314
Correspondence Table. Mean concentrations of sparfloxacin in plasma and skin tissues
Groups 1 2 3
No. of patients 9 11 6
Concentrations skin tissue (T) plasma (P) Gig/g) (mg/L) 0-5610-33 0-8210-27 1-3110-80
0421013' 0-8410-17* 0941024
T/P 1-251055 1-021O42 1-391O90
•vs*; Duben, W., Student, A., Jablonski, M. & Maltottke, R. (1986). Zur Gewebekonzentration und Wirksamkeit von Ofloxacin bei chinirgiachen Patienten. Infection (Munchen) 14, Suppl. 1, 70-2. Kanamura, M., Nakashima, M., Uematsu, T. & Takiuchi, Y. (1988). Pharmacokinetics and safety of a new quinolone, AT-4140 in healthy volunteers. In Program and Abstracts of the Twenty-Eighth Intersdence Conference of Antimicrobial Agents and Chemotherapy, Los Angeles. 1988. Abstract 1490, p. 375. American Society for Microbiology, Washington, DC. Kojima, T., Inoue, M. &. Mitsuhashi, S. (1989). In vitro activity of AT-4140 against clinical bacterial isolates. Antimicrobial Agents and Chemotherapy 33, 1980-8. Malmborg, A.-S. & Rannikko, S. (1988). Enoxacin distribution in human tissues after multiple oral administration. Journal of Antimicrobial Chemotherapy 21, Suppl. B. 57-60. Nakamura, S., Kurobe, N., Ohue, T., Hashimoto, M. & Shimizu, M. (1990). Pharmacokinetics of a novel quinolone. AT-4140, in animals. Antimicrobial Agents and Chemotherapy 34, 89-93.
Intraperitoncal penetration of meropenem
Sir, Meropenem, a new carbapenem, has been shown to display a high degree of activity TOSHTTATSU NOGITA against a wide range of bacterial pathogens YASUMASA 1SHIBASHI including anaerobes (Jones, Barry & Department of Dermatology. Thomsberry, 1989). Pharmacokinetics and tisFaculty of Medicine. sue penetration in healthy volunteers has preUniversity of Tokyo viously been described (Wise et al., 1990). Hongo 7-3-1. Because of its broad spectrum of activity this Bunkyo-ku. Tokyo 113, Japan compound might be considered for the treatment or prophylaxis of abdominal infection, References we therefore studied its intraperitoneal Aigner, K. R. & Dalhoff, A. (1986). Penetration penetration. activities of riprofloxacin into muscle, skin and fat Twenty-four patients undergoing elective following oral administration. Journal of gastrointestinal surgery, for conditions other Antimicrobial Chemotherapy 18, 644-5. Daschner, F. D., Westenfelder, M. & Dalhoff, A. than infection, gave informed consent to enter (1986). Penetration of ciprofloxacin into kidney, the study, the protocol having previously been fat, muscle and skin tissue. European Journal of given approval by the Hospital Ethics Committee. Clinical Microbiology 5, 212-3.
Downloaded from http://jac.oxfordjournals.org/ at Carleton University on June 24, 2015
Malmborg & Rannikko (1988) reported the mean tissue/scrum concentration ratios of enoxacin, at a dose of 200 mg, to be 1-4 and 0-8 in muscle and skin, respectively. Aigner & Dalhoff (1986) found mean concentration ratios of for ciprofloxacin in skin/serum and muscle/serum of 1-8 and 3-3, respectively. In contrast Duban el al. (1986) found the concentration of ofloxacin in subcutaneous fat and skin to be lower than serum concentrations with a dose of 400 mg. These results with sparfloxacin, enoxacin, ciprofloxacin, and ofloxacin are not entirely comparable because of differences in sampling time and the dose used. Daschner, Westenfelder & Dalhoff (1986) evaluated the serum and tissue pharmacokinetics of ciprofloxacin at various times before urologkal surgery and found the concentrations in the skin and subcutaneous tissues to be lower than those in the serum at all sampling intervals. Our data show that the skin/plasma ratio was about 1-00 at 4 h ( 7 ^ and 1-39 at 5 h. The skin concentrations of sparfloxacin in the three groups were all higher than the MIC*, value for Staphylococcus eatreus (0-2 mg/L, personal communication from H. Takahashi, Teikyo University). These results support the potential efficacy of sparfloxacin in the treatment of skin and soft tissue infections.
