BACKGROUND: The efficacy and safety of piperacillin/tazobactam plus ceftazidime (PIPC/TAZ+CAZ) versus sulbactam/ampicillin plus aztreonam (SBT/ABPC+AZT) as empirical therapy for febrile neutropenia were assessed in children with hematologic disease and solid tumor. PROCEDURE: A prospective randomized study was performed to evaluate the clinical response of 70 febrile episodes in the PIPC/TAZ+CAZ arm and 64 evaluable febrile episodes in the SBT/ABPC+AZT arm of the study. Clinical efficacy was evaluated at 120 hours, with treatment outcome criteria defined as follows. Success was defined as disappearance of fever, clinical improvement, eradication of the infecting organism, and maintenance of a response for at least 7 days after discontinuation of treatment. RESULTS: An infection was documented microbiologically in 14 episodes (20%) in the PIPC/TAZ+CAZ arm and in 8 episodes (13%) in the SBT/ABPC+AZT arm. The success rate was 57.1% in the PIPC/TAZ+CAZ arm and 62.5% in the SBT/ABPC+AZT arm (P>0.05). No major adverse effects were observed in the study. CONCLUSIONS: PIPC/TAZ+CAZ and SBT/ABPC+AZT are effective and safe for initial empirical treatment of febrile episodes in neutropenic pediatric patients. The clinical efficacy of SBT/ABPC+AZT is equivalent or superior to that of PIPC/TAZ+CAZ, the effect of which is already proven against febrile neutropenia. Therefore, SBT/ABPC+AZT may be a treatment of choice for febrile neutropenia in pediatric cancer patients.

In a prospective randomized trial, febrile granulocytopenic patients received either moxalactam plus piperacillin or moxalactam plus amikacin as initial empiric antimicrobial therapy. Most patients were also given prophylactic vitamin K. The overall response rates for the two regimens were similar (105 of 136, or 77 percent, for moxalactam plus piperacillin versus 107 of 136, or 79 percent, for moxalactam plus amikacin). For Pseudomonas aeruginosa infections, the response rate was better in patients receiving moxalactam plus amikacin (seven of nine versus one of five, p = 0.06); two patients treated with moxalactam plus piperacillin experienced relapse of P. aeruginosa bacteremia in association with the emergence of beta-lactam-resistant P. aeruginosa isolates. On the other hand, bacteremic enterococcal superinfections occurred in seven patients receiving moxalactam plus amikacin but in none given moxalactam plus piperacillin (p = 0.02). Serious side-effects were minimal with both regimens, and nephrotoxicity was less common in patients receiving moxalactam plus piperacillin (two of 136 versus six of 136, p = 0.28). There was no antibiotic-related hemorrhage. These results suggest that the overall efficacy and toxicity of moxalactam plus piperacillin and moxalactam plus amikacin are similar. Moxalactam/piperacillin therapy may be limited in certain patients by the emergence of beta-lactam-resistant P. aeruginosa, whereas enterococcal superinfections may complicate moxalactam/amikacin therapy.

Recent case reports describe patients receiving piperacillin-tazobactam who were found to have circulating galactomannan detected by the double sandwich enzyme-linked immunosorbent assay (ELISA) system, leading to the false presumption of invasive aspergillosis. Since this property of piperacillin-tazobactam and galactomannan ELISA is not well understood, we investigated the in vitro, in vivo, and clinical properties of this interaction. Among the 12 reconstituted antibiotics representing four classes of antibacterial compounds that are commonly used in immunocompromised patients, piperacillin-tazobactam expressed a distinctively high level of galactomannan antigen in vitro (P = 0.001). After intravenous infusion of piperacillin-tazobactam into rabbits, the serum galactomannan index (GMI) in vivo changed significantly (P = 0.0007) from a preinfusion mean baseline value of 0.27 to a mean GMI of 0.83 by 30 min to slowly decline to a mean GMI of 0.44 24 h later. Repeated administration of piperacillin-tazobactam over 7 days resulted in accumulation of circulating galactomannan to a mean peak GMI of 1.31 and a nadir of 0.53. Further studies revealed that the antigen reached a steady state by the third day of administration of piperacillin-tazobactam. Twenty-six hospitalized patients with no evidence of invasive aspergillosis who were receiving antibiotics and ten healthy blood bank donors were studied for expression of circulating galactomannan. Patients (n = 13) receiving piperacillin-tazobactam had significantly greater mean serum GMI values (0.74 +/- 0.14) compared to patients (n = 13) receiving other antibiotics (0.14 +/- 0.08) and compared to healthy blood bank donors (0.14 +/- 0.06)(P < 0.001). Five (38.5%) of thirteen patients receiving piperacillin-tazobactam had serum GMI values > 0.5 compared to none of thirteen subjects receiving other antibiotics (P = 0.039) and to none of ten healthy blood bank donors (P = 0.046). These data demonstrate that among antibiotics that are commonly used in immunocompromised patients, only piperacillin-tazobactam contains significant amounts of galactomannan antigen in vitro, that in animals receiving piperacillin-tazobactam circulating galactomannan antigen accumulates in vivo to significantly increased and sustained levels, and that some but not all patients receiving this antibiotic will demonstrate circulating galactomannan above the threshold considered positive for invasive aspergillosis by the recently licensed double sandwich ELISA.

