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.     

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.     

Efficacy and tolerability of piperacillin/tazobactam versus ceftazidime in association with amikacin for treating nosocomial pneumonia in intensive care patients: a prospective randomized multicenter trial

OBJECTIVE: To compare clinical and bacteriological efficacy as well as tolerability of two regimens of broad-spectrum antibiotics (ceftazidime versus piperacillin/tazobactam) combined with amikacin in the treatment of nosocomial pneumonia in intensive care patients. DESIGN: Open label, prospective, multicenter, and randomized phase III clinical trial. SETTING: Medical or surgical intensive care units (ICUs) of nine acute-care teaching hospitals in Spain. PATIENTS AND PARTICIPANTS: One hundred and twenty-four ICU patients with nosocomial pneumonia and requiring mechanical ventilation were included. They were randomized to receive amikacin (15 mg/day divided into two doses) combined with either piperacillin (4 g every 6 h) and tazobactam (0.5 g every 6 h) (n = 88) or ceftazidime (2 g every 8 h) (n = 36). MEASUREMENTS AND RESULTS: The causative pathogen was determined in 60.2% of patients in the group of amikacin plus piperacillin/tazobactam and in 76.9% in the group of amikacin plus ceftazidime. A total of 94 bacterial organisms were isolated among which gram-negative bacilli predominated, Pseudomonas aeruginosa being the most frequent. Clinical response at the end of antibiotic therapy was considered satisfactory (cure and/or improvement) in 63.9% of patients in the amikacin plus piperacillin/tazobactam group and in 61.5% in the amikacin plus ceftazidime (odds ratio 1.1; 95% confidence interval 0.44-2.75). Eradication or presumptive eradication rates for each pathogen and for either gram-negative or gram-positive bacteria were similar in both antibiotic combinations (odds ratio 1.2; 95% confidence interval 0.39-3.66). A total of 21 adverse effects (23.9%) occurred in the amikacin plus piperacillin and tazobactam group and six (16.7%) in the amikacin plus ceftazidime group, thrombocytosis, renal dysfunction, and hepatic cytolysis being the most common. The efficacy and tolerability of the two therapeutic regimens were similar not only in the whole study population, but also in the subset of P. aeruginosa-related pneumonia (odds ratio 1; 95% confidence interval 0.08-13.37). CONCLUSIONS: Amikacin associated with either ceftazidime or piperacillin and tazobactam has shown comparable efficacy and tolerability in the treatment of ICU patients with nosocomial pneumonia.     

哌拉西林/他唑巴坦联合阿米卡星治疗绿脓杆菌肺炎疗效分析

目的:观察哌拉西林/他唑巴坦联合阿米卡星治疗绿脓杆菌肺炎的疗效.方法:对我科收治的绿脓杆菌肺炎100例病人采用哌拉西林/他唑巴坦联合阿米卡星治疗,静脉滴注剂量为哌拉西林/他唑巴坦4.5 g,q 8 h,阿米卡星400 mg,qd,疗程7-10 d.结果:总有效率为81%,细菌清除率为72%,不良反应率低.结论:哌拉西林/他唑巴坦联合阿米卡星是治疗绿脓杆菌肺炎的有效选择.     

Piperacillin/tazobactam in complicated urinary tract infections

Piperacillin/tazobactam, at a dosage of 4g/500 mg every 8 h, was administered intravenously to 217 patients with complicated urinary tract infections. The most common diagnosis was pyelonephritis. The most common pathogen wasEscherichia coli (47%) followed byPseudomonas aeruginosa (13%), and enterococci (8%). Among clinically evaluable patients, 86% (115/134) were cured or improved at the study endpoint and 14% (19/134) were clinical failures or relapsed. Among bacteriologically evaluable patients, 85% (95/112) had a favorable clinical response at endpoint. The bacteriological response rate was 73% (82/112) at endpoint. Overall, 82% of all pathogens were eradicated. Therapy was associated with a low incidence of side effects, and adverse experience were mild and of short duration.     

Pharmacodynamics of piperacillin alone and in combination with tazobactam against piperacillin-resistant and -susceptible organisms in an in vitro model of infection.

