Vol. 36, No. 3
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Mar. 1992, p. 677-678
0066-4804/92/030677-02$02.00/0 Copyright X) 1992, Americah Society for Microbiology
Distribution of Ciprofloxacin in Ascitic Fluid Following Administration of a Single Oral Dose of 750 Milligrams M. DAN,`* T. ZUABI,2 C. QUASSEM,2 AND H. H. ROTMENSCH2 Infectious Disease Unit' and Department of Medicine E,2 The E. Wolfson Hospital, Holon 58100, Israel Received 24 June 1991/Accepted 23 December 1991
The penetration of ciprofloxacin into the ascitic fluid of eight patients was studied. Serum and ascitic fluid samples were obtained before and at 1, 2, 3, 6, and 12 h following administration of a single oral dose of 750 mg. Peak levels (mean ± standard deviation) were 4.0 ± 0.7 ,ug/mi in serum and 2.6 + 0.6 pg/ml in ascitic fluid; the areas under the curve (0 to 12 h) were 29.1 + 6.5 pg h/ml in serum and 20.7 + 5.0 pg h/ml in ascitic fluid. The concentrations that were achieved are well above the MICs of ciprofloxacin for the members of the family Enterobacteriaceae that cause spontaneous bacterial peritonitis. -
mically for each subject, the beginning of the terminal elimination phase was determined by eye, and the slope was computed by subsequent linear regression analysis. Peak concentrations (C,,D,) and the time of their occurrence (Tm,,,) were read directly from the observed data. The areas under the plasma and ascitic fluid concentration-versus-time curves (AUCs) were obtained by the trapezoidal rule method until the last datum point (0 to 12 h). The ratio of the AUC of ascitic fluid/AUC of plasma was taken as a measure of the percentage of penetration of ciprofloxacin into ascitic fluid. Serum creatinine levels were within the normal range in all but two patients: for patient 5 it was 1.8 mg/dl and for patient 7 it was 2 mg/dl. Serum alkaline phosphatase was mildly abnormal in four patients (mean, 425 IU; range, 293 to 973 IU). The ascitic fluid leukocyte count was below 500/ml in all but two patients: patient 1 had 1,700/ml and patient 5 had 2,000/ml. Cultures of ascitic fluid from all patients were sterile. The ciprofloxacin concentrations in ascitic fluid and serum are given in Table 1. There was no detectable drug at time zero in any instance. Satisfactory levels in ascitic fluid and serum (>0.6 and >0.8 ,ug/ml, respectively) were observed as long as 12 h after drug administration. The mean (+ standard deviation) Cm.s were 4.0 + 0.7 ,ug/ml in serum and 2.6 + 0.6 p.g/ml in ascitic fluid. The mean TmaX was 2.7 + 1.6 h in serum and 4.8 ± 1.7 h in ascitic fluid. The mean AUC from 0 to 12 h for concentrations in serum was 29.1 + 6.5 ,ug h/ml, and a value of 20.7 + 5.0 ,ug. h/ml was calculated for concentrations in ascitic fluid. The mean penetrability of ciprofloxacin into ascitic fluid (AF), determined by the ratio AUCAF/AUCSerUm was 69 + 18%. Unlike peritonitis resulting from visceral perforation, in patients with spontaneous peritonitis, a single organism is usually isolated from ascitic fluid and blood. Members of the family Enterobacteriaceae are the most common isolates, while anaerobes are rare. Use of appropriate antibiotics is the cornerstone of therapy. Nevertheless, even with early diagnosis and adequate therapy, about one-half of the patients die (7). The fluoroquinolones have given hope for improved therapeutic outcomes for patients with a variety of infectious diseases (4). Our findings are in accordance with this assumption. Very satisfactory concentrations of ciprofloxacin were observed in both serum and ascitic fluid as long as 12 h after drug administration. The levels that were achieved are
