Human pancreatic tissue concentration of bactericidal antibiotics

GASTROENTEROLOGY

Human Pancreatic Tissue Concentration Bactericidal Antibiotics

1992;103:1902-1908

of

MARKUS BijCHLER, PETER MALFERTHEINER, HELMUT FRIEB, RAINER ISENMANN, ERNST VANEK, HEINZ GRIMM, PAUL SCHLEGEL, THOMAS FRIESS, and HANS G. BEGER Departments of Surgery, Gastroenterology, and Infectious Diseases, University of LJlm, Ulm; Institute for Medical Microbiology and Clinical Chemistry, Weingarten; Mibicon Research Laboratory, Freiburg; and Department of Pharmaceutical Research, University of Tiibingen, Ttibingen, Germany

Pancreatic infection represents the most important cause of fatal outcome in human acute pancreatitis. In a comparative analysis, human pancreatic tissue concentrations of 10 different bactericidal antibiotics were determined in 89 patients undergoing pancreatic surgery. Concentrations of the antibiotics were determined in the blood and pancreatic tissue using high-pressure liquid chromatography. Pancreatic tissue concentrations 120 minutes after intravenous administration were as follows: mezlocillin, 19.0 mg/kg; piperacillin, 20.3 mg/kg; cefotaxime, 9.1 mg/kg; ceftizoxime, 7.9 mg/kg; netilmitin, 0.4 mg/kg; tobramycin, 0.4 mg/kg; ofloxacin, 1.7 mg/kg; ciprofloxacin, 0.9 mg/kg; imipenem, 6.0 mg/kg; metronidazole, 3.5 mg/kg. Three groups of antibiotics were established: group A, substances with low tissue concentrations (netilmicin, tobramycin), which were below the minimal inhibitory concentrations of most bacteria found in pancreatic infection; group B, antibiotics with pancreatic tissue concentrations which were sufficient to inhibit some but not all bacteria in pancreatic infection (mezlocillin, piperacillin, ceftizoxime, cefotaxime); group C, substances with high pancreatic tissue levels as well as high bactericidal activity against most of the germs present in pancreatic infection (ciprofloxacin, ofloxacin, imipenem). These data could serve as the basis for adequate antibiotic prophylaxis or treatment of pancreatic infection. ancreatic infection is the most important cause of fatal outcome in human acute pancreatitis.‘*‘Bacterial contamination of pancreatic necrosis has been shown in GO%-70% of patients with necrotizing pancreatitis.3-8 We recently identified the spectrum of bacteria in severe acute pancreatitis, which is mostly gram-negative and resembles an intestinal flora (Table 1). Thus, in addition to adequate surgical or interventional therapy, antibiotic treatment is of potential

P

importance in the general management of severe acute pancreatitis. On the basis of animal data and pancreatic juice data in humans, there has been a great deal of speculation about the adequacy of antibiotics in acute pancreatitis.g”O However, data are still lacking regarding human pancreatic tissue concentrations of bactericidal substances although tissue concentration generally represent the gold standard for antibiotic treatment protocols. We recently proved that there are at least two relevant antibiotics that penetrate human pancreatic tissue.l’ In the present investigation, we analyzed the human pancreatic tissue concentration of 10 bactericidal substances that cover the spectrum of bacteria commonly found in pancreatic infection.3-8 For objective comparison we chose two broad-spectrum penicillins (mezlocillin, piperacillin), two third-generation cephalosporins (cefotaxime, ceftizoxime), two aminoglycosides (netilmicin, tobramycin), and two quinolons (ofloxacin, ciprofloxacin), as well as imipenem and metronidazole. In addition to the tissue concentration analysis, the aim of our study was to correlate penetration data with bacteriological findings and to calculate an efficacy factor for antibiotics to be used in pancreatic infection. Materials and Methods Patients A total of 89 patients undergoing pancreatic surgery were studied between 1987 and 1990 after giving written informed consent. Guidelines stipulated by the German health authorities (Ethical Committee, University of Ulm) for human experimentation were followed. From these patients we analyzed 160 specimens of pancreatic tissue. Group A included 61 patients (51 male, 10 female; me0 1992 by the American