The pharmacodynamics of dosage regimens of piperacillin alone or in combination with tazobactam against piperacillin-resistant or -susceptible bacteria were studied in an in vitro model of infection. Experiments were conducted by using a fixed daily exposure of 12 g of piperacillin, given as 3 g alone or in combination with tazobactam at 0.375 g every 6 h, or the same total dose of the combination given as 4 g of piperacillin plus 0.5 g of tazobactam every 8 h. The addition of tazobactam to piperacillin, irrespective of the dosing interval, did not alter the killing of piperacillin-susceptible organisms (Escherichia coli J53 and Pseudomonas aeruginosa ATCC 27853). In contrast, experiments with an isogenic TEM-3-containing transconjugant of E. coli J53 (E. coli J53.2-TEM-3) that was resistant to piperacillin (MIC, 128 micrograms/ml) showed that the addition of tazobactam resulted in bacterial killing similar to that observed with the wild-type strain. Although tazobactam concentrations fell to less than 4 mg/liter (the concentration associated with a reduction in the piperacillin MIC from 128 to 2 mg/liter) 2 to 3 h after a dose, a similar degree of bacterial killing was observed when the same total 24-h dose of piperacillin-tazobactam was fractionated into dosing intervals of every 6 or 8 h. Investigations with Staphylococcus aureus 7176 (piperacillin MIC, 128 micrograms/ml) showed that the addition of tazobactam, again irrespective of dosing interval, also resulted in net bacterial killing which was not seen with piperacillin alone. These data support the use of extended dosing intervals (every 8 h) of piperacillin-tazobactam in the treatment of infections caused by piperacillin-resistant bacteria.     

Piperacillin–tazobactam: a β-lactam/β-lactamase inhibitor combination

Piperacillin–tazobactam is a β-lactam/β-lactamase inhibitor combination with a broad spectrum of antibacterial activity that includes Gram-positive and -negative aerobic and anaerobic bacteria. Piperacillin–tazobactam retains its in vitro activity against broad-spectrum β-lactamase-producing and some extended-spectrum β-lactamase-producing Enterobacteriaceae, but not against isolates of Gram-negative bacilli harboring AmpC β-lactamases. Piperacillin–tazobactam has recently been reformulated to include ethylenediaminetetraacetic acid and sodium citrate; this new formulation has been shown to be compatible in vitro with the two aminoglycosides, gentamicin and amikacin, allowing for simultaneous Y-site infusion, but not with tobramycin. Multicenter, randomized, double-blinded clinical trials have demonstrated piperacillin–tazobactam to be as clinically effective as relevant comparator antibiotics. Clinical trials have demonstrated piperacillin–tazobactam to be effective for the treatment of patients with intra-abdominal infections, skin and soft tissue infections, lower respiratory tract infections, complicated urinary tract infections, gynecological infections and more recently, febrile neutropenia. Piperacillin–tazobactam has an excellent safety and tolerability profile and continues to be a reliable option for the empiric treatment of moderate-to-severe infections in hospitalized patients.     

小儿肺炎克雷伯菌临床感染及耐药性分析

目的分析住院患儿肺炎克雷伯菌的临床分布及耐药性,以指导临床合理用药。方法对2009年10月至2010年12月儿科送检标本分离出的肺炎克雷伯菌的临床分布特点及耐药情况进行总结分析。结果共分离出肺炎克雷伯菌172株,其中产超广谱β-内酰胺酶(ESBLs)菌41株,占23.84%;主要来源于咽拭子、血液和痰液等,分别占70.93%、9.88%和8.14%;肺炎克雷伯菌对亚胺培南、厄它培南、丁氨卡那霉素和哌拉西林/他唑巴坦敏感性高。结论小儿肺炎克雷伯菌主要引起下呼吸道感染;对氨苄西林、氨苄西林/舒巴坦及头孢类抗菌药物耐药率高,哌拉西林/他唑巴坦和亚胺培南可作为治疗儿童产ESBLs肺炎克雷伯菌感染或非产ESBLs菌严重感染的首选用药。     

Kinetics of piperacillin and tazobactam in ventricular cerebrospinal fluid of hydrocephalic patients.