Although laparoscopic cholecystectomy (LC) is known to be safe in the treatment of acute cholecystitis (AC), the optimal timing of laparoscopic intervention remains controversial. The objective of this study is to prospectively compare the safety and cost effectiveness of early versus delayed LC in AC. Our study population consisted of 43 patients presenting with AC (localized tenderness, white blood cell count >10.0 or temperature >38.0 degrees C, and ultrasound confirmation) who were prospectively randomized to early versus delayed LC during their first admission. Exclusion criteria included a history of peptic ulcer disease or evidence of gallbladder perforation. All patients were treated with bowel rest and antibiotics (piperacillin 2 g intravenous piggyback every 6 hours). Early treatment patients underwent LC as soon as the operating schedule allowed. Delayed treatment patients received anti-inflammatory medication (indomethacin 50 mg per rectum every 12 hours) in addition to bowel rest and antibiotics and underwent operation after resolution of symptoms or within 5 days if symptoms failed to resolve. Early LC was performed in 21 patients, whereas 22 patients underwent delayed LC. There was no difference in age, temperature, or white blood cell count on admission between groups. Early LC slightly reduced operative time and conversion rate. There was no difference in complications. Estimated blood loss was significantly lower in those receiving early LC. There was also a significant reduction in total hospital stay and hospital charges with early LC. We conclude that delay in operation combined with anti-inflammatory medication showed no advantage with regard to operative time, conversion, or complication rate. Furthermore, early laparoscopic intervention significantly reduced operative blood loss, hospital days, and hospital charges.

Empiric therapy for febrile granulocytopenic patients is mandatory, but whether monotherapy is a safe alternative and whether fluoroquinolones are useful agents for this indication are still controversial issues. The use of monotherapy with intravenous ciprofloxacin (200 to 300 mg every 12 h) was evaluated against combined therapy with piperacillin plus amikacin in febrile granulocytopenic patients with solid tumor or lymphoma. The study was discontinued prematurely because patients treated with ciprofloxacin had a significantly lower overall success rate than patients treated with piperacillin plus amikacin (31 of 48 patients [65%] versus 48 of 53 patients [91%], P = 0.002). Patients with gram-positive coccal bacteremia had a particularly poor outcome: therapy failed for six of eight patients (75%) treated with ciprofloxacin, while therapy failed for none of four patients treated with piperacillin plus amikacin. Death from primary infection during initially randomized protocol therapy occurred in 7 of 48 patients (14.5%) treated with ciprofloxacin and in 3 of 53 (6%) treated with piperacillin plus amikacin. This study does not support the use of this dose of intravenous ciprofloxacin as empiric monotherapy for fever in granulocytopenic patients.

BACKGROUND: Although intermittent bolus dosing is currently the standard of practice for many antimicrobial agents, beta-lactams exhibit time-dependent bacterial killing. Maximizing the time above the minimum inhibitory concentration (MIC) for a pathogen is the best pharmacodynamic predictor of efficacy. Use of a continuous infusion has been advocated for maximizing the time above the MIC compared with intermittent bolus dosing. OBJECTIVE: This study compared the pharmacokinetics and pharmacodynamics of piperacillin/tazobactam when administered as an intermittent bolus versus a continuous infusion against clinical isolates of Pseudomonas aeruginosa and Klebsiella pneumoniae. METHODS: Healthy volunteers were randomly assigned to receive piperacillin 3 g/ tazobactam 0.375 g q6h for 24 hours, piperacillin 6 g/tazobactam 0.75 g continuous infusion over 24 hours, and piperacillin 12 g/tazobactam 1.5 g continuous infusion over 24 hours. Five clinical isolates each of P aeruginosa and K pneumoniae were used for pharmacodynamic analyses. RESULTS: Eleven healthy subjects (7 men, 4 women; mean +/- SD age, 28 +/- 4.7 years) were enrolled. Mean steady-state serum concentrations of piperacillin were 16.0 +/- 5.0 and 37.2 +/- 6.8 microg/mL with piperacillin 6 and 12 g, respectively. Piperacillin/tazobactam 13.5 g continuous infusion (piperacillin 12 g/tazobactam 1.5 g) was significantly more likely to produce a serum inhibitory titer > or = 1:2 against P aeruginosa at 24 hours than either the 6.75 g continuous infusion (piperacillin 6 g/tazobactam 0.75 g) or 3.375 g q6h (piperacillin 3 g/ tazobactam 0.375 g). There were no statistical differences against K pneumoniae between regimens. The median area under the inhibitory activity-time curve (AUIC) for the 13.5 g continuous infusion was higher than that for 3.375 g q6h and the 6.75 g continuous infusion against both P aeruginosa and Kpneumoniae (P < or = 0.007, 13.5 g continuous infusion and 3.375 g q6h vs 6.75 g continuous infusion against K pneumoniae). The percentage of subjects with an AUIC > or = 125 was higher with both 3.375 g q6h and the 13.5 g continuous infusion than with the 6.75 g continuous infusion against P aeruginosa and K pneumoniae (both, P < 0.001 vs 6.75 g continuous infusion against K pneumoniae). CONCLUSIONS: Piperacillin 12 g/tazobactam 1.5 g continuous infusion consistently resulted in serum concentrations above the breakpoint for Enterobacteriaceae and many of the susceptible strains of P aeruginosa in this study in 11 healthy subjects. Randomized controlled clinical trials are warranted to determine the appropriate dose of piperacillin/tazobactam.

