Pharmacokinetic and pharmacodynamic profile of high dose extended interval piperacillin–tazobactam

Myo-Kyoung Kima, Dawei Xuana, Richard Quintiliania,b, Charles H. Nightingalea,c and David P. Nicolaua,b,*

a Department of Pharmacy Research, b Division of Infectious Diseases and c Office of Research, Hartford Hospital, Hartford, CT 06102, USA


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A multiple-dose, open-labelled, randomized, two period crossover human volunteer study was performed (i) to describe the pharmacokinetic profile and safety profile of piperacillin and tazobactam (P/T) administered 6.0/0.75 g and 8.0/1.0 g q12h and (ii) to characterize the pharmacodynamic profile of these regimens against a variety of common targeted pathogens. Blood samples were collected after the third dose and concentrations of P/T were determined by a validated high-performance liquid chromatography assay. Pharmacokinetic profiles of P/T were determined by non-compartment analysis. Percentage time above the MIC (%T > MIC) of piperacillin was calculated for a range of MICs. In this study, no adverse events were attributed after multiple administrations of either 6.0/0.75 g or 8.0/1.0 g dose regimens. The peak concentration, half-life and area under the curve (AUC0–0-{tau}) of piperacillin were significantly different by a paired t-test (P < 0.05) between the two study regimens. The trough concentration, half-life and area under the curve (AUC0–0-{tau}) of tazobactam were substantially different from parameters reported previously for conventional regimens. The 8.0/1.0 g regimen provided 50% T > MIC for MICs <=32 mg/L, while a similar value for the 6.0/0.75 g regimen was <= 16 mg/L. High-dose P/T regimens with extended interval were well tolerated and provide adequate dynamic exposure for a variety of susceptible pathogens.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Zosyn consists of piperacillin and tazobactam (P/T) at a fixed ratio of 8:1. Piperacillin is a potent, broad-spectrum ureidopenicillin. When combined with a triazolymethyl penicillanic acid sulphone ß-lactamase inhibitor, tazobactam, the resultant combination possesses a broader spectrum of activity including ß-lactamase-producing Gram-negative, Gram-positive and anaerobic organisms.1 Based on the current understanding of antimicrobial pharmacodynamics for concentration-independent agents like ß-lactams, a calculated time above the MIC of >=50% of the dosing interval is considered to produce an acceptable drug exposure for pathogens.25 Using more up-to-date pharmacodynamic principles, it is postulated that the dosing interval for P/T can be extended if larger doses are administered. This same strategy has been investigated for other extended spectrum penicillins with favourable results.6 Moreover, several investigators have suggested that P/T displayed non-linear pharmacokinetics.713 As more P/T was administered, the elimination was slower, resulting in a longer half-life. Thus, the non-linear pharmacokinetics of P/T may further justify the administration of larger doses and an increased dosing interval in many clinical scenarios involving a variety of pathogens. In addition, Reed et al.14 demonstrated that high doses of P/T are well tolerated even at doses of piperacillin of 100 mg/kg for infants and children. However, the effect of these larger doses in adults has not been characterized. High dose regimens with extended intervals have the potential for cost savings by reducing the number of daily administrations. Also, it is favoured for certain settings including home infusion or nursing homes. By studying healthy subjects in a randomized, crossover design, we evaluated the pharmacokinetics of P/T 9 g q12h and 6.75 g q12h, which are equivalent to total daily doses of 4.5 g q6h and 3.375 g q6h, respectively. These data along with published MICs could reasonably determine situations when P/T can be dosed using an extended interval.

