Combination Of Piperacillin Research Articles

Impact of restriction of third generation cephalosporins on the burden of third generation cephalosporin resistant K. pneumoniae and E. coli in an ICU

To test whether a reduction of third generation cephalosporin (3GC) use has a sustainable positive impact on the high endemic prevalence of 3GC resistant K. pneumoniae and E. coli. Segmented regression analysis of interrupted time series was used to analyse antibiotic consumption and resistance data 30 months before and 30 after the intervention. Surgical intensive care unit (ICU) with 16-bed unit in a teaching hospital. In July 2004, 3GCs were switched to piperacillin in combination with a beta-lactamase-inhibitor as standard therapy for peritonitis and other intraabdominal infections. Segmented regression analysis showed that the intervention achieved a significant and sustainable decrease in the use of 3GCs of -110.2 daily defined doses (DDD)/1,000 pd. 3GC use decreased from a level of 178.9 DDD/1,000 pd before to 68.7 DDD/1,000 pd after the intervention. The intervention resulted in a mean estimated reduction in total antibiotic use of 27%. Piperacillin/tazobactam showed a significant increase in level of 64.4 DDD/1,000 pd, and continued to increase by 2.3 DDD/1,000 pd per month after the intervention. The intervention was not associated with a significant change in the resistance densities of 3GC resistant K. pneumoniae and E. coli. Reducing 3GCs does not necessarily impact positively on the resistance situation in the ICU setting. Likewise, replacing piperacillin with beta-lactamase inhibitor might provide a selection pressure on 3GC resistant E. coli and K. pneumoniae. To improve resistance, it might not be sufficient to restrict interventions to a risk area.

Establishment of In Vitro Susceptibility Testing Methodologies and Comparative Activities of Piperacillin in Combination with the Penem β-Lactamase Inhibitor BLI-489

The novel bicyclic penem inhibitor BLI-489 has demonstrated activity as an inhibitor of class A, C, and D beta-lactamases. To determine the combination of piperacillin and BLI-489 to be used in susceptibility testing that would most accurately identify susceptible and resistant isolates, a predictor panel of beta-lactamase-producing bacteria was utilized to determine the reliability of the combination of piperacillin-BLI-489 at a constant inhibitor concentration of 2 or 4 microg/ml and at ratios of 1:1, 2:1, 4:1, and 8:1. There were a number of strains that would be falsely reported as susceptible or intermediate if tested with the ratios of 1:1 and 2:1, whereas the constant concentration of 2 microg/ml of BLI-489 and the ratio of 8:1 had a tendency to overpredict resistance. Similar MICs were obtained with piperacillin-BLI-489 in a 4:1 ratio and when BLI-489 was held constant at 4 microg/ml. Based on these results, an in vitro testing methodology employing a constant concentration of 4 microg/ml BLI-489 was used to evaluate the combination of piperacillin-BLI-489 against a larger panel of recently identified clinical isolates. Approximately 55% of all of the enteric bacilli tested were nonsusceptible to piperacillin alone (MIC > or = 32 microg/ml). However, 92% of these piperacillin nonsusceptible strains were inhibited by < or =16 microg/ml piperacillin-BLI-489; in contrast, only 66% were inhibited by < or =16 microg/ml piperacillin-tazobactam. The combination of piperacillin-BLI-489 also demonstrated improved activity compared to that of piperacillin-tazobactam against the problematic extended-spectrum beta-lactamase- and AmpC-expressing strains.

Evolution

When a patient's symptoms apparently progressed with treatment, it was necessary to determine whether her original problem had been supplanted by a new one. Three weeks after undergoing coronary artery bypass grafting, a 60-year-old woman from Bangladesh was admitted to the hospital with chest pain. She was noted to have left upper extremity warmth, erythema, and swelling. Vancomycin was ordered, but the erythema and warmth failed to improve after 4 days of therapy. As a result, a combination of piperacillin and tazobactam was added to the vancomycin.