STUDY OBJECTIVE: To compare continuous versus intermittent administration of piperacillin-tazobactam with regard to clinical, microbiologic, and economic outcomes. DESIGN: Prospective, open-label controlled study SETTING: Community teaching hospital. PATIENTS: Ninety-eight hospitalized patients prescribed piperacillin-tazobactam. INTERVENTION: Substitutions were implemented so that 47 patients initially prescribed intermittent infusion of piperacillin-tazobactam were switched to continuous infusion of this drug combination. Dosages varied in accordance with the type of infection and each patient's renal function. Fifty-one other patients with similar demographics and types of infection received intermittent infusion with piperacillin-tazobactam. MEASUREMENTS AND MAIN RESULTS: Clinical success rates were 94% for the continuous-infusion group and 82% for the intermittent-infusion group (p=0.081). Microbiologic success rates were 89% for the continuous-infusion group and 73% for the intermittent-infusion group (p=0.092). Days to normalization of fever were significantly lower (p=0.012) in the continuous-infusion group (1.2 +/- 0.8 days) than in the intermittent-infusion group (2.4 +/- 1.5 days). Level 1 and level 2 costs/patient were both reduced by continuous infusion, although the difference was statistically significant only for level 2 costs ($399.38 +/- 407.22 for continuous infusion vs $523.49 +/- 526.85 for intermittent infusion, p=0.028). CONCLUSION: Continuous infusion of piperacillin-tazobactam provided clinical and microbiologic outcomes equivalent to those for intermittent infusion. Compared with intermittent infusion, continuous infusion significantly shortened the time to temperature normalization, while also offering a significant reduction in level 2 expenditures.

Mathematical solutions for two possible pharmacodynamic interactions (linear nonsaturable and nonlinear saturable) between antibiotics and microorganisms derived from the incorporation of clinically relevant antibiotic dosage regimens such as single bolus dosing, multiple doses, and constant infusion at steady state have been obtained. It is concluded that the saturable nonlinear interaction model between the tested antibiotic and microorganism appears appropriate. The model and its derived equations are capable of describing in vivo bacterial growth of P. aeruginosa after single bolus dosing and multiple doses of piperacillin as described by a linear one-compartment pharmacokinetic model. The activity of piperacillin against P. aeruginosa in the neutropenic mouse systemic infection model can be described by an equation with three dynamic parameters: the bacterial growth rate constant kapp, 0.02345 min-1, the bacterial killing rate constant k'kill, 0.02623 min-1, and the Michaelis-Menten type saturation constant Km, 0.05467 microgram/ml. The concept and derived equations for the optimal dosing interval and minimum critical concentration are of clinical importance for the proper selection of antibiotic dosage regimens.

The objective of the presented prospective, randomized study was to compare the efficacy of empirical antimicrobial monotherapy with piperacillin/tazobactam (PIP/TAZ) to cefepime (CEFP) for treatment of infections in neutropenic patients. From a total of 102 febrile episodes 100 were evaluable. The most frequent microorganisms were gram-negative, documented in 22% vs. 24% of the febrile episodes (gram-positives 18% vs. 16%, fungi 2% vs. 4%). The response rate was similar with 22/51 (43%) of episodes treated with PIP/TAZ vs. 19/49 (39%) with CEFP. Of the different infection types classified at the end of the febrile episodes, patients with fever of unknown origin (FUO) and primary bacteremias showed the best initial responses with 25/44 (57%) and 11/22 (50%). Lower initial response rates were found in pneumonias with totally 3/13 (23%) and other clinically documented infections with 2/21 (10%), without any difference between both groups. Gram positive infections showed a higher response with PIP/TAZ than with CEFP (4/9 vs. 0/8), gram negative responded less frequently (3/11 vs. 7/13). The median time until persistent defervescence was equal in both groups (2.5 vs. 2 days), likewise the response rates after the different steps of therapy modifications (change to imipenem or ceftazidim, or addition of gentamycin, vancomycin or amphotericin B). Totally, 96% of febrile episodes responded in both therapy arms. Overall, we found no significant differences in efficacy between the two therapeutic regimens. In conclusion, PIP/TAZ as well as CEFP might be a sufficient initial therapy for febrile neutropenia, but further randomized trials with larger patient numbers are necessary.

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.

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 degrees 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 x 10(9)/1. 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.