The objectives of this study are to (i) describe the pharmacokinetic (PK) and safety profile of P/T administered at a dosage of 6.75 g (piperacillin 6 g, tazobactam 0.75 g) and 9.0 g (piperacillin 8 g, tazobactam 1 g) every 12 h and (ii) describe the pharmacodynamic profile of these regimens against a variety of commonly targeted pathogens.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Subjects

Twelve healthy human volunteers participated in this randomized, open-labelled, multiple-dose, two-treatment, two-period crossover trial separated by at least 5 days. Study procedures and informed consent were approved by the institutional review board. All volunteers gave their informed consent. Individuals were considered eligible for the study if they were at least 18 years old, did not have a history of hypersensitivity to the study drugs or related compounds, and did not take any medication besides oral contraceptives.

Prospective healthy volunteers underwent screening by a physical examination and a medical history was obtained to rule out the possibility of renal, hepatic, endocrine, cardiovascular or neurological disorders or other diseases that might influence the PK profile of the test agent and also increase the risk of adverse reactions. Blood chemistries, haematology and urinalysis were also performed for each subject before enrolment. Female volunteers were screened by a direct latex agglutination test to rule out pregnancy.

Subjects were excluded from enrolment in the study if they had the following: previous history of hypersensitivity to the study medications, substance abuse, diabetes mellitus, acute illness within 7 days before study entry, any concomitant medication that would need to be used during the study period, use of any anti-infective medication within 2 weeks before study entry, abnormal laboratory values defined as greater than twice the upper limit of normal or pregnancy.

All subjects were admitted and housed overnight at Hartford Hospital's clinical research centre for two 48 h periods. They were not allowed to consume alcoholic beverages, smoke or ingest caffeine-containing beverages or food during the trial period. They were also instructed to refrain from vigorous activity during the trials. They fasted from 8 h pre- to 4 h post-P/T administration.

Study agents and administration

Eligible subjects were randomized to receive a multiple-dose regimen of piperacillin–tazobactam (Zosyn Lot number 426-112 or 426-169; Lederle Piperacillin, Inc., Carolina, Puerto Rico) either 6.75 g (piperacillin 6 g, tazobactam 0.75 g) every 12 h or 9.0 g (piperacillin 8 g, tazobactam 1 g) every 12 h. The dosages were selected to provide the same daily dose (13.5 g and 18 g) as conventional therapy. In addition, these high dosage regimens (c. 80 mg/kg and 100 mg/kg in a 70 kg subject) have been used safely in the paediatric population.14 All intravenous doses were diluted in 100 mL 0.9% sodium chloride injection, USP (Abbott Laboratories, North Chicago, IL, USA) and administered over 1 h to avoid excessively high peak concentrations. Regimens were dosed three times in order to achieve steady state. After an interval of at least 5 days, subjects were administered the dosage regimen not given during the first study period.

Blood sample collection

Blood samples (10 mL) for drug concentration determinations were collected around the time of administration of the third dose from an indwelling iv catheter in a forearm vein contralateral to the one used for drug administration. Time points designated for concentration determinations were as follows: before drug administration (time 0), 1, 2, 3, 4, 6, 8, 10 and 12 h after the initiation of the infusion. All blood samples were clotted for 15 min at room temperature, then centrifuged at 2400 rpm for 10 min. Sera were separated into three vials and stored at –80°C until assayed for drug concentrations.

Assays

Piperacillin serum concentrations were analysed by a validated high-performance liquid chromatographic (HPLC) method. The equipment included a pump (Model 515; Waters, Milford, MA, USA), autosampler (WISP 717 plus; Waters), UV detector (SM 4000; LDC/Milton Roy, Riviera Beach, FL, USA) with wavelength set at 254 nm and a chromatography data system (EZChrome Elite; Scientific Software, San Ramon, CA, USA). Chromatographic separation was performed with a reverse-phase HPLC column (Novapak C18, 3.9 x 150 mm; Waters). The mobile phase consisted of 25% HPLC grade acetonitrile and 75% sodium phosphate buffer (0.02 M, pH 3, v/v) and was delivered at a flow rate of 1.0 mL/min.