Its broad antibacterial spectrum qualifies the combination of piperacillin and tazobactam for therapy of nosocomial bacterial central nervous system (CNS) infections. Since these infections sometimes are accompanied by only minor dysfunction of the blood-cerebrospinal fluid (CSF) barrier, patients with noninflammatory occlusive hydrocephalus who had undergone external ventriculostomy were studied (n = 9; age range, 48 to 75 years). After administration of the first dose of piperacillin (6 g)-tazobactam (0.5 g) over 30 min intravenously, serum and CSF were drawn repeatedly and analyzed by high-performance liquid chromatography. Pharmacokinetics were determined by noncompartmental analysis. Maximum concentrations of piperacillin in CSF ranged from 8.67 to <0.37 mg/liter (median, 3.42 mg/liter), and those of tazobactam ranged from 1.37 to 0.11 mg/liter (median, 0.45 mg/liter). CSF maxima were observed, in median, 1.5 and 2 h after the end of the infusion. Elimination in CSF was considerably slower than in serum (median half-life at beta phase for piperacillin, 5.9 h in CSF versus 1.47 h in serum; for tazobactam, 6.1 h versus 1.34 h). For tazobactam, the ratio of the area under the concentration-time curve (AUC) in CSF to the AUC in serum was approximately three times as high as that for piperacillin (medians, 0.106 versus 0.034). In view of the tazobactam concentrations in CSF observed in this study, the practice of using a constant concentration of 4 mg of tazobactam per liter for MIC determination is inadequate for intracranial infections. Larger amounts of tazobactam than the standard dose of 0.5 g three times daily may be necessary for CNS infections.     

Pharmacokinetics and tissue penetration of tazobactam administered alone and with piperacillin.

The pharmacokinetics of tazobactam (500 mg) administered intravenously alone were compared with the pharmacokinetics of tazobactam coadministered with piperacillin (4 g), and the penetration into an inflammatory exudate in six healthy males was studied. Piperacillin influenced the pharmacokinetics of tazobactam. The mean levels of tazobactam in plasma at 4 h were 0.6 microgram/ml when it was given alone and 1.2 micrograms/ml when it was given with piperacillin (P = 0.0003). The mean total clearances of tazobactam were 203.5 and 134.2 ml/min (P = 0.035) when it was given alone and with piperacillin, respectively There were no significant differences in the elimination half lives, areas under the concentration-time curve from 0 h to infinity, or volumes of distribution. Inflammatory exudate penetration was rapid, and the mean maximum levels of tazobactam attained were 6.4 and 11.3 micrograms/ml when it was given alone or with piperacillin, respectively (P less than 0.06). The mean percent penetration of tazobactam and the area under the concentration-time curve from 0 h to infinity in inflammatory exudate were greater when tazobactam was given with piperacillin. The mean 24-h urinary recoveries of tazobactam were 63.7% +/- 7.9% when it was given alone and 56.8% +/- 2.7% when it was given with piperacillin. The explanation for the differences in the pharmacokinetics of tazobactam when it was administered alone compared with those when it was given with piperacillin was unclear.     

Population pharmacokinetics and pharmacodynamics of piperacillin/tazobactam in patients with complicated intra-abdominal infection

OBJECTIVES: We investigated the population pharmacokinetics and pharmacodynamics of piperacillin and tazobactam in hospitalized patients. PATIENTS AND METHODS: A multicentre, randomized clinical trial was conducted in hospitalized patients with complicated intra-abdominal infection. Patients received piperacillin/tazobactam administered by either continuous infusion (13.5 g over 24 h, n = 130) or intermittent infusion (3.375 g every 6 h, n = 132). NONMEM was used to perform population pharmacokinetic analysis in a subset of patients (n = 56) who had serum samples obtained at steady-state for drug concentration analyses. Classification and regression tree analysis was used to identify the breakpoints of piperacillin PK-PD indexes in 94 patients with causative pathogen's MIC. RESULTS: A one-compartment model was applied to fit the data. Creatinine clearance and body weight were the most significant variables to explain patient variability in piperacillin and tazobactam clearance and volume of distribution. The infusion method had no influence on PK parameters. For patients (n = 30) receiving intermittent infusion in the pharmacokinetic study, mean Cmax and half-life were 122.22 mg/L and 1.17 h for piperacillin, and 15.74 mg/L and 1.81 h for tazobactam. For patients (n = 26) receiving continuous infusion in the pharmacokinetic study, mean steady-state concentration was 35.31 +/- 12.15 mg/L for piperacillin and 7.29 +/- 3.28 mg/L for tazobactam. As a result of a low rate of failures (<11%) observed in the trial and the low MICs for infecting pathogens, no association could be established between clinical/microbiological outcome and drug exposure. CONCLUSIONS: Intermittent infusion and continuous infusion of piperacillin and tazobactam provided sufficient drug exposure to treat those pathogens commonly implicated in intra-abdominal infections.     