Correspondence
315
100
3
r
Ctp Ps.aerugin6sa
o u
—
.
MIC»o Enterobocteriaceoe, Stophytococd and Bocterokhs fragBis £0-25 mg/L ; 0-1 3 Time ( h )
The average age of the patients was 56-39 years (S.D. 13-22) and their average weight was 64-81 kg (S.D. 13-97). An intravenous bolus of 1 g of meropenem, was administered at various times before surgery. On opening of the peritoneum, having ensured haemostasia, three pre-weighed sterile assay discs (6 mm) were placed under a loop of bowel and left for 10 min. A venous blood sample was also taken and the time noted. If the operation continued for long enough, and the peritoneal cavity did not become grossly blood stained, a further set of discs and blood samples were taken. The blood and peritoneal fluid samples were sent immediately from the operating theatre and all arrived in the laboratory for analysis within 10 min. A visual comparison was made with discs onto which human blood had been pipetted to cover 5% or 10% of each disc, and those contaminated with > 10% blood discarded. The discs were reweighed and assayed within one hour (to prevent loss of antimicrobial activity) against standards prepared in buffer containing 20% human serum, the protein content of which is equivalent to peritoneal fluid. Serum standards were prepared in 100% human serum. Meropenem concentration was determined by using an agar diffusion assay using Iso-Sensitest agar (Oxoid, Basingstoke, UK) and Escherichia coli (NIJH) as the indicator organism. The assay plates were incubated overnight at 37°C. The lower limit of sensitivity was 0-1 mg/L and the coefficient of variation 6-3%. The level of meropenem in peritoneal fluid was calculated using the formula:
peritoneal level disc assay level x volume of standard volume of peritoneal fluid on disc Twenty-nine sets of plasma and peritoneal samples were obtained in total, with one set of samples from 19 patients and two sets from 5 patients. The timing of the samples varied from 0-5 to 5 h post dose. The results are shown graphically in the Figure. The minimum inhibitory concentration for 90% (MIC*) of common pathogens associated with intraabdominal infection are also given. The plasma and elimination half-life of meropenem was found to be approximately 11 h, which is similar to that found previously (Wise et al., 1990). The intraperitoneal levels within the first 2 h after administration were 71-95 (mean 26-71, S.E.M. 4-55). The penetration of mcropenem (when individual levels were compared was 95% (s.D. 32). The peritoneal elimination half-life was similar to plasma being approximately 1-5 h. Previous studies have shown that the intraperitoneal penetration of imipenem was 74% (Wise et al., 1986), aztreonam 100-2% (Ashby, Wise & Donovan, 1988) and cefpirome 97-7% (Kavi et al., 1989). Therefore meropenem has a similar degree of penetration to these other /Mactams. The plasma levels observed in this study are similar to those obtained in the pharmacokinetk studies on healthy volunteers. Meropenem penetrates well into peritoneal fluid and exceeds the minimal inhibitory concentration of the organisms shown in the Figure for a considerable period of time. These data suggest that twice daily intravenous dosage with 1 g of meropenem might be
Downloaded from http://jac.oxfordjournals.org/ at Carleton University on June 24, 2015
Figure. Intraperitoneal penetration of meropenetn 24 patients (five patients with samples at two time intervals). • , Plasma level, A . peritoneal level; , line best fit plasma; line best fit peritoneal fluid.
316
CoiT
sufficient to treat most intraperitoneal pathogens with the exception of Pseudomonas aeruginosa and would be suitable in the prophylaxis and treatment of intraabdominal infections. Clinical assessment seems to be warranted. A. HEXTALL* J. M. ANDREWS* I. A. DONOVAN* R. WISE* Departments of'Surgery and ^Medical Microbiology. Dudley Road Hospital. Birmingham BIS 1QH, UK
Pharmacokinetk erideoce of imipenem efficacy in the treatment of KUbsietta pmaanomae Dosocomlal meningitis Sir, Hospital-acquired Gram-negative bacillary meningitis remains a difficult therapeutic problem. Imipenem is characterized by its activity against multi-resistant bacteria, related to its excellent stability to /Mactamases (Neu & Labthavikul, 1982; Neu, 1985). This feature makes it particularly valuable in patients with nosocomia] infections (Rouveix, Bune & Regnier, 1986). There is, however, limited information about its penetration into the cerebrospinal fluid (CSF) of patients with meningitis (Modai et al., 198S; Jacobs et al., 1986; Rouveix et al., 1986). We report here the efficacy of imipenem in the treatment of a Klcbsiella pneumoniae meningitis as demonstrated by serial measurements of concentrations in CSF.