Effects of combined antibiotic therapy in an ovine model of septic shock with smoke inhalation

OBJECTIVE: Sepsis increases morbidity and mortality of smoke inhalation victims. We test the effect of ciprofloxacin and piperacillin combination therapy in an ovine model of Ps. aeruginosa sepsis with smoke inhalation. METHODS: Sheep were surgically prepared for study. After a tracheotomy, acute lung injury was induced by cotton smoke and instillation of Ps. aeruginosa into lung. After the injury, all sheep were awakened, mechanically ventilated, and resuscitated with fluid. Groups: Control (n=6: injured, untreated); Treated (n=6: injured, treated with ciprofloxacin [0.4g, every 12 h] and piperacillin [3g, every 6h] started 12h post injury). RESULTS: All control sheep died before 36h. 50% treated sheep survived over 96h. All sheep showed severe cardiopulmonary dysfunctions and plasma nitrate/nitrite (NOx) level significantly increased at 12h and peaked at 18h. PaO2/FiO2 ratio, mean arterial pressure, NOx were 167±32, 77±8, 14.0±1.3 at 18h vs. 160±42, 109±7, 5.6±1.8, respectively at 30h in treated group. CONCLUSIONS: The combined antibiotic therapy significantly improved the survival, hemodynamics, plasma NOx, but not improved pulmonary function at 30h post-injury. This combined therapy may be an effective treatment option against Ps. aeruginosa-induced sepsis even with delayed onset. SUPPORT: NIH PO12GM066312, R01GM060688, Shriners Hospitals for Children 8450, 8954, 8820

Use of in Vitro Critical Inhibitory Concentration, a Novel Approach to Predict in Vivo Synergistic Bactericidal Effect of Combined Amikacin and Piperacillin Against Pseudomonas aeruginosa in a Systemic Rat Infection Model

This study was undertaken to explore the use of in vitro critical inhibitory concentration (CIC) as a surrogate marker relating the pharmacokinetic (PK) parameters to in vivo bactericidal synergistic effect [pharmacodynamic (PD)] of amikacin + piperacillin combination against Pseudomonas aeruginosa in a systemic rat infection model. The in vitro antibacterial activities of amikacin and piperacillin, alone and in combinations at various ratios of the concentrations, were tested against a standard [5 x 10(5) colony-forming units (CFU)/ml] and a large (1.5 x 10(8) CFU/ml) inoculum of P. aeruginosa ATCC 9027 using a modified survival-time method. The CIC of each individual antibiotic for the different combinations was determined using a cup-plate method. In vivo studies were performed on Sprague-Dawley rats using a systemic model of infection with P. aeruginosa ATCC 9027. PK profiles and in vivo killing effects of the combination at different dosing ratios were studied. An inoculum effect was observed with the antibiotics studied. Synergy was seen against both the inocula at the following concentration ratios: 70% C(ami) + 30% C(pip) and 75% C(ami) + 25% C(pip), where C(ami) and C(pip) are the concentrations of amikacin and piperacillin to produce a 1000-fold decrease in bacterial population over 5 h, respectively. The CIC values determined corroborated with the order of in vitro bacterial killing observed for the antibiotic combinations. The dosing ratio of 12.6 mg/kg amikacin + 36 mg/kg piperacillin (a 70:30 ratio of the individual doses) exhibited the greatest killing in vivo when compared to the other ratios. The PK-PD relationships were described by simple, linear regression equations using the area under the in vivo killing curve as a PD marker and the AUCIC(ami)/CIC(ami) + AUCIC(pip)/CIC(pip), AUC(ami)/CIC(ami) + AUC(pip)/CIC(pip), C(max,ami)/CIC(ami) + C(max,pip)/CIC(pip), and AUCIC(ami)/MIC(ami) + AUCIC(pip)/MIC(pip) as PK markers for the amikacin + piperacillin combination. The combination of amikacin and piperacillin exhibited synergistic killing effect on P. aeruginosa that could be modeled using CIC as a surrogate marker relating the PK parameters to in vivo bactericidal effect.