Serum samples were thawed at room temperature before HPLC analysis. Penicillin G (internal standard) solution was added to all the unknowns as well as to standards. Protein precipitation was accomplished by adding 4 vol. (0.8 mL) of acetonitrile to the samples, vortexing for 30 s and centrifuging at 3600g for 10 min. To the resultant supernatant, 2 mL of dichloromethane was added. The mixture was vortexed for 30 s, the aqueous layer was separated by centrifugation at 3600g for 10 min and injected into the HPLC. The limit of quantification was 0.5 mg/L. The intra-assay coefficients of variation were 0.26 and 0.24% for QC samples of 1 and 40 mg/L, respectively. The inter-assay coefficients of variation were 1.9 and 2.8% for QC samples of 1 and 40 mg/L, respectively.

The HPLC equipment used for the tazobactam assay was the same as the one described above for the piperacillin assay except that the UV wavelength was set at 235 nm. Chromatographic separation was performed with a reverse-phase HPLC column (Nucleosil 100 C18, 4.6 mm x 250 mm; Alltech, Deerfield, IL, USA). The mobile phase consisted of 5% HPLC grade acetonitrile and 95% sodium phosphate buffer (0.01 M, pH = 2.3, v/v) containing 0.004 M tetrabutylammonium hydrogen sulphate and was delivered at a flow rate of 1.2 mL/min.

After thawing at room temperature, serum samples were loaded on to OASIS cartridges (Waters) that were pre-conditioned using 1 mL of methanol followed by 1 mL of water. To the eluent, cephalexin (internal standard) solution was added, followed by the addition of 4 vol. of acetonitrile, vortexing for 30 s and centrifugation at 3600g for 10 min. To the resultant supernatant, 2 mL of dichloromethane was added. After the mixture was vortexed for 30 s, the aqueous layer was separated by centrifugation at 3600g for 10 min and injected into the HPLC. The limit of quantification was 1.0 mg/L. The intra-assay coefficients of variation were 6.7 and 5.4% for QC samples of 3 and 40 mg/L, respectively. The inter-assay coefficients of variation were 5.5 and 2.6% for QC samples of 3 and 40 mg/L, respectively.

Safety assessment

Subjects were monitored throughout the study for adverse events. Post-trial physical examination and laboratory evaluations were implemented to confirm the presence or absence of chemical or haematological adverse events resulting from the study drug.

Pharmacokinetic analysis

Pharmacokinetic parameters were derived individually for each subject and each drug component. The Cmax was obtained directly from a plot of concentration–time data. The terminal elimination rate constant (Kel) was estimated by least squares regression analysis of the terminal phase of the log-linear plot of concentration–time data. Individual half-life (t1/2) values were calculated as 0.693/Kel. The area under the concentration–time curve (AUC0–12) was calculated using the linear-trapezoidal rule. Systemic clearance (CL) was estimated as dose/AUC0–12.

Pharmacodynamic analysis

The percentage time above the MIC (%T > MIC) of piperacillin for each regimen was calculated using Equation 1 from the individual PK parameters of each subject relative to a variety of pathogens including Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Bacteroides fragilis, Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus and other common clinical pathogens.


where Tinf = infusion time (1 h), C1 h = concentration at the end of infusion (= Cmax), C0 h = concentration at the beginning of infusion, K = rate constant and {tau} = dosing interval.

The modal MIC of piperacillin for each pathogen was determined by searching literature through Medline and selecting studies that reported MICs of P/T and were performed with isolates from the USA.1522 In addition, we compared %T > MIC for each regimen with that of each conventional dosing regimen (3.375 g q6h, 4.5 g q8h and 4.5 g q6h),23,24 since %T > MIC is the best pharmacodynamic predictor of efficacy for ß-lactams. The %T > MIC values of conventional dosing regimens were calculated from the mean of the PK parameters in two studies published previously, using Equation 1.