The external lumbar drainage allowed us to sample serially the CSF, and imipenem concentrations were assayed in serum and CSF two days after this drug was started. The samples were frozen and stored at — 80°C for no longer than 24 h. Assay of imipenem was performed by an agar diffusion method with Bacillus subtilis (IP 5262 strain) as the indicator organism. The associated aminoglycoside was removed by cellulose phosphate binding. Vancomycin assay, performed by the TDX system (Abbott Laboratories, USA), failed to detect vancomycin in CSF and sera. As shown in the Table, the concentration of imipenem in CSF largely exceeded the MIC of this drug (0-25 mg/L) for K. pneumoniae in all the samples (range: 0-8-2-6 mg/L). The imipenem peak concentration in CSF depended on the intravenous dose since it was 1-6 mg/L after 1 g and 2-6 mg/L after an iv dose of 1 g administered over 2 h and 1 h respectively. The half-life of imipenem in blood was identical with the two procedures
Downloaded from http://jac.oxfordjournals.org/ at Carleton University on June 24, 2015
References Ashby, J. P., Wise, R. & Donovan, I. A . (1988). The intraperitoneal penetration of aztreonam. International Journal of Experimental and Clinical Chemotherapy 1, 61-2. Jones, R. N., Barry, A. L. & Thormberry, C. (1989). In vitro studies of meropenem. Journal of Antimicrobial Chemotherapy 24, Suppl. A, 9-29. Kavi, J., Ashby, J. P., Wise, R. & Donovan, I. A. (1989). Intraperitoneal penetration of cefpirome. European Journal of Clinical Microbiology and Infectious Diseases 8, 556-8. Wise, R., Donovan, I. A., Lockley, M. R., Dnnnm, J. & Andrews, J. M. (1986). The pharmacolrinetics and tissue penetration of imipenem. Journal of Antimicrobial Chemotherapy 18, Suppl. E. 93-101. Wise, R., Logan, M. N., Cooper, M., Ashby, J. P. & Andrews, J. M. (1990). The pharmacokinetic* of meropenem and its penetration into an inflpmmatory exudate. Antimicrobial Agents and Chemotherapy 34, 1515-7.
A 69-year-old man (height 1-70 m; weight 76-5 kg), admitted for the relapse of a sphenoidal mucocele treated by surgery two years previously, had trans-sphenoidal surgery for a second time. The postoperative course was complicated by a persistent nasal discharge of CSF caused by damage to the dura mater. Five days after surgery meningitis was diagnosed. Streptococcus pneumoniae was isolated from the CSF and therapy was commenced with amoxycillin (12 g per day) and fosfomycin (16 g per day). Two days later clinical improvement was evident and the CSF became sterile. Eighteen days after the original operation further surgery was done to close the dura mater, and an external lumbar drainage was made on the following day. At the same time a second meningitis occurred accompanied by a generalized epileptic seizure, and a combination of imipenem/cilastatin (1 g imipenem iv every 6 h), vancomycin (2 g per day, in continuous infusion) and gentamicin (10 mg per day by the intrathecal route) was administered. Klebsiella pneumoniae was isolated from CSF. Twenty-four hours later the patient became afebrile, the CSF was sterile and vancomycin plus gentamicin was stopped. Since no extended-spectrum /Mactamase was found in the causative isolate, treatment was changed to cefotaxime (1 g iv every 4 h) and pefloxacin 400 mg iv every 8 h). Imipenem was given for a total of three days and cefotaxime plus pefloxacin for a total of 18 days. The patient had a complete recovery and no relapse has occurred during four months follow-up.
