%, followed by cefepime 2 g every 12 hrs, ceftazidime 2 g every 8 hrs, piperacillin/tazobactam 4.5 g every 6 hrs and 3.375 g every 6 hrs, cefepime 1 g every 12 hrs, and ceftazidime 1 g every 8 hrs with target attainments of 95.0%, 92.5%, 92.3%, 91.3%, 90.3%, and 67.9%, respectively. Ciprofloxacin presented the lowest probability of achieving its bactericidal target of an AUC/MIC ratio of 125, with target attainments of 54.7% and 12.0% when given as 400 mg every 8 hrs and 400 mg every 12 hrs, respectively. CONCLUSIONS: Meropenem, imipenem, cefepime, ceftazidime (2 g every 8 hrs), and piperacillin/tazobactam have high probabilities of achieving adequate pharmacodynamic exposures when given for the empirical treatment of nosocomial pneumonia in the absence of methicillin-resistant S. aureus. Ceftazidime 1g every 8 hrs and ciprofloxacin produce low target attainment rates and will not likely result in high clinical success rates when given as monotherapy.     

Outcomes of patients with melioidosis treated with meropenem

Melioidosis, an infection due to Burkholderia pseudomallei, is endemic in southeast Asia and northern Australia. We reviewed our experience with meropenem in the treatment of severe melioidosis in 63 patients over a 6-year period. Outcomes were similar to those of ceftazidime-treated patients (n = 153) despite a deliberate selection bias to more-unwell patients receiving meropenem. The mortality among meropenem-treated patients was 19%. One patient had a possible drug fever associated with the use of meropenem. We conclude that meropenem (1 g or 25 mg/kg every 8 h intravenously for >/=14 days) is an alternative to ceftazidime and imipenem in the treatment of melioidosis. The use of meropenem may be associated with improved outcomes in patients with severe sepsis associated with melioidosis.     

Evaluation of pathogen detection from clinical samples by real-time polymerase chain reaction using a sepsis pathogen DNA detection kit

Introduction

Altered pharmacokinetics (PK) in critically ill patients can result in insufficient serum β-lactam concentrations when standard dosages are administered. Previous studies on β-lactam PK have generally excluded the most severely ill patients, or were conducted during the steady-state period of treatment. The aim of our study was to determine whether the first dose of piperacillin-tazobactam, ceftazidime, cefepime, and meropenem would result in adequate serum drug concentrations in patients with severe sepsis and septic shock.

Methods

Open, prospective, multicenter study in four Belgian intensive care units. All consecutive patients with a diagnosis of severe sepsis or septic shock, in whom treatment with the study drugs was indicated, were included. Serum concentrations of the antibiotics were determined by high-pressure liquid chromatography (HPLC) before and 1, 1.5, 4.5 and 6 or 8 hours after administration.

Results

80 patients were treated with piperacillin-tazobactam (n = 27), ceftazidime (n = 18), cefepime (n = 19) or meropenem (n = 16). Serum concentrations remained above 4 times the minimal inhibitory concentration (T > 4 × MIC), corresponding to the clinical breakpoint for Pseudomonas aeruginosa defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), for 57% of the dosage interval for meropenem (target MIC = 8 μg/mL), 45% for ceftazidime (MIC = 32 μg/mL), 34% for cefepime (MIC = 32 μg/mL), and 33% for piperacillin-tazobactam (MIC = 64 μg/mL). The number of patients who attained the target PK profile was 12/16 for meropenem (75%), 5/18 for ceftazidime (28%), 3/19 (16%) for cefepime, and 12/27 (44%) for piperacillin-tazobactam.

Conclusions

Serum concentrations of the antibiotic after the first dose were acceptable only for meropenem. Standard dosage regimens for piperacillin-tazobactam, ceftazidime and cefepime may, therefore, be insufficient to empirically cover less susceptible pathogens in the early phase of severe sepsis and septic shock.     