Statistical analysis

A two-tailed paired t-test was used to compare the estimated PK parameters for each drug component between the regimens studied.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Subjects and safety assessments

Twelve subjects were enrolled. Two subjects were withdrawn; one subject developed cystitis during the washout period and the other received an erroneous dose. The 10 subjects who completed both two-way treatments comprised six males and four females. They ranged in age from 20 to 43 years (mean ± S.D., 30.7 ± 7.6), in weight from 48.2 to 97.5 kg (mean ± S.D., 73.7 ± 15.5) and in height from 155 to 178 cm (mean ± S.D., 166 ± 7). Each subject's ratio of actual body weight (ABW) to ideal body weight (IBW) was <1.15 when IBW was calculated using the following formulae; 50 + (2.3 x male height in inches over 5 feet) or 45.5 + (2.3 x female height in inches over 5 feet). Serum creatinine values ranged from 75.1 to 101.7 µmol/L (mean ± S.D., 84.0 ± 15.9). Subjects tolerated both regimens well, with the exception of mild phlebitis noted for one subject following the first administration of P/T at 6.75 g. However, the phlebitis subsided over time despite the administration of two additional doses. Interestingly, phlebitis was not induced by the administration of P/T at 9 g in the following week. Therefore, the phlebitis may have been triggered by the minor trauma associated with catheter insertion or other factors rather than the study medication. In addition, one subject had mild diarrhoea, which resolved without any intervention. No physical, chemical or haematological abnormalities were detected per post-physical examination and post-study laboratory test.

Pharmacokinetic analysis

The serum concentration versus time profiles for both dosage regimens of piperacillin and tazobactam are presented in the FigureGo. The two trough concentrations (0 h and 12 h) of piperacillin were not significantly different from each other; thus indicating that steady state had been achieved during the sampling period. This also held true for tazobactam. As shown in the FigureGo, the piperacillin: tazobactam plasma concentration ratio was not proportional at all time points. The ratio averaged 34:1 and 21:1 for the peak of 9 g and 6.75 g, respectively, and decreased to 8:1 close to 3 h post-administration for both regimens. Furthermore, the tazobactam concentration exceeded the piperacillin concentration at approximately 7 h post-administration.



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Figure. Serum concentrations of piperacillin and tazobactam. Subjects were administered multiple-dose regimens of P/T 9.0 g q12h and 6.75g q12h and concentrations were measured at around the time of administration of the third dose. Values are mean ± S.D. of 10 subjects. ({circ}) Piperacillin 8 g (P/T 9 g); ({blacktriangleup}) piperacillin 6 g (P/T 0.75 g); ({diamondsuit}) tazobactam 1 g (P/T 9 g); ({square}) tazobactam 0.75 g (P/T 0.75 g).

 
Mean PK parameters (± S.D.) of P/T for each dosing regimen are presented in Table IGo. The t1/2, Kel, Cmax, Cmin and AUC of piperacillin were significantly different (P < 0.05) between the two study regimens. The Cmin of tazobactam was also significantly different (P < 0.05) between the two study regimens. The differences in the half-lives of piperacillin and those of tazobactam in both study dose regimens achieved statistical significance (P < 0.01).


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Table I. Mean (± S.D.) PK parameters of piperacillin and tazobactam
 
Pharmacodynamic analysis

The mean percentage time above the MIC (%T > MIC) of piperacillin S.D.) for various pathogens was calculated for both study regimens and are displayed in Table IIGo. The 9 g q12h regimen achieved at least 50% T > MIC at MIC <= 32, while the 6.75 g q12h regimen achieved this at MIC <= 16. As listed in Table IIGo, the study regimens provided high %T > MIC for most Gram-positive pathogens, B. fragilis and some Gram-negative pathogens with lower MICs. In addition, the current study regimens also provided >50% T > MIC for some relatively less piperacillin-susceptible Gram-negative pathogens including Enterobacter spp., Citrobacter spp., Acinetobacter spp. and P. aeruginosa.