Correspondence Table. Mean concentrations of sparfloxacin in plasma and skin tissues
Groups 1 2 3
No. of patients 9 11 6
Concentrations skin tissue (T) plasma (P) Gig/g) (mg/L) 0-5610-33 0-8210-27 1-3110-80
0421013' 0-8410-17* 0941024
T/P 1-251055 1-021O42 1-391O90
•vs*; Duben, W., Student, A., Jablonski, M. & Maltottke, R. (1986). Zur Gewebekonzentration und Wirksamkeit von Ofloxacin bei chinirgiachen Patienten. Infection (Munchen) 14, Suppl. 1, 70-2. Kanamura, M., Nakashima, M., Uematsu, T. & Takiuchi, Y. (1988). Pharmacokinetics and safety of a new quinolone, AT-4140 in healthy volunteers. In Program and Abstracts of the Twenty-Eighth Intersdence Conference of Antimicrobial Agents and Chemotherapy, Los Angeles. 1988. Abstract 1490, p. 375. American Society for Microbiology, Washington, DC. Kojima, T., Inoue, M. &. Mitsuhashi, S. (1989). In vitro activity of AT-4140 against clinical bacterial isolates. Antimicrobial Agents and Chemotherapy 33, 1980-8. Malmborg, A.-S. & Rannikko, S. (1988). Enoxacin distribution in human tissues after multiple oral administration. Journal of Antimicrobial Chemotherapy 21, Suppl. B. 57-60. Nakamura, S., Kurobe, N., Ohue, T., Hashimoto, M. & Shimizu, M. (1990). Pharmacokinetics of a novel quinolone. AT-4140, in animals. Antimicrobial Agents and Chemotherapy 34, 89-93.
Intraperitoncal penetration of meropenem
Sir, Meropenem, a new carbapenem, has been shown to display a high degree of activity TOSHTTATSU NOGITA against a wide range of bacterial pathogens YASUMASA 1SHIBASHI including anaerobes (Jones, Barry & Department of Dermatology. Thomsberry, 1989). Pharmacokinetics and tisFaculty of Medicine. sue penetration in healthy volunteers has preUniversity of Tokyo viously been described (Wise et al., 1990). Hongo 7-3-1. Because of its broad spectrum of activity this Bunkyo-ku. Tokyo 113, Japan compound might be considered for the treatment or prophylaxis of abdominal infection, References we therefore studied its intraperitoneal Aigner, K. R. & Dalhoff, A. (1986). Penetration penetration. activities of riprofloxacin into muscle, skin and fat Twenty-four patients undergoing elective following oral administration. Journal of gastrointestinal surgery, for conditions other Antimicrobial Chemotherapy 18, 644-5. Daschner, F. D., Westenfelder, M. & Dalhoff, A. than infection, gave informed consent to enter (1986). Penetration of ciprofloxacin into kidney, the study, the protocol having previously been fat, muscle and skin tissue. European Journal of given approval by the Hospital Ethics Committee. Clinical Microbiology 5, 212-3.
Downloaded from http://jac.oxfordjournals.org/ at Carleton University on June 24, 2015
Malmborg & Rannikko (1988) reported the mean tissue/scrum concentration ratios of enoxacin, at a dose of 200 mg, to be 1-4 and 0-8 in muscle and skin, respectively. Aigner & Dalhoff (1986) found mean concentration ratios of for ciprofloxacin in skin/serum and muscle/serum of 1-8 and 3-3, respectively. In contrast Duban el al. (1986) found the concentration of ofloxacin in subcutaneous fat and skin to be lower than serum concentrations with a dose of 400 mg. These results with sparfloxacin, enoxacin, ciprofloxacin, and ofloxacin are not entirely comparable because of differences in sampling time and the dose used. Daschner, Westenfelder & Dalhoff (1986) evaluated the serum and tissue pharmacokinetics of ciprofloxacin at various times before urologkal surgery and found the concentrations in the skin and subcutaneous tissues to be lower than those in the serum at all sampling intervals. Our data show that the skin/plasma ratio was about 1-00 at 4 h ( 7 ^ and 1-39 at 5 h. The skin concentrations of sparfloxacin in the three groups were all higher than the MIC*, value for Staphylococcus eatreus (0-2 mg/L, personal communication from H. Takahashi, Teikyo University). These results support the potential efficacy of sparfloxacin in the treatment of skin and soft tissue infections.