Necrotizing fasciitis

Ten cases of necrotizing fasciitis are reviewed. Three patients died but only two of these deaths were due to uncontrolled septicaemia. All isolated organisms were sensitive to a combination of piperacillin and ampicillin which we now regard as the initial antibiotic combination of choice. Prompt and aggressive surgical debridement remains the cornerstone of management.

Pharmacokinetics of piperacillin–tazobactam: intermittent dosing versus continuous infusion

In the present study 24 hospitalized patients requiring empirical antibiotic treatment were randomly assigned to receive the β-lactam antibiotic/β-lactamase inhibitor combination piperacillin–tazobactam either as an intermittent or as a continuous infusion. According to pharmacokinetic modelling, the daily dose was reduced by 33% in patients receiving continuous infusion compared with intermittent infusion. Dose reduction because of impaired renal function was required in the intermittent dosing group for 5 of 12 patients compared with 1 of 12 patients in the continuous infusion group. However, the mean daily dose in the continuous group was 15% less than the intermittent infusion group. Mean serum concentrations of piperacillin were to 39.0 μg/ml after the end of bolus distribution, exceeding by far the minimal inhibitory concentration of the most clinically relevant pathogens. The corresponding mean value for tazobactam was 6.3 μg/ml. Pharmacokinetic/pharmacodynamic modelling suggests that both treatment schemes should produce virtually identical anti-infective responses to sensitive, intermediate and resistant strains. In the present study the continuous infusion of piperacillin/tazobactam provided adequate antibacterial activity over the 24-h dosing period and offers the potential for a substantial reduction in the total daily dose.

In Vitro Activities of Antibiotic Combinations Against Clinical Isolates of Pseudomonas Aeruginosa

Combination therapy has been recommended to treat Pseudomonas aeruginosa infections worldwide. The purpose of the present study was to determine the in vitro activities of piperacillin, cefepime, aztreonam, amikacin, and ciprofloxacin alone and in combination against 100 clinical isolates of P. aeruginosa from one medical center in southern Taiwan. The combination susceptibility assay was performed using the checkerboard technique. The percentage of resistance of P. aeruginosa to single agents in our study was relatively high for the Asia-Pacific area, except to aztreonam. Piperacillin plus amikacin exhibited the highest potential for synergy (59/100) in this study. Moreover, a high percentage of synergism was also noted with amikacin combined with cefepime (7/100) or aztreonam (16/100). The combination of two beta-lactams, such as cefepime with piperacillin, and aztreonam with cefepime or piperacillin, showed synergistic effects against some P. aeruginosa isolates. Although ciprofloxacin is a good anti-pseudomonal agent, a very low potential for synergy with other antibiotics was demonstrated in this study. No antagonism was exhibited by any combination in our study. Among piperacillin-resistant strains, there was synergy with a beta-lactam plus amikacin, including the combination of piperacillin and amikacin. However, the combination of two beta-lactams, such as piperacillin and cefepime or aztreonam, did not have any synergistic activity against these strains. In summary, the combinations of amikacin with the tested beta-lactams (piperacillin, aztreonam, cefepime) had a greater synergistic effect against P. aeruginosa, even piperacillin-resistant strains, than other combinations. Understanding the synergistic effect on clinical strains may help clinicians choose better empirical therapy in an area with high prevalence of multidrug-resistant P. aeruginosa.

Effects of Freezing, Long-Term Storage, and Microwave Thawing on the Stability of Piperacillin Plus Tazobactam in 5% Dextrose for Infusion