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Table II. Time above MIC dose predictions for P/T in 10 adult healthy subjects
 
The %T > MIC values of the current study regimens versus those of conventional dosage regimens23,24 are listed in Table IIIGo. At an MIC of 16, the study regimen of 6.75g q12h yielded higher %T > MIC values than the conventional dosage regimens of 3.375 g q6h and 4.5 g q8h; the %T > MIC with the 6.75 g q12h regimen approached 50%. In addition to achieving a T > MIC of >50% at a MIC of 32, the 9 g q12h regimen was the only one to approach a value of 50% T > MIC. Other dosage regimens achieved %T > MIC values ranging from 34 to 39% at an MIC of 32 mg/L.


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Table III. Percentage time above MIC (%T > MIC) of the study regimens and calculated %T > MIC of conventional regimens from literature PK parameters
 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Ureidopenicillins have been described as displaying non-linear pharmacokinetics by several investigators who demonstrated increases in terminal elimination half-life (t1/2) of piperacillin or decreases in its total clearance (CL).713 However, some investigators have shown that piperacillin has linear PK properties.14,2527 Because of this discrepancy, the concept of non-linear kinetics for piperacillin has aroused controversy. To date, all previous studies compared the PK parameters of piperacillin doses up to 4.0 g. Instead of using conventional doses, we utilized doses up to 8 g to compare PK parameters in our study.

In order to compare the parameters of our study dosage regimens with those of conventional dosage regimens, we adopted PK data published by Klepser et al.23 for 3.375 g q6h and 4.5 g q8h and by Richerson et al.24 for 4.5 g q6h. These studies were performed at our institution and utilized the same procedure (including a total of three doses) except for different dosage regimens and infusion time (0.5 h). As shown in Table IGo, the t1/2 of piperacillin (1.12 ± 0.05 h) for the 9 g P/T q12h regimen differed significantly from that of the 6.75 g P/T regimen (1.07 ± 0.05 h, P < 0.05). The t1/2 in the conventional studies23,24 was 0.83 ± 0.08 h, 0.93 ± 0.06 h and 0.81 ± 0.22 h for 3.375 g q6h, 4.5 g q8h and 4.5 g q6h, respectively. When compared, the half-lives of both the 6.75 g and 9 g q12h regimens were significantly different from that of the conventional regimens (P < 0.01).

In contrast to the statistically significant differences observed between the half-lives of the 6.75 g and 9 g q12h dosage regimens, the difference between the total elimination CL values in the two high dose regimens did not achieve statistical significance. This discrepancy may be due to high variability of CL caused by administration of a fixed dose to subjects ranging in weight from 48.2 to 97.5 kg. However, the CL values of both 6.75 g q12h (107.8 mL/min) and 9 g q12h (105.9 mL/min) were significantly different (P < 0.01, two-tailed independent t-test) from the values of 3.375 g q6h (234.7 mL/min), 4.5 g q8h (230.7 mL/min) and 4.5 g q6h (211.9 mL/min).

As a result of the non-linear pharmacokinetics of piperacillin, %T > MIC values of our study regimens were elongated compared with conventional regimens (Table IIIGo). As shown in Table IIGo, our study regimens achieved at least 50% T > MIC for most pathogens including P. aeruginosa. However, when the NCCLS breakpoint for P/T against P. aeruginosa is adopted (MIC90 64 mg/L), the %T > MIC value for P. aeruginosa is lower than the values listed in Table IIGo. With the 9 g q12h regimen, the %T > MIC approached 40%. Furthermore, all other regimens including conventional regimens provided only 20– 30% T > MIC for pathogens for which the MIC was 64 mg/L. However, in clinical practice this problem is circumvented by using combination therapy. P. aeruginosa infections are commonly treated with a minimum of two agents since the addition of a second agent lowers the MIC.2830 Therefore, high dose regimens of P/T with extended intervals may be a prudent antibiotic option for P. aeruginosa infections since the study dose regimens provided greater %T > MIC than conventional doses.