Ascitic fluid is a favorable milieu for bacterial proliferation. Consequently, spontaneous bacterial peritonitis is not an uncommon complication in patients with ascites. A variety of pathogens have been implicated, the most common being Escherichia coli and streptococci (7). Despite the increased awareness of the entity and the tendency toward early diagnosis and aggressive antimicrobial therapy, the mortality from spontaneous bacterial peritonitis remains high (6). Ciprofloxacin combines a broad antibacterial spectrum, with particularly good activity against gram-negative organisms, with good intestinal absorption and generally mild adverse effects (1). Such characteristics make it an interesting agent for the treatment of spontaneous bacterial peritonitis. This prompted us to investigate the pharmacokinetics of ciprofloxacin in uninflamed ascitic fluid. Eight patients with ascites secondary to abdominal malignancy (four patients) or advanced heart failure (four patients) were studied. The study was approved by the Hospital Ethical Committee, and informed consent was obtained from all patients. There were four men and four women with a mean (+ standard deviation) age of 65.3 + 15.1 years (range, 42 to 85 years) and a mean body weight of 71.8 + 10.8 kg (range, 62 to 88 kg). None of the patients had received antacids or antimicrobial agents in the preceding 72 h or had clinical evidence of peritonitis. A single dose of 750 mg of ciprofloxacin was administered orally. Blood and ascitic fluid samples were collected via indwelling catheters before drug administration (time zero) and at 1, 2, 3, 6, and 12 h thereafter. Serum was separated from blood by centrifugation, and all samples were stored at -70°C until the time of assay. Ciprofloxacin levels were determined by high-pressure liquid chromatography by the method described by Gau et al. (2). The limit of sensitivity of the method was 0.05 ,ug/ml; the coefficients of variation determined for concentrations of 1 ,ug/ml were 4.1% for intraday variations and 6.3% for interday variations. Samples obtained before drug administration were also tested for alkaline phosphatase, creatinine (serum), cell count, and culture (ascitic fluid). Pharmacokinetic evaluation. The plasma and ascitic fluid concentration-versus-time curves were plotted semilogarith*
-
Corresponding author. 677
678
ANTIMICROB. AGENTS CHEMOTHER.
NOTES
TABLE 1. Ciprofloxacin concentrations in ascitic fluid and serum at various times after a single oral dose of 750 mg Patient no. (condition)a
1h
Concn (Ag/ml) in ascitic fluid/serum at: 2h 3h 6h
12 h
1 (M) 0.1/0.55 1.0/3.1 2.5/4.5 3.0/3.75 1.75/1.8 2 (M) 1.0/1.3 0.45/3.8 1.35/3.0 1.75/2.1 0.7/0.9 3 (M) 1.3/4.15 3.6/3.85 2.2/3.3 1.7/2.25 0.6/0.8 4 (HF) 0/2.35 0.3/4.25 2.0/3.15 2.4/2.1 1.75/0.9 5 (HF) 1.0/1.85 0.61/3.4 1.75/4.25 2.9/3.5 2.5/3.0 6 (HF) 0/0.5 0.17/2.0 1.35/2.5 2.3/2.5 1.85/2.2 7 (HF) 0.1/2.1 2.0/2.9 3.1/4.8 3.0/3.6 2.3/2.55 8 (M) 0.1/3.5 b,/3.75 1.8/3.05 1.75/2.55 1.6/1.05 a Underlying disease conditions were malignancy (M) and heart failure (HF). b _, sample not available.
tion rate of 95 ± 35%, which is not much different from the results obtained in the study described here. We are not aware of any previously published study on the concentration of the drug in ascitic fluid. On the basis of the present findings of high and lasting levels of ciprofloxacin in ascitic fluid and the excellent in vitro activity of the agent against members of the family Enterobacteriaceae, this fluoroquinolone appears to be very promising for the treatment of spontaneous bacterial peritonitis. Good therapeutic results should be expected in cases of infections caused by the Enterobacteriaceae; one should be more cautious, however, with streptococcal peritonitis, because of the relatively high MICs of ciprofloxacin against these organisms.