Background: A combination of piperacillin with tazobactam is often administered to hospital patients by infusion. Advance preparation of IV solutions of these drugs could be an efficient way to improve the quality, time management, and cost associated with drug delivery, but little is known about the stability of these drugs after freezing followed by microwave thawing. Objective: The purpose of the study was to investigate how a process of freezing, long-term storage, and microwave thawing affects the stability of piperacillin with tazobactam in 5% dextrose for infusion. Methods: Five replicates of a mixtures of 4 g piperacillin and 0.5 g tazobactam in 20 mL of water plus 100 mL of 5% dextrose were prepared and stored in polyvinyl chloride (PVC) bags. The stability of the mixtures was studied after freezing for 3 months at -20°C followed by thawing in a microwave oven and additional storage at 4°C for up to 60 days. The concentrations of piperacillin and tazobactam in each sample were measured by high-pressure liquid chromatography. The samples were inspected visually, and pH was measured. Results: After 3 months of storage at -20°C, microwave thawing, and 35 days of storage at 4°C, more than 90% of the initial concentration of both piperacillin and tazobactam remained. At this point, the lower 95% confidence limit of the best-fit line by linear regression of percent remaining was 90.1% for piperacillin and 90.3% for tazobactam. The pH decreased by 1.16 units over 35 days of storage at 4°C, but no colour change of precipitation was observed. From 35 to 60 days, the concentrations of both piperacillin and tazobactam fell below the acceptable limit and pH values continued to decrease slightly. Conclusions: The combination of piperacillin (4 g/120 mL) and tazobactam (0.5 g/120 mL) in 5% dextrose stored in PVC bags, frozen for 3 months at -20°C, thawed in a microwave oven, and then stored at 4°C for an additional 35 days retained more than 90% of the initial concentration of each drug. This should allow for advance preparation of this drug combination.

Necrotizing fasciitis: management and outcome.

To observe the various clinical presentations of necrotizing fasciitis and evaluate their management and outcome. An observational descriptive study. Surgical-c unit of Khyber Teaching Hospital, Peshawar, from July 2001 to June 2002. The study included 20 patients of necrotizing fasciitis treated during this period. Age, gender, clinical presentation and predisposing factors were recorded. Pus was cultured and the isolated organism and their sensitivity identified. Management included broad-spectrum antibiotics, extensive and frequent debridements along with supportive measures. Common age group was 21-40 years with a male predominance. eight patients had necrotizing fasciitis of inguinoscrotal and perineal region, while 6 each had abdomen and 6 with necrotizing fasciitis of the limbs involvement. Factors predisposing to infection were diabetes in 5 patients, abscess in 6, trauma in 3 and surgery in 3 patients, while no specific cause was found in 3 cases. Escherichia (E. coli), Bacteroids, Enterococci and Streptococci were the commonest organisms isolated. All were sensitive to a combination of piperacillin and ampicillin. Debridements were done 1-5 times in most cases. Fifteen patients (75%) had complete recovery, 2 (10%) went to other hospitals on their own, 2 (10%) patients expired while one patient was referred to the plastic surgery unit. Necrotizing fasciitis has multiple etiology and predisposing factors. The bacteriology is poly microbial. Early presentation and diagnosis, supportive measures, broad-spectrum antibiotics, prompt and aggressive surgical debridements remains the cornerstone of management.

In vitro effects of combinations of antipseudomonal agents against seven strains of multidrug-resistant Pseudomonas aeruginosa.

The aim of this study was to evaluate the combined effects of antibiotic combinations by agar incorporation inhibitory tests and by time-kill tests on seven geographically and epidemiologically distinct isolates of multidrug-resistant Pseudomonas aeruginosa. All seven strains were resistant to piperacillin, meropenem, ceftazidime, cefoperazone-sulbactam, aztreonam, amikacin and ciprofloxacin. Strains were distinguished by pulsed-field gel electrophoresis after DNA extraction and restriction with SpeI. MICs of the seven antibiotics listed above were determined by agar dilution. The effect of combinations of these agents was determined by agar incorporation tests and by time-kill studies. Among the two-drug combinations, the combination aztreonam and amikacin was the most effective, inhibiting proliferation in five of the seven strains. Among the three-drug combinations, the combinations of piperacillin, ceftazidime and amikacin, and that of ceftazidime, aztreonam and amikacin were the most effective, inhibiting proliferation in all seven strains. In the killing tests, the three-drug combination of ceftazidime, aztreonam and amikacin was the most effective. This three-drug combination had bacteriostatic effects on all seven strains 2, 4, 6 and 24 h after drug addition, synergic effects on 2-3 strains and bactericidal effects on 1-2 strains after 4, 6 and 24 h. The three-drug combination of ceftazidime, aztreonam and amikacin may be effective against P. aeruginosa resistant to all commonly used antipseudomonal drugs, and deserves further study.