A study performed by Occhipinti et al.26 indicated that conventional dosage regimens (3.375 g q6h and 4.5 g q8h) provided >60% T > MIC for E. coli, S. aureus, K. pneumoniae, B. fragilis and P. aeruginosa. However, the MICs for the organisms used in their study ranged from 0.25 mg/L (K. pneumoniae) to 4 mg/L (P. aeruginosa). Since Occhipinti and associates used P. aeruginosa 27853, whose MIC was 4 mg/L, their assertion that conventional regimens provide >60% T > MIC against such a strain cannot be applied to all P. aeruginosa.

The PK parameters of tazobactam, especially t1/2, in our study were substantially different from those of conventional regimens. The half-lives of 9 g q12h and 6.75 g q12h were 5.6 h and 4.6 h, respectively, compared with 0.89 h for 4.5 g q8h and 0.93 h for 3.375 g q6h as shown by Occhipinti et al.26 This difference may reflect non-linear tazobactam kinetics and competitive inhibition of tazobactam elimination by piperacillin.

A study conducted by Sorgel & Kinzig7 demonstrated the non-linear PK properties of tazobactam. The t1/2 and total CL were evaluated for tazobactam administered as single doses ranging from 0.1 to 1.0 g. The half-lives of single dose tazobactam increased from 0.35 h (0.1 g) to 0.63 h (0.1 g) and the total CL decreased from 418 mL/min (0.1 g) to 327 mL/min (1.0 g). In the same trial, Sorgel & Kinzig also studied the effect of piperacillin on tazobactam PK parameters and the converse effect of tazobactam on piperacillin by administering various P/T combinations to human volunteers. Although piperacillin PK characteristics were unaffected by tazobactam, tazobactam PK characteristics were significantly altered by co-administration of piperacillin. When 4 g piperacillin was added to 0.5 g tazobactam, the t1/2 increased from 0.63 h to 0.93 h and the renal CL decreased from 268 to 188 mL/min. Since both piperacillin and tazobactam undergo primarily renal elimination (especially renal secretion), Sorgel & Kinzig7 postulated that piperacillin competitively inhibits the renal elimination of tazobactam.

Two other studies lend support to the idea of piperacillin inhibiting tazobactam elimination. In a human volunteer study performed by Wise et al.,31 the tazobactam concentrations were measured after tazobactam administration with and without piperacillin. Also, the total CL of tazobactam was determined for dosage regimens including tazobactam 0.5 g with and without 4 g piperacillin. The difference in tazobactam concentrations reached a maximum at 4 h post-administration (P < 0.01); the concentration was increased from 0.6 mg/L to 1.2 mg/L by co-administration with 4 g piperacillin. In addition, the total CL of tazobactam was decreased from 203.5 to 134.2 mL/min (P < 0.05). Of interest, they also found that co-administration of piperacillin with tazobactam enhanced tazobactam tissue penetration. Therefore, increased tazobactam tissue penetration resulting from high piperacillin doses may also have contributed to the high tazobactam t1/2 observed in our studies.

Komuro et al.32 also suggested competitive renal tubular secretion as a possible mechanism of decreased tazobactam elimination. A beagle dog model was employed, as protein binding of piperacillin and tazobactam in beagles closely parallel the binding seen in humans. The investigators demonstrated that concomitant administration of probenecid with tazobactam and piperacillin significantly decreased renal CLs of piperacillin and tazobactam.

A consequence of decreased tazobactam elimination secondary to competitive inhibition by piperacillin is the disturbance of the fixed 8:1 ratio for P/T. This phenomenon was reported with conventional doses, although the magnitude of the disturbed ratio was smaller compared with our high dose P/T regimen. Sorgel & Kinzig7 reported that immediately after a 5 min infusion of 4.5 g P/T, the P/T ratio was 11:1. The ratio 3–4 h post-infusion was 7:1. When P/T 4.5 g was infused for 30 min, the peak concentration ratio was 8:1; it fell to 4:1 3–4 h later. In our study, even more impressive alterations in P/T ratios were seen. The ratios at the peak were 34:1 and 21:1 for 9 g and 6.75 g, respectively, while they declined to 8:1 nearly 3–4 h later and finally to <1:1 6 h post-administration in both regimens.