1.
well above the MICs for E. coli (0.016 ,ug/ml) and other members of the family Enterobacteriaceae, such as Proteus mirabilis and Klebsiella pneumoniae (0.03 ,ug/ml) (1). No significant difference was observed in the levels of drug in ascitic fluid between patients with normal or pathologic levels of serum alkaline phosphatase or between patients with different causes of ascites. In comparison with ill elderly patients (3), the subjects included in this study revealed reduced Cm. and AUC in serum and a prolonged Tm.. The lower Cm. and the prolonged Tm. can probably be explained by a reduced rate of absorption in our patients, secondary to the deranged venous and lymphatic circulations observed in association with ascites (7). The reduced AUC may be related to the younger mean age of our patients and the increased volume of distribution. Published data on intraperitoneal penetration of ciprofloxacin are extremely sparse. Lockley et al. (5) have studied the concentration in uninflamed peritoneal fluid after a single intravenous administration of 100 mg of ciprofloxacin in patients undergoing elective surgery. They found a penetra-
2.
3.
4. 5. 6.
7.
REFERENCES Campoli-Richards, D. M., J. P. Monk, A. Price, P. Benfield, P. A. Todd, and A. Ward. 1988. Ciprofloxacin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs 35:373-447. Gau, W., H. J. Ploschke, K. Schmidt, and B. Weber. 1985. Determination of ciprofloxacin (Bay 09867) in biological fluids by high pressure liquid chromatography. J. Liquid Chromatogr. 8:485-497. Guay, D. R. P., W. M. Awni, P. K Peterson, S. Obaid, R. Breitenbucher, and G. R. Matzke. 1987. Pharmacokinetics of ciprofloxacin in acutely ill and convalescent elderly patients. Am. J. Med. 82(Suppl. 4A):124-129. Hooper, D. C., and J. S. Wolfson. 1991. Fluoroquinolone antimicrobial agents. N. Engl. J. Med. 324:384-394. Lockley, M. R., R. Waldron, R. Wise, and I. A. Donovan. 1986. Intraperitoneal penetration of ciprofloxacin. Eur. J. Clin. Microbiol. 5:209-210. Weinstein, M. P., P. B. Iannini, and C. W. Stratton. 1978. Spontaneous bacterial peritonitis: a review of 28 cases with emphasis on improved survival and factors influencing prognosis. Am. J. Med. 64:592-598. Wilcox, C. M., and W. E. Dismukes. 1987. Spontaneous bacterial peritonites. A review of pathogenesis, diagnosis, and treatment. Medicine 66:447-456.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Mar. 1992, p. 677-678
0066-4804/92/030677-02$02.00/0 Copyright X) 1992, Americah Society for Microbiology
Distribution of Ciprofloxacin in Ascitic Fluid Following Administration of a Single Oral Dose of 750 Milligrams M. DAN,`* T. ZUABI,2 C. QUASSEM,2 AND H. H. ROTMENSCH2 Infectious Disease Unit' and Department of Medicine E,2 The E. Wolfson Hospital, Holon 58100, Israel Received 24 June 1991/Accepted 23 December 1991
The penetration of ciprofloxacin into the ascitic fluid of eight patients was studied. Serum and ascitic fluid samples were obtained before and at 1, 2, 3, 6, and 12 h following administration of a single oral dose of 750 mg. Peak levels (mean ± standard deviation) were 4.0 ± 0.7 ,ug/mi in serum and 2.6 + 0.6 pg/ml in ascitic fluid; the areas under the curve (0 to 12 h) were 29.1 + 6.5 pg h/ml in serum and 20.7 + 5.0 pg h/ml in ascitic fluid. The concentrations that were achieved are well above the MICs of ciprofloxacin for the members of the family Enterobacteriaceae that cause spontaneous bacterial peritonitis. -
mically for each subject, the beginning of the terminal elimination phase was determined by eye, and the slope was computed by subsequent linear regression analysis. Peak concentrations (C,,D,) and the time of their occurrence (Tm,,,) were read directly from the observed data. The areas under the plasma and ascitic fluid concentration-versus-time curves (AUCs) were obtained by the trapezoidal rule method until the last datum point (0 to 12 h). The ratio of the AUC of ascitic fluid/AUC of plasma was taken as a measure of the percentage of penetration of ciprofloxacin into ascitic fluid. Serum creatinine levels were within the normal range in all but two patients: for patient 5 it was 1.8 mg/dl and for patient 7 it was 2 mg/dl. Serum