Penetration of piperacillin and tazobactam into pneumonic human lung tissue measured by in vivo microdialysis.

The pharmacokinetic profile of antibiotics at the site of anti-infective action is one of the most important determinants of drug response, since it correlates with antimicrobial effect. Up to now, only limited information on the lung tissue pharmacokinetics of antibiotic agents has been available. The aim of this study was to measure, using a new microdialysis-based approach, antibiotic penetration into the extracellular space fluid of pneumonic human lung parenchyma. The lung penetration of a combination of piperacillin and tazobactam, substances with low protein binding, was determined in five patients suffering from pneumonia and metapneumonic pleural empyema. The condition was treated by decortication after lateral thoracotomy. Intra-, or post-operatively, respectively, two microdialysis probes were inserted into pneumonic lung tissue, and into healthy skeletal muscle to obtain reference values. Serum and microdialysis samples were collected at 20-min intervals for at last 8 h following i.v. administration of a single dose of 4 g piperacillin and 500 mg tazobactam. The mean free interstitial concentration profiles of piperacillin in infected lung tissue and serum showed a maximal tissue concentration (Cmax) of 176.0 +/- 105.0 mg l-1 and 326.0 +/- 60.6 mg l-1, respectively. The mean AUC (area under the curve) for infected lung tissue was 288.0 +/- 167.0 mg.h l-1 and for serum 470.0 +/- 142.0 mg.h l-1. There was a statistically significant difference between AUC (lung) and AUC (serum) (P = 0.018) as well as between AUC (lung) and AUC (muscle) (P = 0.043). The intrapulmonary concentrations of piperacillin and tazobactam exceeded the minimum inhibitory concentrations (MIC) for most relevant bacteria for 4-6 h. The procedure was well tolerated by all patients and no adverse events or microdialysis-associated side-effects were observed. This microdialysis technique enabled continuous tissue pharmacokinetic measurement of free, unbound anti-infective agents in the lung tissue of patients with pneumonia. The present data corroborate the use of piperacillin and tazobactam in the treatment of lung infections caused by extracellular bacteria and demonstrate the distribution of piperacillin and tazobactam in the interstitial space of pneumonic lung tissue.

Evaluating Possible Pharmacokinetic Interactions between Tobramycin, Piperacillin, and a Combination of Piperacillin and Tazobactam in Patients with Various Degrees of Renal Impairment

A study was performed to further investigate the apparent instability of tobramycin when coadministered with piperacillin/tazobactam in subjects with renal impairment. Twenty‐six otherwise healthy volunteers between 23 and 74 years of age were studied. Eight subjects had moderate renal impairment, 10 had mild renal impairment, and 8 had normal renal function. Each subject received single doses of piperacillin/tazobactam and tobramycin alone as well as combined doses in a randomized, three‐way crossover design. The subjects with normal renal function also received combined doses of piperacillin and tobramycin. Considerable care was taken to protect against in vitro inactivation of plasma and urine samples after collection. No systematic changes in pharmacokinetic parameters were observed. It is concluded that piperacillin, either alone or with tazobactam, did not change the pharmacokinetics of tobramycin in subjects with renal impairment. The apparent in vivo inactivation of tobramycin in the presence of piperacillin or piperacillin/tazobactam reported by others may be an artifact of ex vivo inactivation.

Failure of systemic antibiotics to eradicate gram-negative bacilli from the airway of mechanically ventilated very low–birth-weight infants

