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Antimicrobial Agents and Chemotherapy, November 2008, p. 4149-4152, Vol. 52, No. 11
0066-4804/08/$08.00+0     doi:10.1128/AAC.00509-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Piperacillin-Tazobactam Penetration into Human Pancreatic Juice{triangledown}

Elisa Bertazzoni Minelli,1* Anna Benini,1 Luigina Franco,1 Claudio Bassi,2 and Paolo Pederzoli2

Departments of Medicine and Public Health, Pharmacology Section,1 Surgical and Gastroenterological Sciences, University of Verona, Verona, Italy2

Received 18 April 2008/ Returned for modification 2 July 2008/ Accepted 9 September 2008


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ABSTRACT
 
Piperacillin-tazobactam was administered as a single dose (4.5 g intravenous) to five patients with stabilized external pancreatic fistula. The penetration into pancreatic juice was prompt, and inhibitory concentrations were achieved and maintained for different periods (0.5 to 6 h) according to bacterial susceptibility and patients' characteristics. Piperacillin and tazobactam showed superimposable pharmacokinetics in both serum and pancreatic juice.


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TEXT
 
Piperacillin-tazobactam (PIP-TZ), a β-lactam/β-lactamase inhibitor combination, appears to have a useful role in the treatment of patients with complicated intra-abdominal infections (5, 12, 15); however, PIP-TZ's use has not been established for pancreatic infections, and it is unknown whether the degree of PIP and TZ penetration into human pancreatic juice (PJ) is high enough to eradicate relevant pathogens.

For that reason, we evaluated the elimination of PIP-TZ in PJ and the pharmacodynamic properties of the combination against clinical isolates.

This was a single-dose, open-label, noncomparative study. The protocol was approved by the local hospital ethics committee, and informed consent was obtained from all patients.

Five patients, operated on by duodenopancreatectomy for periampullary tumors, and their Wirsung-cutaneous stabilized, high-output pancreatic fistulas managed with external surgical drains were given 4 g PIP and 0.5 g TZ (8:1 ratio) (Tazocin; Wyeth Lederle, Aprilia, Italy) as a single dose by 30 min of intravenous (i.v.) infusion. Treatment started after complete surgical recovery with normalization of pancreatic exocrine function, when PJ may be considered similar to that produced by the normal pancreas.

Venous blood samples were obtained from an indwelling contralateral catheter immediately before (time zero) and 5, 60, 90, 120, 360, and 480 min after PIP-TZ administration. Simultaneously, PJ samples were obtained from stabilized external pancreatic fistula. Serum and PJ samples were frozen at –80°C until analysis.

Antibiotic concentrations in serum, PJ, and standards were processed in parallel by high-performance liquid chromatography (HPLC) and bioassay (antimicrobial activity in the presence of PJ).

The concentrations of PIP and TZ were determined using a gradient elution, reverse-phase HPLC method with UV detection (214 nm) according to Westphal et al. (26) with lower limits of sensitivity of 0.1 mg/liter for PIP and 0.05 mg/liter for TZ both in serum and in PJ.

Pharmacokinetic parameters were determined by the model-independent approach (noncompartmental analysis) using the GraphPad Prism 3.0 software program (GraphPad Software, San Diego, CA).

The concentrations of PIP and TZ alone and in combination were determined in serum and PJ by an agar well diffusion method (2, 4, 27) according to CLSI (formerly NCCLS) guidelines (19) utilizing Pseudomonas aeruginosa NCTC 10701 (0.02% final concentration) as the test microorganism and Difco antibiotic medium 1. All samples were assayed in duplicate or triplicate. PIP and the PIP-TZ combination were linear over a range of concentrations of 3.12 to 50.0 mg/liter (r2 = 0.99).

The MICs of PIP and PIP-TZ against P. aeruginosa NCTC 10701, Klebsiella pneumoniae NCTC 11228, and 39 different species of microorganisms isolated from patients in our surgical department were tested in 96-well microtiter plates (19). Serial twofold dilutions of PIP and PIP-TZ were prepared in Mueller-Hinton broth from 500 mg/liter to 0.97 mg/liter (200 µl per well) (19).

The MIC90s of PIP alone and PIP-TZ were 2.4 mg/liter and 1.2 mg/liter, respectively, against both P. aeruginosa NCTC 10701 and K. pneumoniae NCTC 11228. The MIC90s were <0.97 mg/liter for Staphylococcus aureus strains (3) and Escherichia coli strains (9), 1.6 mg/liter for different E. coli strains (6), 2.4 mg/liter for Enterococcus faecalis (6), and 7.8 mg/liter for S. liquefaciens strains (3). All H. alvei and C. freundii strains and six strains of E. coli were resistant to the PIP-TZ combination (MIC, >500 mg/liter). The MIC90 of PIP alone against S. liquefaciens was 62.5 mg/liter, compared to 7.8 mg/liter for the combination and 9.4 and 1.6 mg/liter, respectively against E. coli.

We evaluated the time period when PIP-TZ concentrations exceed the MIC (TMIC) in serum and PJ against clinical isolates by graphic expression from the concentration-time curves.

Patient characteristics are summarized in Table 1.