Gastroenterological

0016-5085/92/$3.00

Association

December

ANTIBIOTICS IN THE PANCREAS 1903

1992

Table 1. Frequency According

of Bacteria in Pancreatic Infection to References 3,4, and 5

Escherichia coli Pseudomonas species Staphylococcus aureus Klebsiella species Proteus species Streptococcus faecalis Enterobacter species Different anaerobes

Table 3. Antibiotic Treatment Pancreatic Surgery

15.9%

15.3% 10.1% 10.1% 4.4% 2.5% 15.6% 100.0%

dian age, 42 years; range, 25-64 years) with chronic pancreatitis. A duodenum-preserving pancreatic head resection” was performed in 44 patients, cystojejunostomy in 9 patients, and pancreatic left resection in the remaining 8 patients. Tissue for the analysis of antibiotic concentrations was taken from the pancreatic head and body. Group B included 20 patients with pancreatic (n = 15) or periampullary (n = 5) carcinoma (13 male, 7 female; median age, 61.5 years; range, 32-76 years). A Whipple procedure was performed in 15 patients, pancreatic left resection in 3 patients, and pancreatic biopsy procedure in 2 patients. Group C included 8 patients with acute necrotizing pancreatitis (5 male, 3 female; median age, 57 years; range, 40-79 years) who underwent necrosectomy.‘3 Tissue samples of vital pancreatic parenchyma close to the necrosis were taken from the pancreatic head (n = 2), body (n = 4), or tail (n = 2). Administration

ofAntibiotics

were administered

intravenously

20-

30 minutes before laparotomy. The drug infusion time was 10-20 minutes. The dose and diluent of the antibiotics are shown in Table 2. Dosages were chosen in accordance with the manufacturer’s recommendations for intravenous therapeutic application in Germany. Antibiotics were given either alone or in combinations consistent with standard medical practice in Germany. Ta-

ble 3 gives a survey of antibiotic combinations and underlying diseases of the patients. According to previous investigations”,‘4-‘8 there were no apparent interferences or

Table 2. Doses and Diluents of Antibiotics Antibiotic Mezlocillin Piperacillin Cefotaxime Ceftizoxime Tobramycin Netilmicin Ofloxacin Ciprofloxacin lmipenem/cilastatin Metronidazole

Disease

25.9%

Total

Antibiotics

in 89 Patients Undergoing

Dose 4!z 4g 2g 2g 80 mg 150 mg 200 mg 200 mg lg 500 rng

Diluent 40 mL 100 mL 40 mL 100 mL 100 mL 100 mL 100 mL 100 mL 100 mL 100 mL

water sodium water sodium sodium sodium water water water water

chloride (0.9%) chloride (0.9%) chloride (0.9%) chloride (0.9%)

Acute pancreatitis

Antibiotic treatment Piperacillin Ceftizoxime Imipenem Ciprofloxacin Ofloxacin Mezlocillin + netilmicin Cefotaxime + netilmicin Mezlocillin + tobramycin Cefotaxime + tobramycin Mezlocillin + metronidazole Mezlocillin + metronidazole netilmicin Mezlocillin + metronidazole tobramycin Total

Chronic pancreatitis

Total

0 0 0 0 0

10

3

1

1

5

0

7

1

8

0

5

1

6

0

4

1

5

4

4

1

9

1

1

0

2

0

1

1

2

8

61

20

89

13 15 9 9 6

13 6 4 6

+

+

interactions that might have influenced netic profile of the drugs analyzed. Sampling