Empiric therapy for secondary peritonitis: a pharmacodynamic analysis of cefepime, ceftazidime, ceftriaxone, imipenem, levofloxacin, piperacillin/tazobactam, and tigecycline using Monte Carlo simulation

BACKGROUND: Inappropriate antibiotic therapy (ie, the selection of an empiric agent without activity against the responsible pathogen) of secondary peritonitis may result in poor patient outcomes. The selection of an appropriate agent can be challenging because of the emerging resistance of target organisms to commonly prescribed antibiotics. OBJECTIVE: The aim of this study was to perform a pharmacodynamic analysis, using recent global surveillance data, of commonly prescribed antibiotic agents and a newer agent, tigecycline, indicated in 2005 for the treatment of complicated intra-abdominal infections, to determine their probability for achieving microbiologic success against aerobic bacteria associated with secondary peritonitis. METHODS: A 2-compartment model was constructed using pharmacokinetic data from critically ill patients and global surveillance data on MIC distributions for microorganisms encountered in secondary peritonitis. A Monte Carlo simulation of the modeled data was performed to determine drug-appropriate pharmacodynamic end points, including free-drug time above the MIC, steady-state concentration above the MIC, and AUC/MIC ratios. A cumulative fraction of response (CFR) against aerobic bacteria involved in secondary peritonitis was calculated for cefepime, ceftazidime, ceftriaxone, imipenem, levofloxacin, pip eracillin/tazobactam, and tigecycline. A CFR > or =90% was considered microbiologic success. The following treatment regimens, administered as 30-minute N infusions, were examined: cefepime 1 and 2 g q12h, ceftazidime 1 and 2 g q8h, ceftriaxone 1 and 2 g q24h, imipenem 500 mg q6h, levofloxacin 750 mg q24h, pip eracillin/tazobactam 3.375 g q6h, and tigecycline 50 mg q12h, after a loading dose of 100 mg. RESULTS: A CFR > or =90% against nonenterococcal bacteria was predicted for imipenem 500 mg q6h (96.8%), cefepime 2 and 1 g q12h (95.3% and 92.4%, respectively), ceftazidime 2 g q8h (94.2%), and piperacillin/tazobactam 3.375 g q6h (91.2%). A CFR of 84.5% was predicted for tigecycline 50 mg q12h. Ceftriaxone and levofloxacin were predicted to have a CFR <80%. When enterococci were included in the model, the predicted CFRs for imipenem, piperacillin/tazobactam, and tigecycline were 93.4%, 88.4%, and 86.7%, respectively. CONCLUSIONS:: MIC distribution and pathogen prevalence strongly influence the likelihood of microbiological success in secondary peritonitis; therefore, decisions regarding empiric therapy should consider local epidemiology. Using current global data, the following regimens are adequate choices if Enterococcus is not targeted: Combination therapy (with metronidazole) using cefepime 1 g or 2 g q12h, or ceftazidime 2 g q8h; or monotherapy with imipenem 500 mg q6h or piperacillin-tazobactam 3.375 g q6h. When Enterococcus is included in the epidemiologic mix, imipenem, piperacillin/tazobactam, and tigecycline all appear to be viable monotherapeutic choices.     

Review of piperacillin/tazobactam in the treatment of bacteremic infections and summary of clinical efficacy

One method of resistance to beta-lactam antimicrobials involves production of beta-lactamases, enzymes that render the beta-lactam ineffective. Beta-lactamase inhibitors have been combined with beta-lactam antibiotics to combat beta-lactamase producing organisms. One such agent, piperacillin/tazobactam, has been shown to be safe and effective therapy for infections usually treated with a combination of antibiotics such as polymicrobial and nosocomial infection, and has been used for empiric therapy in cases of serious infection. A survey of the literature shows that piperacillin/tazobactam is a safe and efficacious therapy for bacteremia as well as soft tissue, intra-abdominal, and lower respiratory tract infections. When combined with an aminoglycoside, it is also useful in the treatment of severe nosocomial respiratory infections.     