Cefepime monotherapy for febrile neutropenia in patients with lung cancer

We assessed the efficacy and safety of cefepime monotherapy (1 g intravenously every 8 h) for febrile neutropenia in patients with lung cancer in a multi-institutional phase II study. Patients treated with chemotherapy with or without radiotherapy for lung cancer were eligible for this study. Other eligibility criteria included fever (temperature of ≥38.0 °C) and an absolute neutrophil count of <500/mm³ or <1000/mm³ with an expected decline to <500/mm³ within the next 48 h. Risk assessment was performed using the Multinational Association of Supportive Care in Cancer risk-index score. Cefepime 1 g was given intravenously every 8 h. The primary endpoint was the response rate at the end of cefepime therapy. Co-administration of granulocyte-colony-stimulating factor was permitted. Of 54 patients enrolled, 39 were classified in the low-risk group and 15 in the high-risk group. Overall response rate was 78% (95% CI: 64.4–88.0%). The response rates were 85% (95% CI: 69.5–94.1%) in the low-risk group and 60% (95% CI: 32.3–83.7%) in the high-risk group, respectively. One patient died from septic shock due to Enterobacter cloacae bacteremia. There was no significant adverse event. Cefepime 1 g intravenously every 8 h appears to be effective for febrile neutropenia in patients with lung cancer, especially in those with low-risk febrile neutropenia, and is well tolerated.Clinical trial registrationUMIN Clinical Trials Registry, UMIN000006157.     

Piperacillin/tazobactam plus tobramycin versus ceftazidime plus tobramycin as empiric therapy for fever in severely neutropenic patients

The objective of this trial was to evaluate the potential advantages of the combination of piperacillin and tazobactam in the control of fever in neutropenic patients. In this single-center study, patients who experienced a total of 247 febrile episodes were prospectively randomized to receive either our standard regimen, ceftazidime 3 g/day (1 g t.i.d.) plus tobramycin 3 mg/kg per day (1.5 mg/kg b.i.d.), or piperacillin 12 g/day plus tazobactam 1.5 g/day (4 g+0.5 g t.i.d.) plus tobramycin 3 mg/kg per day (1.5 mg/kg b.i.d.). Vancomycin was added in all cases of persistent fever in the ceftazidime arm, but only when there was microbiologically documented resistance in the piperacillin/tazobactam arm. All 247 episodes were evaluable by "intent-to-treat" analysis. The two populations were well matched in terms of age, gender, underlying disease, chemotherapy received, oral decontamination, clinical and bacterial documentation, and severity and duration of neutropenia. Initial antibacterial therapy was successful (apyrexia at 72 h, without antibiotic change) more frequently (P=0.008) with the regimen containing piperacillin/tazobactam (54.4%) than with the one including ceftazidime (37.6%). Fewer (P=0.02) major infectious events (infectious death or delay in treatment of underlying disease due to infection) were observed during piperacillin/ tazobactam treatment (2.6%) than with the ceftazidime regimen (11.3%), despite a lower frequency of glycopeptide addition when piperacillin/tazobactam was used (54.4% versus 77.4%) according to the rules adopted. This trial confirmed the efficacy of the piperacillin/tazobactam combination for empirical treatment of febrile neutropenic patients. This antibiotic combination permitted a dramatic decrease in empiric glycopeptide antibiotic administration in such patients. Electronic publication: 12 January 1999     

Insufficient β-lactam concentrations in the early phase of severe sepsis and septic shock

Introduction

Altered pharmacokinetics (PK) in critically ill patients can result in insufficient serum β-lactam concentrations when standard dosages are administered. Previous studies on β-lactam PK have generally excluded the most severely ill patients, or were conducted during the steady-state period of treatment. The aim of our study was to determine whether the first dose of piperacillin-tazobactam, ceftazidime, cefepime, and meropenem would result in adequate serum drug concentrations in patients with severe sepsis and septic shock.