alkaline phosphatase was mildly abnormal in four patients (mean, 425 IU; range, 293 to 973 IU). The ascitic fluid leukocyte count was below 500/ml in all but two patients: patient 1 had 1,700/ml and patient 5 had 2,000/ml. Cultures of ascitic fluid from all patients were sterile. The ciprofloxacin concentrations in ascitic fluid and serum are given in Table 1. There was no detectable drug at time zero in any instance. Satisfactory levels in ascitic fluid and serum (>0.6 and >0.8 ,ug/ml, respectively) were observed as long as 12 h after drug administration. The mean (+ standard deviation) Cm.s were 4.0 + 0.7 ,ug/ml in serum and 2.6 + 0.6 p.g/ml in ascitic fluid. The mean TmaX was 2.7 + 1.6 h in serum and 4.8 ± 1.7 h in ascitic fluid. The mean AUC from 0 to 12 h for concentrations in serum was 29.1 + 6.5 ,ug h/ml, and a value of 20.7 + 5.0 ,ug. h/ml was calculated for concentrations in ascitic fluid. The mean penetrability of ciprofloxacin into ascitic fluid (AF), determined by the ratio AUCAF/AUCSerUm was 69 + 18%. Unlike peritonitis resulting from visceral perforation, in patients with spontaneous peritonitis, a single organism is usually isolated from ascitic fluid and blood. Members of the family Enterobacteriaceae are the most common isolates, while anaerobes are rare. Use of appropriate antibiotics is the cornerstone of therapy. Nevertheless, even with early diagnosis and adequate therapy, about one-half of the patients die (7). The fluoroquinolones have given hope for improved therapeutic outcomes for patients with a variety of infectious diseases (4). Our findings are in accordance with this assumption. Very satisfactory concentrations of ciprofloxacin were observed in both serum and ascitic fluid as long as 12 h after drug administration. The levels that were achieved are
Ascitic fluid is a favorable milieu for bacterial proliferation. Consequently, spontaneous bacterial peritonitis is not an uncommon complication in patients with ascites. A variety of pathogens have been implicated, the most common being Escherichia coli and streptococci (7). Despite the increased awareness of the entity and the tendency toward early diagnosis and aggressive antimicrobial therapy, the mortality from spontaneous bacterial peritonitis remains high (6). Ciprofloxacin combines a broad antibacterial spectrum, with particularly good activity against gram-negative organisms, with good intestinal absorption and generally mild adverse effects (1). Such characteristics make it an interesting agent for the treatment of spontaneous bacterial peritonitis. This prompted us to investigate the pharmacokinetics of ciprofloxacin in uninflamed ascitic fluid. Eight patients with ascites secondary to abdominal malignancy (four patients) or advanced heart failure (four patients) were studied. The study was approved by the Hospital Ethical Committee, and informed consent was obtained from all patients. There were four men and four women with a mean (+ standard deviation) age of 65.3 + 15.1 years (range, 42 to 85 years) and a mean body weight of 71.8 + 10.8 kg (range, 62 to 88 kg). None of the patients had received antacids or antimicrobial agents in the preceding 72 h or had clinical evidence of peritonitis. A single dose of 750 mg of ciprofloxacin was administered orally. Blood and ascitic fluid samples were collected via indwelling catheters before drug administration (time zero) and at 1, 2, 3, 6, and 12 h thereafter. Serum was separated from blood by centrifugation, and all samples were stored at -70°C until the time of assay. Ciprofloxacin levels were determined by high-pressure liquid chromatography by the method described by Gau et al. (2). The limit of sensitivity of the method was 0.05 ,ug/ml; the coefficients of variation determined for concentrations of 1 ,ug/ml were 4.1% for intraday variations and 6.3% for interday variations. Samples obtained before drug administration were also tested for alkaline phosphatase, creatinine (serum), cell count, and culture (ascitic fluid). Pharmacokinetic evaluation. The plasma and ascitic fluid concentration-versus-time curves were plotted semilogarith*
-
Corresponding author. 677
678
ANTIMICROB. AGENTS CHEMOTHER.