Clinafloxacin versus piperacillin/tazobactam in the treatment of severe skin and soft-tissue infections in adults at a Veterans Affairs medical center

BACKGROUND: Severe skin and soft-tissue infections (SSTIs), particularly diabetic foot infections, are a source of considerable morbidity and mortality. Inappropriate antimicrobial therapy may contribute to the increasing emergence of bacterial resistance, as well as to increased health care costs. Thus, there is a continuing search for reasonably safe, well-tolerated, and effective antimicrobial agents that are less susceptible to the development of resistance than older agents. OBJECTIVE: The Department of Veterans Affairs (VA) Medical Center in Nashville, Tennessee, was I site in a multicenter, Phase III, randomized, investigator-blinded clinical trial comparing the safety and efficacy of clinafloxacin with those of piperacillin/tazobactam in the treatment of adult patients with SSTI. METHODS: Over an 18-month period, patients aged > or = 18 years with physical findings of acute bacterial SSTI requiring hospitalization and intravenous antimicrobial therapy were randomized in a 1:1 ratio to receive either clinafloxacin 200 mg IV every 12 hours or piperacillin/tazobactam 3.375 g IV every 6 hours. After a minimum of 3 days of intravenous therapy, a switch to oral therapy with clinafloxacin 200 mg PO every 12 hours or amoxicillin/clavulanate 500 mg PO every 8 hours could be made in the respective treatment groups. RESULTS: The center enrolled 84 patients (42 in each group), all but I of whom were male, reflecting the typical VA medical center population. The mean age was 60 years (range, 36-80 years) in the clinafloxacin group and 65 years (range, 35-87) in the piperacillin/tazobactam group; the latter group was significantly older (P = 0.0482), which could have affected recovery rates. Sixty-six patients were white and 18 were black. The mean ( +/- SD) duration of treatment was 10.69 +/- 5.34 days in the clinafloxacin group and 12.07 +/- 5.06 days in the piperacillin/tazobactam group; the mean length of stay was 10.83 +/- 10.28 days and 14.95 +/- 19.20 days, respectively. Fifty-three (63%) patients were switched to oral therapy (21 in the clinafloxacin group, 32 in the piperacillin/tazobactam group). The most commonly isolated pathogens were Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa, and Enterobacter cloacae. Clinical cure rates and microbiologic eradication rates were similar between the 2 treatments. The piperacillin/ tazobactam arm experienced more all-cause adverse events than the clinafloxacin arm, although the difference was not statistically significant. The clinafloxacin arm experienced significantly more adverse events (eg, photosensitivity) that were judged by the investigator to be drug related (P = 0.034). CONCLUSIONS: In this study population of hospitalized adults, clinafloxacin was as effective as piperacillin/tazobactam in the treatment of complicated SSTIs. Appropriate precautions must be taken against exposure to sunlight and ultraviolet light in patients receiving clinafloxacin, and adequate monitoring is necessary. Further investigation is necessary into how the phototoxic effects of the flu oroquinolones can be limited.     

Review of piperacillin/tazobactam in the treatment of bacteremic infections and summary of clinical efficacy

One method of resistance to beta-lactam antimicrobials involves production of beta-lactamases, enzymes that render the beta-lactam ineffective. Beta-lactamase inhibitors have been combined with beta-lactam antibiotics to combat beta-lactamase producing organisms. One such agent, piperacillin/tazobactam, has been shown to be safe and effective therapy for infections usually treated with a combination of antibiotics such as polymicrobial and nosocomial infection, and has been used for empiric therapy in cases of serious infection. A survey of the literature shows that piperacillin/tazobactam is a safe and efficacious therapy for bacteremia as well as soft tissue, intra-abdominal, and lower respiratory tract infections. When combined with an aminoglycoside, it is also useful in the treatment of severe nosocomial respiratory infections.A portion of the data presented herein have been presented previously by Dr. Wise at the 17th International Congress of Chemotherapy, Berlin, 1991     

Amikacin and Cephalothin: Empiric Regimen for Granulocytopenic Cancer Patients

Amikacin (15 mg/kg per day) was used in combination with cephalothin (7 g/m(2) per day) as an empiric regimen for de novo febrile (>101 degrees F [38.3 degrees C]) episodes in 93 granulocytopenic (<1,000/mm(3)) cancer patients. Both drugs were given intravenously in four equal doses every 6 h. The response rate for all documented infections was 83%, including 11 of 17 (65%) bacteremias. Escherichia coli (14 cases) was the most common pathogen, whereas Pseudomonas aeruginosa (2 cases) caused fewer infections. Mean amikacin serum levels were 8.7 mug/ml at 1 h and 2.2 mug/ml at 5 h. Failure of bone marrow recovery in association with a bacteremia was a bad prognostic sign (only two of eight improving). Ototoxicity occurred in two (2%) patients, whereas presumed antibiotic-induced nephrotoxicity developed in six (7%) patients. Surveillance cultures (nose, gums axilla, and rectum) of all hospitalized patients revealed no significant change in the incidence of amikacin resistance. The combination of amikacin and cephalothin in this dose and schedule was safe and efficacious in these granulocytopenic patients.     