Methods

Open, prospective, multicenter study in four Belgian intensive care units. All consecutive patients with a diagnosis of severe sepsis or septic shock, in whom treatment with the study drugs was indicated, were included. Serum concentrations of the antibiotics were determined by high-pressure liquid chromatography (HPLC) before and 1, 1.5, 4.5 and 6 or 8 hours after administration.

Results

80 patients were treated with piperacillin-tazobactam (n = 27), ceftazidime (n = 18), cefepime (n = 19) or meropenem (n = 16). Serum concentrations remained above 4 times the minimal inhibitory concentration (T > 4 × MIC), corresponding to the clinical breakpoint for Pseudomonas aeruginosa defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), for 57% of the dosage interval for meropenem (target MIC = 8 μg/mL), 45% for ceftazidime (MIC = 32 μg/mL), 34% for cefepime (MIC = 32 μg/mL), and 33% for piperacillin-tazobactam (MIC = 64 μg/mL). The number of patients who attained the target PK profile was 12/16 for meropenem (75%), 5/18 for ceftazidime (28%), 3/19 (16%) for cefepime, and 12/27 (44%) for piperacillin-tazobactam.

Conclusions

Serum concentrations of the antibiotic after the first dose were acceptable only for meropenem. Standard dosage regimens for piperacillin-tazobactam, ceftazidime and cefepime may, therefore, be insufficient to empirically cover less susceptible pathogens in the early phase of severe sepsis and septic shock.     

Is cefepime safe for clinical use? A Bayesian viewpoint

Cefepime hydrochloride is approved for pneumonia, empirical therapy for febrile neutropenia, uncomplicated and complicated urinary tract infections, uncomplicated skin and skin structure infections and complicated intra-abdominal infections. A recent meta-analysis by Yahav et al. (Lancet Infect Dis 2007; 7: 338-48) concluded that cefepime was associated with a statistically significant increase in mortality (risk ratio 1.26, 95% confidence interval 1.08-1.49) when compared with other antibiotics. The US FDA decided to re-evaluate the meta-analysis data in collaboration with the drug sponsor. Two years later the FDA Alert summarized that 'data do not indicate a higher rate of death in cefepime-treated patients. Cefepime remains an appropriate therapy for its approved indications.' However, a thorough evaluation of the 52-page FDA report still shows that safety remains an unresolved issue. A Bayesian re-appraisal of the findings by the FDA and by Yahav et al. indicates that there is a 90.9% (by FDA trial-level meta-analysis), 80.8% (by FDA patient-level meta-analysis) and 99.2% (by Yahav et al. meta-analysis) probability that cefepime raises mortality in neutropenic fever patients, which translates into the following numbers needed to harm (NNH), i.e. to cause one extra death with the use of cefepime: FDA trial-level meta-analysis, NNH?=?109; FDA patient-level meta-analysis, NNH?=?76; Yahav et al. meta-analysis, NNH?=?54. A similar harmful probability was observed with skin structure infections but not with pneumonias, intra-abdominal infections and urinary tract infections. In conclusion, cefepime should be avoided in patients with neutropenic fever or with skin structure infections.     