Correspondence
315
100
3
r
Ctp Ps.aerugin6sa
o u
—
.
MIC»o Enterobocteriaceoe, Stophytococd and Bocterokhs fragBis £0-25 mg/L ; 0-1 3 Time ( h )
The average age of the patients was 56-39 years (S.D. 13-22) and their average weight was 64-81 kg (S.D. 13-97). An intravenous bolus of 1 g of meropenem, was administered at various times before surgery. On opening of the peritoneum, having ensured haemostasia, three pre-weighed sterile assay discs (6 mm) were placed under a loop of bowel and left for 10 min. A venous blood sample was also taken and the time noted. If the operation continued for long enough, and the peritoneal cavity did not become grossly blood stained, a further set of discs and blood samples were taken. The blood and peritoneal fluid samples were sent immediately from the operating theatre and all arrived in the laboratory for analysis within 10 min. A visual comparison was made with discs onto which human blood had been pipetted to cover 5% or 10% of each disc, and those contaminated with > 10% blood discarded. The discs were reweighed and assayed within one hour (to prevent loss of antimicrobial activity) against standards prepared in buffer containing 20% human serum, the protein content of which is equivalent to peritoneal fluid. Serum standards were prepared in 100% human serum. Meropenem concentration was determined by using an agar diffusion assay using Iso-Sensitest agar (Oxoid, Basingstoke, UK) and Escherichia coli (NIJH) as the indicator organism. The assay plates were incubated overnight at 37°C. The lower limit of sensitivity was 0-1 mg/L and the coefficient of variation 6-3%. The level of meropenem in peritoneal fluid was calculated using the formula:
peritoneal level disc assay level x volume of standard volume of peritoneal fluid on disc Twenty-nine sets of plasma and peritoneal samples were obtained in total, with one set of samples from 19 patients and two sets from 5 patients. The timing of the samples varied from 0-5 to 5 h post dose. The results are shown graphically in the Figure. The minimum inhibitory concentration for 90% (MIC*) of common pathogens associated with intraabdominal infection are also given. The plasma and elimination half-life of meropenem was found to be approximately 11 h, which is similar to that found previously (Wise et al., 1990). The intraperitoneal levels within the first 2 h after administration were 71-95 (mean 26-71, S.E.M. 4-55). The penetration of mcropenem (when individual levels were compared was 95% (s.D. 32). The peritoneal elimination half-life was similar to plasma being approximately 1-5 h. Previous studies have shown that the intraperitoneal penetration of imipenem was 74% (Wise et al., 1986), aztreonam 100-2% (Ashby, Wise & Donovan, 1988) and cefpirome 97-7% (Kavi et al., 1989). Therefore meropenem has a similar degree of penetration to these other /Mactams. The plasma levels observed in this study are similar to those obtained in the pharmacokinetk studies on healthy volunteers. Meropenem penetrates well into peritoneal fluid and exceeds the minimal inhibitory concentration of the organisms shown in the Figure for a considerable period of time. These data suggest that twice daily intravenous dosage with 1 g of meropenem might be
Downloaded from http://jac.oxfordjournals.org/ at Carleton University on June 24, 2015
Figure. Intraperitoneal penetration of meropenetn 24 patients (five patients with samples at two time intervals). • , Plasma level, A . peritoneal level; , line best fit plasma; line best fit peritoneal fluid.
316
CoiT
sufficient to treat most intraperitoneal pathogens with the exception of Pseudomonas aeruginosa and would be suitable in the prophylaxis and treatment of intraabdominal infections. Clinical assessment seems to be warranted. A. HEXTALL* J. M. ANDREWS* I. A. DONOVAN* R. WISE* Departments of'Surgery and ^Medical Microbiology. Dudley Road Hospital. Birmingham BIS 1QH, UK
Pharmacokinetk erideoce of imipenem efficacy in the treatment of KUbsietta pmaanomae Dosocomlal meningitis Sir, Hospital-acquired Gram-negative bacillary meningitis remains a difficult therapeutic problem. Imipenem is characterized by its activity against multi-resistant bacteria, related to its excellent stability to /Mactamases (Neu & Labthavikul, 1982; Neu, 1985). This feature makes it particularly valuable in patients with nosocomia] infections (Rouveix, Bune & Regnier, 1986). There is, however, limited information about its penetration into the cerebrospinal fluid (CSF) of patients with meningitis (Modai et al., 198S; Jacobs et al., 1986; Rouveix et al., 1986). We report here the efficacy of imipenem in the treatment of a Klcbsiella pneumoniae meningitis as demonstrated by serial measurements of concentrations in CSF.