The treatment of severe intra-abdominal infections: The role of piperacillin/tazobactam

Intra-abdominal infections require treatment effective against both aerobic and anaerobic bacteria. Piperacillin/tazobactam, a beta-lactam/beta-lactamase-inhibitor combination, has a spectrum that includes Gram-positive and Gram-negative aerobic and anaerobic organisms. In one comparative study of piperacillin/tazobactam and gentamicin/clindamycin, 88% of patients treated with piperacillin/tazobactam had a favorable clinical outcome at endpoint compared to 74% of patients treated with gentamicin plus clindamycin. Bacteriological response at endpoint was 87% in the piperacillin/tazobactam group and 74% in the gentamicin plus clindamycin group. In a comparative trial of piperacillin/tazobactam versus imipenem/cilastatin, the clinical cure rate was 91% in the piperacillin/tazobactam group and 69% in the imipenem/cilastatin group (p=0.005). Among microbiologically evaluable patients, the infecting organism was eradicated in 93% of piperacillin/tazobactam-treated patients compared to 76% eradication among imipenem/cilastatin-treated patients (p=0.029). Results of these clinical trials and others have shown that piperacillin/tazobactam is a safe and effective alternative to either combination or monotherapy for intra-abdominal infections.     

Population pharmacokinetics of extended-infusion piperacillin-tazobactam in hospitalized patients with nosocomial infections

While extended infusions of piperacillin-tazobactam (TZP) are increasingly used in practice, the effect of infusion on the pharmacokinetic (PK) profile of TZP has not been widely assessed. To assess its effect on the pharmacokinetic profile of TZP, seven serum samples were collected from 11 hospitalized patients who received 3.375 g TZP intravenously for 4 h every 8 h. Population pharmacokinetic models were fit to the PK data utilizing first-order, Michaelis-Menten (MM), and parallel first-order/MM clearance. A population PK model with first-order clearance was fit to the tazobactam PK data. Monte Carlo simulations (MCSs) were used to determine the most effective administration schedule to ensure that free piperacillin concentrations were above the MIC for at least 50% of the dosing interval (50% fT>MIC) and to quantify the extent of the nonlinear clearance. The model incorporating parallel linear/MM clearance best fit the piperacillin PK data. The MCSs demonstrated that approximately 50% of the administered piperacillin is cleared by the nonlinear clearance mechanism. The results of the MCSs also revealed that more intensive TZP extended infusion dosing schemes (3.375 to 4.5 g intravenously [3-h infusion] every 6 h) than those commonly used in clinical practice were needed to maximize the 50% fT>MIC for MICs of ≥8 mg/liter. This study suggests that extended infusion of TZP is the most effective method of administration for patients with nosocomial infections. Due to the hyperclearance nature of the hospitalized patient populations studied, more intensive TZP dosing regimens may be needed to maximize fT>MIC in certain hospitalized populations.     

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     

The treatment of severe intra-abdominal infections: The role of piperacillin/tazobactam

Intra-abdominal infections require treatment effective against both aerobic and anaerobic bacteria. Piperacillin/tazobactam, a beta-lactam/beta-lactamase-inhibitor combination, has a spectrum that includes Gram-positive and Gram-negative aerobic and anaerobic organisms. In one comparative study of piperacillin/tazobactam and gentamicin/clindamycin, 88% of patients treated with piperacillin/tazobactam had a favorable clinical outcome at endpoint compared to 74% of patients treated with gentamicin plus clindamycin. Bacteriological response at endpoint was 87% in the piperacillin/tazobactam group and 74% in the gentamicin plus clindamycin group. In a comparative trial of piperacillin/tazobactam versus imipenem/cilastatin, the clinical cure rate was 91% in the piperacillin/tazobactam group and 69% in the imipenem/cilastatin group (p=0.005). Among microbiologically evaluable patients, the infecting organism was eradicated in 93% of piperacillin/tazobactam-treated patients compared to 76% eradication among imipenem/cilastatin-treated patients (p=0.029). Results of these clinical trials and others have shown that piperacillin/tazobactam is a safe and effective alternative to either combination or monotherapy for intra-abdominal infections.