Pancreatic cancer

the pharmacoki-

Design

Blood samples were taken before and every 30 minutes after the administration of antibiotics for a total sampling period of up to 360 minutes. At each pancreatic tissue sampling (depending on the kind of disease and the type of surgical procedure), an additional blood sample was taken. Pancreatic tissue samples (25 x 5 mm) were taken from the resected portion of the gland, except in 2 patients in whom biopsy procedures were carried out. After sampling, pancreatic tissue specimens were immediately shock-frozen with liquid nitrogen and stored at -80°C until the final determination. Blood samples were centrifuged at 19OOg for 10 minutes. Afterwards, the serum was immediately frozen and stored at -80°C. This procedure was not found to have any influence on the concentration of the analyzed antibiotics.” The determination of antibiotics in serum and pancreatic tissue was carried out by high-pressure liquid chromatography (HPLC) using methods as follows. HPLC determination

of antibiotics

For the determination of all antibiotics, a reversedphase isocratic liquid chromatograph equipped with a Nuand cleosil 7C18, 5ym, 250 X 4-mm column (Macharey Nagel, Diiren, Germany), a Gynkotek 600/200 pump (Gynkotek GmbH, Munich, Germany), and an autosampler and

1904 BijCHLER ET AL.

integrator (Shimadzu CR-5-A; Gynkotek GmbH) were used. The eluates were monitored with a variable spectral photometer (Shimadzu SP6; Gynkotek GmbH) for HPLC. For the measurement of mezlocillin, ceftizoxime, cefotaxime, metronidazol, ofloxacin, and ciprofloxacin in serum, a 200~uL sample was placed in a screwcap test tube and precipitated with 200 uL of methanol. The mixture was agitated for 30 seconds with a vortex mixer, then centrifuged for 5 minutes at 2500g. One hundred microliters of the clear supernatant was transferred to a sample vial of the automatic sampling system. For sample preparation of pancreatic tissue, the deep-frozen samples were microhomogenized with two volumes of methanol. The samples were extracted for 120 minutes by vigorous shaking, centrifuged for 10 minutes at 25OOg, and then subjected to same procedure as described for serum samples. For the measurement of piperacillin, netilmicin, and tobramycin, samples (0.5 mL) were placed in a IO-mL centrifuge tube followed by 500 pL of Tris-(hydroxymethyl-)amoniomethan solution and 500 pL of acetonitril. The tube contents were mixed vigorously. The clear supernatant (200 pL) was transferred to a microvial, and 200 pL of the derivating reagent l-fluor-2,4-dinitrobenzol (FDNB) was added. Samples reacted for 45 minutes at 85“C. For imipenem determination, tissue samples were homogenized and suspended with an equal part of morpholinoethanosulfonate (MES) buffer. After centrifugation (2500g for 5 minutes), the supernatant was used for HPLC determination. One milliliter of supernatant or serum was diluted with 1 mL of 0.25 mol/L MES buffer (pH 6.0). Ultrafiltration was performed to separate large protein molecules. Twenty microliters of the supernatant was then used to determine imipenem concentrations. For chromatographic determination of the described antibiotics (except imipenem), an elution solvent was used consisting of a mixture of 0.067 mol/L KH,PO, buffer (pH 3.5-5.0) and methanol (piperacillin, netilmicin, and tobramycin) or acetonitril (metronidazole, ceftizoxime, cefotaxime, ofloxacin, ciprofloxacin, and mezlocillin). The eluant for imipenem determination consisted of 0.1 mol/L sodium phosphate buffer (pH 7.0) and methanol (98 + 2). Elution was performed at a flow rate of 1.0-2.0 mL/min. For detection the detector wavelength was set at 214 nm for mezlocilbn and piperacilbn, 254 nm for ceftizoxime, 270 nm for cefotaxime, 365 nm for netilmicin, 355 nm for tobramycin, 313 nm for metronidazole, 254 nm for ofloxatin, 273 nm for ciprofloxacin, and 298 nm for imipenem. This wavelength corresponded to the highest optical absorption of the described antibiotics dissolved in the mobile phase. There was no interference from the biological matrix. Under these conditions, the retention times for described antibiotics were between 3.0 and 7.0 minutes. For standardization, standard curves in serum and pancreatic tissue were prepared by spiking aliquots with described antibiotics from 0 to 200 pg/mL in blank human serum or blank human pancreatic tissue. The calibration curves for the antibiotics described, extracted from serum and pancreatic tissue, were all linear within the range of concentrations studied. Reproducibility was checked by analyzing serum samples and tissue with several different concentrations of the antibiotics. The recovery for de-