Background: Gram-negative bacillary (GNB) airway colonization in mechanically ventilated newborns is associated with morbidity and mortality, which may be reduced if systemic antimicrobial therapy eradicates GNB from the airway. Efforts to do so in adults have met with variable success; similar experiences in newborns have not been reported. Methods: From 1991 through 1998, 531 very low–birth-weight infants were mechanically ventilated longer than 2 weeks. The study group was 106 infants with GNB airway colonization. Sixty-four other neonates in whom GNB nosocomial bloodstream infections developed served as antibiotic treatment outcome control. Results: Isolated from the airway were enteric (70 cases) and environmental (36 cases) GNB. Gentamicin alone or with ceftazidime (79), ceftazidime (11), piperacillin in combination with tazobactam or tobramycin (8), and tobramycin, in combination with ampicillin/sulbactam or mezlocillin (8) were the antimicrobials selected. Systemic antibiotics failed to eradicate GNB colonization in 97% of the cases. Six of the 106 infants with airway colonization died for reasons unrelated to infection. Sixty-four infants experienced 67 bloodstream infections as a result of enteric (53) and environmental (14) GNB. Gentamicin alone (23), with ceftazidime (26), or with clindamycin or ampicillin/sulbactam (9), piperacillin with tazobactam or tobramycin (3) and ceftazidime alone (6) were the antimicrobials selected. Survival occurred in 84% of the 67 nosocomial bloodstream infections. Conclusions: Systemic antibiotics do not consistently eradicate GNB from the airway of mechanically ventilated newborns, therefore its empirical use for prophylaxis or treatment of airway colonization should be discouraged. (AJIC Am J Infect Control 2000;28:286-90)

Pseudomonas aeruginosaStomatitis as a Sequel to Trichomoniasis in Captive Saker Falcons (Falco cherrug)

Twelve adult female saker falcons developed reduced appetite, progressive weight loss, and unilateral or bilateral sinusitis. Nodular white or yellow caseous lesions were visible on the oropharynx and tongue of all birds. One falcon had 2 caseous masses on either side of the tracheobronchial syrinx, resulting in severe tracheal stenosis. All 12 birds had a history of mild to moderate trichomonal infections 3–4 weeks before examination. In all birds, bacterial culture of samples from these masses yielded pure growths of Pseudomonas aeruginosa. The birds were treated with a combination of piperacillin (100 mg/kg) and tobramycin (10 mg/kg) administered intramuscularly q12h for 7 days. Oropharyngeal lesions were debrided, and the oral cavity of each bird was sprayed with a 1% povidone iodine mouthwash preparation. In birds with unilateral or bilateral sinusitis, a solution of 0.2 ml of a 5% chlorhexidine gluconate preparation diluted to 20 ml with sterile saline was used to flush the affected sinus q12h for 3–5 days. Tracheal masses in the 1 falcon were removed by curettage during tracheoscopy. Oropharyngeal lesions in all birds were completely resolved within 8–18 days of treatment. Trichomoniasis coupled with stress during the training and hunting seasons may have predisposed these falcons to infection with P aeruginosa.

Benzocaine-Induced Methemoglobinemia

Benzocaine-Induced Methemoglobinemia

Activity of a broad-spectrum cephalosporin (Ro 48-8391) alone and in combination with two novel β-lactamase inhibitors (Ro 48-5545 and Ro 48-8724)

The susceptibility of a group of β-lactamase–producing and drug-resistant Gram-positive and Gram-negative organisms was tested against a novel cephalosporin (Ro 48-8391) alone and in combination with two bridged carbacephem β-lactamase inhibitors (Ro 48-5545 or Ro 48-8724) and compared with that of ceftriaxone, ceftazidime, and cefepime (representative “third- and fourth-generation” cephalosporins), imipenem, and a combination of piperacillin and tazobactam. Five hundred and one selected clinical isolates were tested using the reference broth microdilution method (National Committee for Clinical Laboratory Standards). Ro 48-8391 has a spectrum of activity and potency most similar to ceftriaxone but with improved activity against Gram-positive species. The two β-lactamase inhibitors, Ro 48-5545 and Ro 48-8724, have modest antimicrobial activity. When combined with Ro 48-8391, the β-lactamase inhibitor Ro 48-8724 was superior to the combination of Ro 48-8391 and Ro 48-5545 in spectrum and enzyme inhibition against extended spectrum β-lactamase enzyme-producing Escherichia coli and Klebsiella pneumoniae, and against Enterobacteriaceae with “stably derepressed” Bush-Jacoby-Medeiros gr. 1 enzymes (ceftazidime-resistant Enterobacter and Citrobacter). Ro 48-5545 and Ro 48-8724 appear to be promising β-lactamase inhibitors with potential application against chromosomal- and plasmid-mediated enzymes. Ro 48-8391, although superior to some currently available “third-generation” cephems, was not a well-matched active codrug because of limited activity against several commonly isolated species of clinically important bacteria. Further efforts are necessary to find a penicillin or cephem with activity more complementary to that of the tested β-lactamase inhibitors and the Ro 48-8391 compound could be focused for therapeutic use in serious streptococcal infections.