To date, it is unclear whether a P/T ratio deviating from 8:1 has a significant impact on P/T efficacy against ß-lactamase-producing pathogens. However, some studies have implied that such a deviation did not have a deleterious effect on its efficacy. In a study performed by Lister et al.,33 the bactericidal effects of two P/T dosage regimens were compared. The regimens included simultaneous administration of piperacillin 3 g and tazobactam 0.375 g and the sequential administration of 3 g piperacillin with 0.5 h post-tazobactam administration into an in vitro PK model in order to break the 8:1 ratio. These two regimens achieved similar bactericidal effects against ß-lactamase-producing pathogens used in their study.

In the same study,33 the authors postulated that maintaining tazobactam concentrations above a ‘minimum critical concentration (MCC)’ was more critical to accomplishing sustained antimicrobial activity than a fixed P/T ratio of 8:1. They demonstrated that when the tazobactam concentration was below the MCC, significantly larger amounts of piperacillin were required to maintain antimicrobial activity. The opposite was true when the tazobactam concentration was above the MCC.

Kuck et al.1 assessed the effect of fixed concentrations of tazobactam, 2 or 4 mg/L, on piperacillin MICs for ß- lactamase-producing clinical isolates. Both concentrations of tazobactam substantially reduced piperacillin MICs for most ß-lactamase-producing pathogens. However, the 4 mg/L tazobactam concentration induced a greater reduction in piperacillin MICs than the lower concentration. Of interest, in our study, the mean of the trough concentrations (Cmin) of P/T 9 g (tazobactam 1 g) was 4.2 mg/L, which was significantly higher (P < 0.05) than the Cmin of 3.0 mg/L obtained with P/T 6.75 g (tazobactam 0.75 g). This suggests that the 9 g q12h regimen may have a beneficial impact on piperacillin efficacy against ß-lactamaseproducing pathogens.

Although the best pharmacodynamic parameter for tazobactam has not been fully determined by a well-designed study, some researchers suggested that the AUC appears to be an important parameter for the antibiotic activity of combinations with ß-lactamase inhibitors against ß-lactamase-producing pathogens.34,35 The AUC0–24 values of tazobactam in our study were 249.6 and 215.8 mg•h/L for 9 g q12h and 6.75 g q12h, respectively, while those for 4.5 g q8h and 3.375 g q6h were only 120.0 and 120.1 mg•h/L from the study performed by Occhipinti et al.26

In conclusion, high dose P/T dosage regimens with extended interval were well tolerated and were shown to enhance P/T PK parameters. In addition to offering the convenience of less frequent dosing, the 9 g q12h regimen and 6.75 g q12h regimen achieved adequate pharmacodynamic profiles for pathogens with MIC <= 32 and MIC <= 16, respectively. Further studies on high dose P/T dosage regimens with extended interval are warranted to determine the clinical utility of these regimens.


    Acknowledgments
 
We thank Christina Turley and Min Ye for their technical assistance and all other individuals in the pharmacy research department at Hartford Hospital for their assistance with sampling procedures. This study was supported by a grant from Wyeth-Ayerst Laboratories, Pearl River, NY. This study was presented at The American Society for Microbiology, 40th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICCAC), September 2000, Toronto, Ontario, Canada (Abstract No. 2249).


    Notes
 
* Correspondence address. Division of Infectious Diseases, 80 Seymour Street, Hartford, CT 06102, USA. Tel: +1-860-545-3941; Fax: +1-860-545-3992; E-mail: dnicola{at}harthosp.org Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Received 26 November 2000; returned 30 January 2001; revised 2 March 2001; accepted 20 April 2001