GASTROENTEROLOGY Vol. 103, No. 6

scribed antibiotics over the concentration range studied was between 92% and 98%, and precision was between 2.5% and 6.0% for serum; the respective values for pancreatic tissue were 88%-92% (recovery) and 5% (precision). To avoid a determination distortion caused by blood (hemoglobin) contamination of pancreatic specimens,‘g-21 the concentration of antibiotics was corrected according to the following equation:

c, = c, -

sg!% , B

where C, is the real concentration in the pancreatic specimen, C, is the concentration determined in the pancreatic specimen, C, is the corresponding concentration in the blood, Hb, is the hemoglobin concentration in the pancreatic specimen, and Hb, is the hemoglobin concentration in the blood.

Results Serum and Pancreatic Antibiotics

Concentrations

of

The pharmacokinetic data in blood and pancreatic tissue are shown in Table 4. There were no significant differences in the tissue concentrations of antibiotics with respect to the underlying disease (acute pancreatitis, chronic pancreatitis, cancer of the pancreas) in our patients (Table 5). The highest pancreatic tissue concentrations were measured for the penicillins piperacillin and mezlocillin (22.5 mg/kg The showed

and 19.0 mg/kg). chinolones ciprofloxacin and ofloxacin the best penetration (C,/C,, 1.0 and 0.87)

into the pancreas. The aminoglycosides netilmicin and tobramycin showed the lowest pancreatic tissue concentrations [0.4 mg/kg (range, 0.3-0.8 mg/kg) and 0.5 mg/kg (range, 0.1-1.4 mg/kg)] as well as the lowest penetration results [0.14 (range, 0.06-0.27) and 0.12 (range, 0.04-1.08)].

Ejjicacy Factor Analysis To calculate a potential clinical effectiveness of the analyzed antibiotic drugs, we carried out an efficacy factor analysis taking into account three variables: (a) type and frequency of bacteria (FB) found in patients with pancreatic infections according to Table 1; (b) pancreatic tissue concentrations of the different antibiotic drugs 120 minutes after intravenous infusion (Cp120)[calculated for each antibiotic by computer regression analysis (TopFit; Goedecke AG/Thomae GmbH/Schering AG, Germany) using measured pancreatic tissue concentrations and times after infusion]; (c) percentage of inhibited bacteriologic strains (PIS), according to the litera-

December

1992

ANTIBIOTICS IN THE PANCREAS

1905

Table 4. Pharmacokinetic Serum and Pancreas Parameters and Efficacy Factors of the Tested Antibiotics

c Serum n Netilmicin

17

Tobramycin

20

Mezlocillin

26

Piperacillin

13

Ceftizoxime

15

Cefotaxime

15

Ciprofloxacin

6.9 (4.8-14.4) 9.6 (5.6-21.3) 186.4 (146.4-316.4) 132.8 (104.1-237.6) 71.5 (44.7-123.2) 129.2 (28.4-216.4) 1.9 (1.3-15.2) 3.3 (2.8-4.1) 37.5 (20.4-56.2) 11.3 (6.4-14.5)

14

Ofloxacin

8

Imipenem

15

Metronidazole

17

t l/Z

(range)

84 145 69 92 102 65

G/G

G

(range)

(range)

0.14 (0.06-0.27) 0.12 (0.04-1.08) 0.27 (0.07-0.60)

CP,ZO

EF

0.4

0.21

0.4

0.22

19.0

0.71

20.3

0.72

7.9

0.76

9.1

0.78

0.9

0.86

1.7

0.87

6.0

0.98

(0.3:t.8) (O.lT.4) 19.0 (3.2-37.4) 22.5 (2.2-56.0) 7.3 (1.3-19.0)

0.49 (0.07-0.86) 0.32 (0.04-0.53) 0.32 (0.05-0.49)

(l.OY2.9)

170

101

(O.:.& 0.87 (0.72-1.38) 0.43 (0.32-1.21) 0.5 (0.23-1.22)