Tolerability of piperacillin/tazobactam in children and adolescents after high dose radio-/chemotherapy and autologous stem cell transplantation.

The combination of piperacillin with tazobactam (PIP/TAZ) extends the activity of piperacillin against gram-positive, gram-negative, and anaerobic bacteria. The broad-spectrum of this formulation, together with its low degree of organ toxicity observed in adults, makes PIP/TAZ a tempting choice for children with radio-/chemotherapy-induced neutropenia. However, the use of PIP/TAZ is not yet approved for children under 12 years of age. The tolerability of PIP/TAZ was assessed in 19 children and adolescents between 2 and 18 years of age who developed a fever during aplasia after high dose radio-/chemotherapy and autologous stem cell transplantation (HD-SCT) for primary multifocal or relapsed solid tumours. Treatment with PIP/TAZ was initiated on average 3 days after HD-SCT, and the treatment was continued for approximately 10 days. Both clinical observation and laboratory studies showed no relevant alterations that would have been attributable to PIP/TAZ treatment. These results indicate that PIP/TAZ appears to be well tolerated in children during the acute phase of HD-SCT.

Ceftazidime Compared with Piperacillin and Tobramycin for the Empiric Treatment of Fever in Neutropenic Patients with Cancer: A Multicenter Randomized Trial

To compare piperacillin and tobramycin with ceftazidime alone for the empiric treatment of fever in the neutropenic patient without evidence of skin infections or anaerobic infections. A multicenter, randomized, controlled trial. 876 febrile, neutropenic episodes in 696 patients (83% acute leukemia or bone marrow transplantation); 92 episodes were excluded from analysis because of protocol violation. Patients received either intravenous ceftazidime (2 g every 8 h) or piperacillin (12 to 18 g/d in 4 to 6 divided doses plus tobramycin (1.7 to 2.0 mg/kg body weight every 8 h). Treatment could be modified at any time at the discretion of the investigator. Percentage of satisfactory response, eradication of the infecting organism, development of superinfections, and occurrence of adverse events. As a single agent, ceftazidime was as effective as the combination of piperacillin and tobramycin (62.7% satisfactory responses compared with 61.1%; odds ratio, 1.07%; 95% Cl, 0.79 to 1.44; P > 0.2). Equivalent responses were also obtained in episodes of profound neutropenia (odds ratio, 0.76; Cl, 0.43 to 1.33; P > 0.2). Infectious mortality was 6% for ceftazidime and 8% for the combination therapy. Eradication of the infecting organisms was achieved in 79% of bacteremic episodes treated with ceftazidime compared with 68% of the episodes treated with the combination therapy (odds ratio, 1.76; Cl, 0.92 to 3.38; P = 0.08), and rates for gram-negative rod bacteremia were also similar (95% compared with 77%; odds ratio, 5.25; Cl, 1.0 to 27.5; P = 0.03). Superinfections developed in 38 episodes in each group. An adverse event occurred in 8% of episodes treated with ceftazidime compared with 20% of episodes treated with combination therapy (P < 0.001). Ceftazidime alone was as effective but safer than the combination of piperacillin and tobramycin for the empiric treatment of febrile, neutropenic patients, even those with profound and prolonged granulocytopenia.

In vitro and in vivo efficacy of tazobactam and piperacillin combination and their most effective combination ratio

<I>In vitro</I> and <I>in vivo</I> efficacy of tazobactam and piperacillin combination and their most effective combination ratio