Treatment of febrile neutropenia with cefepime monotherapy

BACKGROUND AND OBJECTIVE: The empirical administration of a broad-spectrum beta-lactam antibiotic, either as monotherapy or in combination with an aminoglycoside, is an essential component of the initial management of patients with fever and severe neutropenia. Multiple antibiotics have been tested for this indication. Cefepime is a fourth-generation cephalosporin with in vitro activity against most gram-negative and many gram-positive bacteria. We have studied the use of this agent as monotherapy in this indication. METHODS: One hundred and twenty-six episodes of febrile neutropenia in 98 adults with hematological malignancies were treated with cefepime monotherapy. Cefepime was given at a dose of 2 g every 8 h i.v. Most episodes (49%) were fever of unexplained origin, while a microbiologically documented and clinically documented infection occurred in 25% episodes each. Seventy-six (61%) episodes occurred after conventional chemotherapy, while 51 (41%) after a hematopoietic stem cell transplantation. Results: Twelve episodes (10%) were not evaluable for response. Among the 114 evaluable episodes, 69 (55% of the initial sample and 61% of those evaluable) responded to cefepime monotherapy, while therapy failed in 45 cases (36% of the initial sample and 39% of those evaluable), including 14 cases who developed breakthrough bacteremia during therapy. There were no deaths due to bacterial infection. At the end of all antibiotic therapy (final outcome) 69 episodes were cured only with monotherapy, 47 were cured with modification of therapy and 10 patients died from an unrelated cause. The only variable that appeared to correlate with response to therapy was the duration of neutropenia, which was longer among patients who failed or developed breakthrough bacteremia than among those who responded to monotherapy. INTERPRETATION AND CONCLUSIONS: Initial empirical antibiotic therapy with cefepime as a single agent in patients with febrile neutropenia and a hematological malignancy is effective, but patients with prolonged neutropenia appear to be at higher risk for failure. However, with appropriate therapeutic changes the risk of dying from a bacterial infection is very low.     

Tolerability of teicoplanin in 117 hospitalized adults with previous vancomycin-induced fever,rash, or neutropenia: A retrospective chart review

Background: Vancomycin has reliable antibacterial activity against many gram-positive pathogens but is associated with many adverse events. Teicoplanin, another glycopeptide, is associated with fewer adverse events, but its use in patients with previous vancomycininduced adverse reactions remains controversial.Objectives: The aims of this work were to evaluate the clinical characteristics of hospitalized patients with vancomycin-induced fever (ie, drug fever), rash, or neutropenia and to examine the tolerability of teicoplanin in these patients.Methods: This was a retrospective review of the medical charts of patients aged ≥18 years who were hospitalized between January 2002 and October 2007 at National Cheng Kung University Hospital in Tainan, Taiwan. Patients were included if they experienced drug-induced fever (ie, “drug fever”), rash, or neutropenia during vancomycin treatment. Their antimicrobial therapy was subsequently switched to teicoplanin. Clinical information and the development of drug fever, rash, or neutropenia with teicoplanin were determined from the charts.Results: Antibiotic therapy was switched to teicoplanin in 117 patients with vancomycin-induced fever alone (n = 24), rash alone (n = 77), both drug fever and rash (n = 8), or neutropenia (n = 8). The mean (SD) age of these patients was 53.1 (22.8) years, and 65 (56%) were male. The major clinical indications for vancomycin therapy among these patients were wound infections (21%), respiratory tract infections (14%), and bacteremia (13%). The dosages for vancomycin ranged from 1 g every 5 days to 1 g BID, and for teicoplanin ranged from 400 mg daily to 400 mg q72h, adjusted by the degree of renal dysfunction. Overall, 12 patients with vancomycin-induced fever (n = 2), rash (n = 6), or neutropenia (n = 4) subsequently developed teicoplanin-induced fever (n = 3), rash (n = 3), or neutropenia (n = 6). Specifically, of 8 patients with vancomycin-induced neutropenia, 4 (50%) subsequently developed neutropenia after switching to teicoplanin. Vancomycin- and teicoplanininduced neutropenia was often noted after 1 week of treatment. Among patients with vancomycin-induced fever, rash, or neutropenia, there were no differences between patients with or without teicoplanin-induced fever, rash, or neutropenia in terms of age, sex, weight, dosage or duration of vancomycin therapy, dosage of teicoplanin, or underlying disease. There was no difference in mortality rates between patients with or without teicoplanin-induced fever, rash, or neutropenia. The cause of all deaths was progression of infectious or underlying disease, unrelated to vancomycin or teicoplanin use.Conclusions: Based on this retrospective chart review of hospitalized patients with vancomycin-induced fever, rash, or neutropenia, only 10% experienced subsequent teicoplanin-induced fever, rash, or neutropenia. However, it should be noted that half of the patients with vancomycin-induced neutropenia developed teicoplanin-induced neutropenia.     