(0.4%) 1.4 (0.8-2.9) (1.6:.9) 3.8 (1.0-13.0)

3.5

ratio; n, Number of tissue samples; Cserum, serum peak concentration (mg/L); t,,,, serum half-life (min); C,/C,, pancreatic tissue/serum C,, median pancreatic tissue concentration (mg/kg); C,,,0, calculated pancreatic tissue concentration 120 min after infusion; Ef, efficacy factor.

ture,22-4g at CplZO.From these data, an efficacy factor (EF) was calculated according to the following formula:

(FBX PI%. + FB

EF =

coli+ (FB X PISh%udomonas

X PW~.aurews

+

+ (FB X PWKletzasie,lo

. . . +

cFB

’

Discussion In previous studies, pharmacokinetic data on antibiotics relating to the human pancreas were obtained by analysis of pancreatic juice50-58 or fistula fluid.5g-65 In both of these conditions the fluid studied might be a mixture of pancreatic juice and serous

p1s)z4naerobes

100

Table 5. Pancreatic in the Three

An EF of 1.00 would be optimal, i.e., an antibiotic that would inhibit all bacteria commonly found in pancreatic infection. Table 6 shows the calculation of the EF for cefotaxime, as an example. For all other antibiotics calculations were done in the same way. According to the calculation of the EF, there were three groups of antibiotics: (a) substances with low tissue concentrations (netilmicin, tobramycin) that were far below the minimal inhibitory concentration (MIC) of most bacteria found in pancreatic infection; (b) antibiotics with pancreatic tissue concentrations sufficient to inhibit some but not all bacteria in pancreatic infection (mezlocillin,-piperacillin, ceftizoxime, cefotaxime); (c) substances with high pancreatic tissue levels as well as high bactericidal activity against most of the germs present in pancreatic infection (ciprofloxacin, ofloxacin, imipenem). Metronidazole, an antibiotic used exclusively for the treatment of anaerobes, was not included in the analysis of efficacy because of its small antibacterial spectrum.

Tissue Concentrations Different Diseases

Acute pancreatitis Mezlocillin

23.9 (12.8-32.3)

Piperacillin Cefotaxime Ceftizoxime

ofAntibiotics

Chronic pancreatitis 15.4 (3.2-37.4) 18.5 (3.1-56.0) 7.9 (1.0-23.1) 7.3 (1.9-19.0)

(4.3-36.5) 22.5 (2.2-37.1) 11.7 (1.3-21.4) 5.0 (1.3-8.7)

(0.3::8)

(0.3-0.6)

(0.10-15.4)

0.45 (0.1-0.8)

1.4 (0.8-2.9) 0.75 (0.4-1.0)

(0.5%)

(2.029)

(4.4-8.2)

Netilmicin Tobramycin Ofloxacin Ciprofloxacin Imipenem

NOTE. Data represent

18.5

0.3 (0.3Y4)

Metronidazole

Pancreatic cancer

4.95 3.4 (1.8-4.0)

(1.04-.133.0)

median (range) in milligrams per kilogram.

1906

GASTROENTEROLOGY Vol. 103, No. 6

BtiCHLER ET AL.

Table 6. Calculation of Efficacy Factor for Cefotaxime FB E. coli Pseudomonas species S. aureus Klebsiella species Proteus species S. faecalis Enterobacter species Different anaerobes Efficacy factor

0.26 0.16 0.15 0.10 0.10 0.04 0.03 0.16

PIS X X x x X X x X

99 44 85 99 89 20 90 65

FB, frequency of bacteria in pancreatic percentage of strains inhibited at C&,.