NOTES
TABLE 1. Ciprofloxacin concentrations in ascitic fluid and serum at various times after a single oral dose of 750 mg Patient no. (condition)a
1h
Concn (Ag/ml) in ascitic fluid/serum at: 2h 3h 6h
12 h
1 (M) 0.1/0.55 1.0/3.1 2.5/4.5 3.0/3.75 1.75/1.8 2 (M) 1.0/1.3 0.45/3.8 1.35/3.0 1.75/2.1 0.7/0.9 3 (M) 1.3/4.15 3.6/3.85 2.2/3.3 1.7/2.25 0.6/0.8 4 (HF) 0/2.35 0.3/4.25 2.0/3.15 2.4/2.1 1.75/0.9 5 (HF) 1.0/1.85 0.61/3.4 1.75/4.25 2.9/3.5 2.5/3.0 6 (HF) 0/0.5 0.17/2.0 1.35/2.5 2.3/2.5 1.85/2.2 7 (HF) 0.1/2.1 2.0/2.9 3.1/4.8 3.0/3.6 2.3/2.55 8 (M) 0.1/3.5 b,/3.75 1.8/3.05 1.75/2.55 1.6/1.05 a Underlying disease conditions were malignancy (M) and heart failure (HF). b _, sample not available.
tion rate of 95 ± 35%, which is not much different from the results obtained in the study described here. We are not aware of any previously published study on the concentration of the drug in ascitic fluid. On the basis of the present findings of high and lasting levels of ciprofloxacin in ascitic fluid and the excellent in vitro activity of the agent against members of the family Enterobacteriaceae, this fluoroquinolone appears to be very promising for the treatment of spontaneous bacterial peritonitis. Good therapeutic results should be expected in cases of infections caused by the Enterobacteriaceae; one should be more cautious, however, with streptococcal peritonitis, because of the relatively high MICs of ciprofloxacin against these organisms.
1.
well above the MICs for E. coli (0.016 ,ug/ml) and other members of the family Enterobacteriaceae, such as Proteus mirabilis and Klebsiella pneumoniae (0.03 ,ug/ml) (1). No significant difference was observed in the levels of drug in ascitic fluid between patients with normal or pathologic levels of serum alkaline phosphatase or between patients with different causes of ascites. In comparison with ill elderly patients (3), the subjects included in this study revealed reduced Cm. and AUC in serum and a prolonged Tm.. The lower Cm. and the prolonged Tm. can probably be explained by a reduced rate of absorption in our patients, secondary to the deranged venous and lymphatic circulations observed in association with ascites (7). The reduced AUC may be related to the younger mean age of our patients and the increased volume of distribution. Published data on intraperitoneal penetration of ciprofloxacin are extremely sparse. Lockley et al. (5) have studied the concentration in uninflamed peritoneal fluid after a single intravenous administration of 100 mg of ciprofloxacin in patients undergoing elective surgery. They found a penetra-
2.
3.
4. 5. 6.
7.
REFERENCES Campoli-Richards, D. M., J. P. Monk, A. Price, P. Benfield, P. A. Todd, and A. Ward. 1988. Ciprofloxacin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs 35:373-447. Gau, W., H. J. Ploschke, K. Schmidt, and B. Weber. 1985. Determination of ciprofloxacin (Bay 09867) in biological fluids by high pressure liquid chromatography. J. Liquid Chromatogr. 8:485-497. Guay, D. R. P., W. M. Awni, P. K Peterson, S. Obaid, R. Breitenbucher, and G. R. Matzke. 1987. Pharmacokinetics of ciprofloxacin in acutely ill and convalescent elderly patients. Am. J. Med. 82(Suppl. 4A):124-129. Hooper, D. C., and J. S. Wolfson. 1991. Fluoroquinolone antimicrobial agents. N. Engl. J. Med. 324:384-394. Lockley, M. R., R. Waldron, R. Wise, and I. A. Donovan. 1986. Intraperitoneal penetration of ciprofloxacin. Eur. J. Clin. Microbiol. 5:209-210. Weinstein, M. P., P. B. Iannini, and C. W. Stratton. 1978. Spontaneous bacterial peritonitis: a review of 28 cases with emphasis on improved survival and factors influencing prognosis. Am. J. Med. 64:592-598. Wilcox, C. M., and W. E. Dismukes. 1987. Spontaneous bacterial peritonites. A review of pathogenesis, diagnosis, and treatment. Medicine 66:447-456.