Evaluation of Several Dosing Regimens of Cefepime, with Various Simulations of Renal Function, against Clinical Isolates of Pseudomonas aeruginosa in a Pharmacodynamic Infection Model

The objectives of this study were as follows: (i) to examine the killing activity of 2-g doses of cefepime against two clinical isolates (mucoid and nonmucoid) of Pseudomonas aeruginosa in a pharmacodynamic in vitro infection model, (ii) to compare the percentage of time above the MIC (T > MIC) for each of the regimens against P. aeruginosa, and (iii) to evaluate the area under the bactericidal curve for each regimen. Cefepime was administered at intervals of 8, 12, and 24 h with and without tobramycin, and two different levels of renal function were simulated: normal (creatinine clearance [CL_CR] = 90 ml/min) and decreased (CR_CL = 60 ml/min). Also, the killing activity of cefepime with and without tobramycin was compared to the killing activity of ceftazidime (2 g every 8 h) with and without tobramycin. The T > MIC was 100% in the central chamber except for the regimen in which cefepime was administered every 12 h and the CL_CR was 90 ml/min, which provided concentrations above the MIC for 92% of the dosing interval against the C31 (mucoid; MIC of cefepime, 4 μg/ml) isolate and for 75% of the interval against the C34 (nonmucoid; MIC of cefepime, 8 μg/ml) isolate. All cefepime and ceftazidime monotherapy simulations resulted in 99.9% killing of the nonmucoid isolate within 4 to 8 h and within 4 to 6 h, respectively. Against the mucoid isolate, 99.9% killing was achieved only with combination therapy. The results of this study indicate that cefepime dosed at 2 g every 12 h under conditions of normal renal function and every 24 h with decreased creatinine clearance (60 ml/min) is effective both as monotherapy and in combination therapy against a nonmucoid strain of P. aeruginosa. With cefepime MICs of 4 and 8 μg/ml, the single-agent regimens provided T > MIC values in the central chamber for 92 and ≥75% of the dosing interval against the mucoid and nonmucoid isolates, respectively. Cefepime dosed at 2 g every 12 h, with a creatinine clearance of 90 ml/min, and every 24 h, with a creatinine clearance of 60 ml/min, resulted in killing activity equivalent to that of ceftazidime dosed at 2 g every 8 h. None of the monotherapies provided adequate killing of the mucoid strain of P. aeruginosa despite drug concentrations being above the MIC for ≥92% of all dosing intervals. Finally, combination therapy with tobramycin and either cefepime or ceftazidime enhanced the killing of both the mucoid and nonmucoid P. aeruginosa isolates.     

Monotherapy with piperacillin/tazobactam versus combination therapy with ceftazidime plus amikacin as an empiric therapy for fever in neutropenic cancer patients

Between July 1993 and September 1996, 107 consecutive febrile episodes in 83 neutropenic cancer patients with a median age of 41 years were randomized to treatment either with piperacillin/tazobactam 4.5 g every 8 h i.v. or ceftazidime 2 g every 8 h plus amikacin 15 mg/kg i.v. per day. In the case of fever >38° C 48 h after initiation of the antibiotic therapy, vancomycin 500 mg every 6 h i.v. was added. The study population was at serious risk of a poor outcome, since 67% of the patients had leukemia or lymphoma, 19% of the febrile events occurred after autologous bone marrow or blood stem cell transplantation, the median total duration of neutropenia was 16 days, and the median neutrophil count at study inclusion was 0.09 × 10⁹/l. The two patient groups were comparable in terms of risk factors. Bacteremia was found in 37%, other microscopically documented infections in 16%, and clinically documented infections in 26% of the febrile episodes. Most (96) febrile episodes were evaluable for response. No significant difference was found between piperacillin/ tazobactam and ceftazidime plus amikacin in terms of success rate (81% versus 83%), empirical addition of vancomycin (42% versus 38%), median time to fever defervescence (3.3 versus 2.9 days) or median duration of antibiotic therapy (7.2 versus 7.4 days). No patient died from the infection. Both antibiotic regimens were well tolerated, the study treatment being stopped only in 1 patient because of toxicity (cutaneous allergy to piperacillin/tazobactam). On the basis of the 107 febrile events encountered, we conclude that piperacillin/tazobactam is a safe and effective monotherapy. To define the definitive value of piperacillin/ tazobactam as a monotherapy for febrile neutropenic patients a large randomized trial is warranted.     