= = = = = = = =

infection

25.7 7.0 12.7 9.9 8.9 0.8 2.7 10.4 K/100

= 0.78

(Table 1); PIS,

and infectious additions as well as bile.5s Some information has been acquired from animal studies showing antibiotic penetration into the pancreas of rats and dogs.54+70 Tissue concentrations and the ratio between tissue and serum concentrations are the most important criteria in deciding on antibiotic treatment in infectious conditions,71-73 and to date no data on these parameters in connection with the human pancreas have been made available. Therefore, our approach was to analyze human pancreatic tissue during elective and emergency pancreatic surgery to determine the concentrations of various antibiotics. The 10 drugs used for analysis were chosen according to their bactericidal capacity in microorganisms commonly found in pancreatic infection.3-8 In infected pancreatic necrosis as well as in pancreatic abscess, two thirds of the bacteria are gram-negative enteric organisms; about 20% are gram-positive, and 15% are anaerobes (Table 1). In contrast to animal data 52*88 the concentrations of antibiotics in human pancreatic tissue were largely comparable in patients with and without acute inflammation. Aminoglycosides, which are first-choice drugs for intra-abdominal and pancreatic infection in the United States,Qs74-7sdo not sufficiently penetrate the human pancreas if given intravenously in the dosages recommended by the manufacturer. Pancreatic tissue concentrations 120 minutes after intravenous administration were 0.4 for both netilmicin (EF, 0.21) and tobramycin (EF, 0.22). These values were far below the MIC for bacteria commonly found in pancreatic infection. Our data on aminoglycosides confirm the results from pancreatic juice analysis in animals6s~sQ~70 and humans. 5*Therefore, it does not seem reasonable to treat patients suffering from infectious complications of pancreatitis with aminoglycosides. Our results show that a second group of antibiotics consisting of mezlocillin, piperacillin, ceftizoxime, and cefotaxime had adequate pancreatic tissue concentrations and acceptable pancreatic-to-serum ra-

tios of 0.8-0.5. These acylureidopenicillins and third-generation cephalosporins were given intermediate EFs between 0.7 and 0.8 because they are very effective bactericidal agents against gram-negative microorganisms but are much less effective against gram-positive bacteria and anaerobes.35s4”‘77If used in patients with pancreatic infections, these compounds should be combined with drugs used to treat anaerobes and/or gram-positive bacteria. A third group of antibiotics had adequate tissue concentrations and good (imipenem) or high (ciprofloxacin, ofloxacin) tissue-to-serum ratios. Because of their broad-spectrum bactericidal activity against gram-negative and gram-positive germs (ciprofloxatin, ofloxacin, imipenem) and against anaerobes (imipenem), these drugs were judged as having high EFs of 0.86-0.98. From pharmacokinetic and microbiological aspects, these three antibiotics represent first-choice drugs to treat pancreatic infection. Metronidazole, a compound with a bactericidal spectrum almost exclusively against anaerobes, showed good penetration into the pancreas and a high tissue-to-serum ratio. Because anaerobes play a role in pancreatic infection3-a this drug should be included in treatment regimes in combination with antibiotics that are not active against anaerobic bacteria. A clinically important question is which patients with acute pancreatitis need antibiotic treatment. In three prospective controlled trials,78-60 prophylactic antibiotics were not helpful. However, in none of these studies were antibiotics that enter the pancreas used, nor did the authors recruit patients bearing the risk of pancreatic infection. Recent studies show3-5 that in patients with necrotizing pancreatitis there is a 40%-60% risk of pancreatic infection, which is why these patients should be treated with antibiotics from the beginning. Future clinical trials involving patients with necrotizing pancreatitis will prove whether our pharmacokinetic data on bactericidal antibiotics are valid for the clinical situation. References 1. Bradley EL. Later complications of acute pancreatitis. In: Glazer G, Ranson JHC, eds. Acute pancreatitis. London: Balhere Tindall, 1988:390-431. _ Beger HG. Surgical management of necrotizing pancreatitis. Surg Clin North Am 1989;69:529-549. Beger HG, Bittner R, Block S, Biichler M. Bacterial contamination of pancreatic necrosis. Gastroenterology 1986;91:433438. Gerzof SG, Banks PA, Robbins AH, Johnson WC, Spechler SJ, Wetzner SM, Snider JM, Langevin RE, Jay ME. Early diagnosis of pancreatic infection by computed tomography-guided aspiration. Gastroenterology 1987;93:1315-1320. Bassi C, Falconi M, Girelli R, Nifosi F, Elio A, Martini N, Pe-

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