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  		TABLE 1. Patient characteristics in this study

The mean serum and PJ concentration-versus-time profiles of PIP and TZ, as determined by HPLC, are shown in Fig. 1a. Peak concentrations of PIP and TZ in PJ were obtained 30 to 90 min after i.v. infusion, ranging from 4.3 µg/ml to 26.0 µg/ml for PIP and from 0.8 µg/ml to 8.0 µg/ml for TZ. The penetration indices were 8.2% ± 4.6% (mean ± standard deviation) for PIP and 13.6% ± 7.1% for TZ, exhibiting adequate penetration capacities of both compounds and very similar pharmacokinetics despite the substantial intersubject variability of drug concentrations. Table 2 shows the main pharmacokinetic parameters and the ratio of PIP to TZ concentrations in serum and PJ. The initial 8:1 ratio of PIP to TZ was maintained in serum, while the ratio in PJ was variable at different sampling times (30, 60, and 90 min), ranging from 4:1 to 10.4:1 (with 8:1 and 4:1 considered optimal and effective ratios) (28).


Figure 1
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  		FIG. 1. PIP and TZ concentrations in serum and PJ following 4.0 g plus 0.5 g as a single i.v. dose, determined by HPLC (a) and by a microbiological method (P. aeruginosa test microorganism) (b). Data are means ± standard deviations from five patients.


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  		TABLE 2. Main pharmacokinetic parameters of PIP and TZ in serum and PJ determined by HPLC

The concentrations of the PIP-TZ combination, as evaluated by the microbiological method, seem slightly higher than the theoretical sum of PIP plus TZ obtained with the HPLC data (Fig. 1a and 1b), confirming an effective antimicrobial activity against a gram-negative strain. The penetration index of PIP-TZ was 8.9% ± 4.1%, corresponding to the HPLC data. The relationship between HPLC and bioassay was linear (r2 = 0.98). A certain intersubject variability in serum and PJ concentrations was recorded (Fig. 2) according to patients' characteristics; therefore the TMIC of PIP-TZ in PJ ranged from 170 to 400 min against susceptible bacteria (MIC, ≤0.97 mg/liter); from 45 to 360 min against strains with a MIC of 1.9 or 2.4 mg/liter and from 30 to 240 min against microorganisms with a MIC of 7.8 mg/liter (S. liquefaciens).


Figure 2
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  		FIG. 2. Inhibitory period of PIP-TZ in serum and PJ against clinical isolates with different susceptibilities (MIC90) by graphic expression from the concentration-time curves for patients (Pt.) 1 to 5. At a MIC90 of 0.97 mg/liter, E. coli (six strains) and S. aureus susceptible, the TMIC in PJ ranged from 170 to 400 min; at a MIC90 of 1.2 to 2.4 mg/liter, P. aeruginosa (one strain), E. coli (six strains), and E. faecalis (six strains) intermediately susceptible, the TMIC in PJ ranged from 45 to 360 min; at a MIC90 of 7.8 mg/liter, Serratia liquefaciens intermediately susceptible, the TMIC in PJ ranged from 30 to 240 min.

According to these data, in some cases (patients 1 and 5) PIP-TZ given every 8 h is an adequate treatment regimen. In patients 3 and 4 (patients with high diuresis and fistula outputs) PIP-TZ inhibited intermediately susceptible bacteria for a reduced period (Fig. 2). In parallel, standard doses of PIP-TZ produced inhibitory serum concentrations against the majority of clinical isolates similar to those observed in healthy subjects (12, 21), ensuring prolonged systemic antimicrobial activity (>6 h). Altered renal function (clearance) and/or age can modify the PIP-TZ pharmacokinetic parameters (17), as well as high fistula output.

Few broad-spectrum antibiotics present appropriate characteristics for the treatment of pancreatic tissue infections (2, 6, 20, 22, 25). β-Lactam drugs exhibit time-dependent bactericidal activity, extravascular distribution, and tissue extracellular fluid concentration: the therapeutic goal is to optimize the duration of antimicrobial exposure (10, 18). This is a critical point for infections caused by gram-negative bacilli (9, 23) and for particular infection sites, such as the pancreas (2-4, 6). β-Lactam agents are useful for treatment of infected acute necrotizing pancreatitis (1, 2, 6, 8, 11, 25), a disease associated with a high mortality rate (7, 24).

Our results suggest more frequent administration of PIP-TZ to obtain and maintain inhibitory antibiotic levels in PJ in all treated patients. Currently, we do not know whether different PIP-TZ administration modalities (13, 14, 16) or higher PIP-TZ doses can improve the PIP-TZ penetration into PJ. Knowledge of the elimination of antibiotics with the PJ is important for the efficacy of therapy, since the amount of drug secreted into the PJ is an indicator of greater concentrations in the pancreatic tissue. The dose, duration, and modality of drug administration remain open questions in the treatment of pancreatic infections.

In conclusion, on the basis of pharmacokinetic and pharmacodynamic characteristics PIP-TZ may be considered a suitable alternative agent for treating pancreatic infections.


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ACKNOWLEDGMENTS
 
This work was supported by Italian MIUR grant no. 9805223148_002.


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FOOTNOTES
 
* Corresponding author. Mailing address: Department of Medicine and Public Health, Pharmacology Section, Policlinico G. B. Rossi, P.le LA Scuro, 37134 Verona, Italy. Phone: 39 045 8027603. Fax: 39 045 8027452. E-mail: elisa.bertazzoni{at}univr.it Back

{triangledown} Published ahead of print on 22 September 2008. Back


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Antimicrobial Agents and Chemotherapy, November 2008, p. 4149-4152, Vol. 52, No. 11
0066-4804/08/$08.00+0     doi:10.1128/AAC.00509-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.




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