Comparative Effects of Ceftazidime Two or Three Times Daily in Patients with Skin and Skin Structure Infections

BACKGROUND: Skin and skin structure infections are among the most common infectious diagnoses in both the hospital and community settings. If untreated, these infections can produce serious complications. Successful antimicrobial therapy for these infections requires coverage against the causative pathogens, particularly Staphylococcus aureus. OBJECTIVE: This randomized, single-blind, multicenter study was designed to compare the efficacy and safety of intravenous ceftazidime 2 g given two times daily (BID) with that of intravenous ceftazidime 1 g given three times daily (TID) for the treatment of skin and skin structure infections caused by ceftazidime-sensitive pathogens. METHODS: Adults (greater-than-or-equal18 years) were eligible for enrollment if they were hospitalized or in home health care settings and they had a skin or skin structure infection caused by a ceftazidime-sensitive pathogen. Patients were randomly assigned to receive ceftazidime 2 g every 12 h or ceftazidime 1 g every 8 h as an intermittent infusion over 15--30 min. Treatment was continued for 2--3 days beyond the time the patient became asymptomatic or evidence of bacterial eradication was obtained; however, total treatment duration had to be at least 5 days. Patients were assessed for their clinical and bacteriological response at the end of treatment and for their clinical response at follow-up. RESULTS: A total of 806 patients were enrolled in the study, 406 of whom received ceftazidime 2 g BID and 400 of whom received ceftazidime 1 g TID. Both treatments were administered for a mean duration of 9 days. At the end of therapy, 248 of 264 (94%) clinically evaluable patients receiving ceftazidime BID and 258 of 275% (94%) clinically evaluable patients receiving ceftazidime TID achieved clinical cure or improvement (p = 0.953). Pathogens were eradicated or presumed to be eradicated from 217 of 256 (85%) bacteriologically evaluable patients receiving ceftazidime BID and from 228 of 266 (86%) bacteriologically evaluable patients receiving ceftazidime TID (p = 0.760). Of 1131 isolates, the most common pathogens were S. aureus (30%) and Pseudomonas aeruginosa (10%). Both regimens were well tolerated with only 13 patients (3%) in the BID group and 16 patients (4%) in the TID group withdrawing because of an adverse event. CONCLUSIONS: These data indicate that ceftazidime 2 g given twice daily is as effective as ceftazidime 1 g given three times daily for the treatment of skin and skin structure infections. In addition, the twice-daily regimen has the advantage of convenience.     

Prospective randomized comparison of cefepime and cefotaxime for treatment of bacterial meningitis in infants and children.

Ninety infants and children were prospectively randomized to receive cefepime (n = 43) or cefotaxime (n = 47) for therapy of bacterial meningitis. The two treatment groups were comparable in terms of age, duration of illness before enrollment, history of seizures, clinical status on admission, and etiology. Six (7%) patients died--two treated with cefepime and four treated with cefotaxime. Clinical response, cerebrospinal fluid sterilization, development of complications, antibiotic toxicity, and hospital stay were similar for the two treatment regimens. Concentrations of cefepime in cerebrospinal fluid varied from 55 to 95 times greater than the maximal MIC required by the causative pathogens. Audiologic and/or neurologic sequelae were found in 16% of the cefepime-treated patients and 15% of the cefotaxime-treated patients examined 2 to 6 months after discharge. We conclude that cefepime is safe and therapeutically equivalent to cefotaxime for management of bacterial meningitis in infants and children.