The external lumbar drainage allowed us to sample serially the CSF, and imipenem concentrations were assayed in serum and CSF two days after this drug was started. The samples were frozen and stored at — 80°C for no longer than 24 h. Assay of imipenem was performed by an agar diffusion method with Bacillus subtilis (IP 5262 strain) as the indicator organism. The associated aminoglycoside was removed by cellulose phosphate binding. Vancomycin assay, performed by the TDX system (Abbott Laboratories, USA), failed to detect vancomycin in CSF and sera. As shown in the Table, the concentration of imipenem in CSF largely exceeded the MIC of this drug (0-25 mg/L) for K. pneumoniae in all the samples (range: 0-8-2-6 mg/L). The imipenem peak concentration in CSF depended on the intravenous dose since it was 1-6 mg/L after 1 g and 2-6 mg/L after an iv dose of 1 g administered over 2 h and 1 h respectively. The half-life of imipenem in blood was identical with the two procedures
Downloaded from http://jac.oxfordjournals.org/ at Carleton University on June 24, 2015
References Ashby, J. P., Wise, R. & Donovan, I. A . (1988). The intraperitoneal penetration of aztreonam. International Journal of Experimental and Clinical Chemotherapy 1, 61-2. Jones, R. N., Barry, A. L. & Thormberry, C. (1989). In vitro studies of meropenem. Journal of Antimicrobial Chemotherapy 24, Suppl. A, 9-29. Kavi, J., Ashby, J. P., Wise, R. & Donovan, I. A. (1989). Intraperitoneal penetration of cefpirome. European Journal of Clinical Microbiology and Infectious Diseases 8, 556-8. Wise, R., Donovan, I. A., Lockley, M. R., Dnnnm, J. & Andrews, J. M. (1986). The pharmacolrinetics and tissue penetration of imipenem. Journal of Antimicrobial Chemotherapy 18, Suppl. E. 93-101. Wise, R., Logan, M. N., Cooper, M., Ashby, J. P. & Andrews, J. M. (1990). The pharmacokinetic* of meropenem and its penetration into an inflpmmatory exudate. Antimicrobial Agents and Chemotherapy 34, 1515-7.
A 69-year-old man (height 1-70 m; weight 76-5 kg), admitted for the relapse of a sphenoidal mucocele treated by surgery two years previously, had trans-sphenoidal surgery for a second time. The postoperative course was complicated by a persistent nasal discharge of CSF caused by damage to the dura mater. Five days after surgery meningitis was diagnosed. Streptococcus pneumoniae was isolated from the CSF and therapy was commenced with amoxycillin (12 g per day) and fosfomycin (16 g per day). Two days later clinical improvement was evident and the CSF became sterile. Eighteen days after the original operation further surgery was done to close the dura mater, and an external lumbar drainage was made on the following day. At the same time a second meningitis occurred accompanied by a generalized epileptic seizure, and a combination of imipenem/cilastatin (1 g imipenem iv every 6 h), vancomycin (2 g per day, in continuous infusion) and gentamicin (10 mg per day by the intrathecal route) was administered. Klebsiella pneumoniae was isolated from CSF. Twenty-four hours later the patient became afebrile, the CSF was sterile and vancomycin plus gentamicin was stopped. Since no extended-spectrum /Mactamase was found in the causative isolate, treatment was changed to cefotaxime (1 g iv every 4 h) and pefloxacin 400 mg iv every 8 h). Imipenem was given for a total of three days and cefotaxime plus pefloxacin for a total of 18 days. The patient had a complete recovery and no relapse has occurred during four months follow-up.
