Journal of Antimicrobial Chemotherapy (1992) 29, 719-724
Penetration of rifampicin into the cerebrospinal fluid of adults with tminflamed meninges
Department of Neurology" and Newosurgery1, University of Gdttingen, Institute of Experimental Biology and Medicine, Research Institute Borstelb, Germany The penetration of rifampicin into CSF was studied in seven patients who had undergone external ventriculostomy for occlusive hydrocephalus without major disturbance of the blood-CSF barrier. After the first dose of rifampicin 600 mg iv over 3 h, blood and CSF concentrations were determined serially by HPLC. Peak CSF concentrations obtained 0-8 h (median = 1 h) after the end of the infusion ranged from 0-57 to 1-24 mg/L (median =• 0-73 mg/L). Elimination from CSF was slower than from serum (Tintaf: 9-1-21-0 h (median - 14-5 h, n - 5); Tl/2/mm: 2-2-5-8 h (median - 3-6 h, n - 7)). Based on the ratios of the areas under the concentration-time curves in CSF and serum, the overall penetration of rifampicin into CSF was 0-13-042 (median = 0-22). These results demonstrate effective CSF penetration and favourable pharmacokinetics of rifampicin in the absence of meningeal inflammation. They support the use of rifampicin as part of a combination therapy not only for tuberculosis of the central nervous system (CNS), but also for staphylococcal and listerial infections of the CNS in which there may be little meningeal inflammation.
Introduction
Rifampicin is highly active against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus, multiresistant Streptococcus pneumoniae and Listeria monocytogenes and Mycobacterium tuberculosis. Neisseria meningitidis and Haemophilus mfluenzae are also sensitive (Zinner, Lagast & Klastersky, 1981; Hof & Emmerling, 1984; Kucers & Bennett, 1987). Unlike many other antibiotics it is lipid soluble, penetrates cell membranes and kills intracellular bacteria (Van der Auwera, Matsumoto & Husson, 1988). These properties may qualify rifampicin for the treatment of tuberculous meningitis (D'Oliveira, 1972) and for other conditions such as meningitis caused by S. pneumoniae and H. mfluenzae resistant to conventional chemotherapy, CNS infections in immunocompromised hosts and listeria meningoencephalitis and ventriculitis (Gombert et al., 1981; Hof & Emmerling, 1984). Because there is little meningeal inflammation in some CNS infections, particularly in listeria brain stem encephalitis and ventricular shunt infections, we studied the diffusion of rifampicin into the CSF of 7 patients with uninflamed meninges. Correspondence to: Dr Roland Nau, Dept of Neurology, University of Gdttingen, Robert-Koch-StraBe 40, D-3400 G6tungen, Germany. 719 0305-7453/92/060719+06 S02.00/0
© 1992 The Britiih Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at University of North Carolina at Greensboro on November 6, 2014
Roland Nan*, Hflmar W. Prange', SyMa Menck*, Herbert Kolenda', Hans Vfaser* and Joachim K. Seydd*
720
R. Nan et aL
Patients and methods
HPLC assay Serum and CSF samples were deproteinized with acetonitrile and filtered through disposable 25 mm syringe filters of pore size 0-2 fim (Nalge Comp., Rochester, NY, USA). The samples were assayed on Chromosphere C,8 (10 cm column length) with a mobile phase of 62-65% methanol in phosphate buffered saline pH 7-4 pumped at a flow rate of 0-6 mL/min. Detection was by UV absorption at 280 nm. The retention time of rifampicin was 4-2-4-8 min. Quantitation was by multipoint calibration and peak area comparison using a model 760 integrator (Nelson Analytical). The calibrator solutions were not filtered because of a shortage of control CSF although rifampicin Table I. Characterization of investigated patients in the sequence of descending peak CSF rifampicin concentrations after an iv infusion of 600 nig over 3 h
no.
Body weight (kg)
1
100
Patient
2 3 4 5 6 7
70 80 70 70 95 55
CSF
CSF
WBC/
xlO"'
mm1
RBC/
313
8-4
4
1112
618
15-9
45
none
353
1-5
8
1149
768
10-4
28
1153
812
9-2
28
8021
308
09
1
512
1113
3-3
7
4941
CSF Age (sex)
Diseases
54 (M) Intracerebral haemorrhage, 66 (F) Subarachnoid haemorrhage, ventriculitis 57 (M) Intracerebral haemorrhage, 61 (M) Subarachnoid haemorrhage, 48 (F) Subarachnoid haemorrhage, 46 (M) Intracerebral haemorrhage, 70 (F) Intra cerebral haemorrhage,
protein (mg/L)
QAM
mm5
RTI RTI, UTI RTI, TBC RTI, UTI RTI, UTI RTI
RTI, Respiratory tract infection; UTI, urinary tract infection; TBC, history of tuberculosis; g A t l , CSF/serum albumin ratio.
Downloaded from http://jac.oxfordjournals.org/ at University of North Carolina at Greensboro on November 6, 2014
The study protocol was approved by the Hospital Ethics Commission. Informed consent for participation was obtained from the nearest relative of each patient. Seven patients with cerebrovascular diseases (four males, three females, age 48-70 years), who had undergone external ventriculostomy for occlusive hydrocephalus, were treated with rifampicin because of extracerebral infections. Co-medication varied according to clinical necessities but did not include barbiturates. The permeability of the blood-CSF barrier was assessed by determining the CSF protein content and the CSF/serum albumin ratio. Further details on the patients are shown in Table I. Rifampicin 600 mg (Rifa®, Griinenthal, Stolberg, Germany) was administered iv over 3 h once daily. Simultaneous blood and CSF samples were drawn 1, 2 and 3 h after the start, and 0-5, 1, 2, 4, 6, 8, 10, 12, 14 and 22 h after termination of the first rifampicin infusion. Samples were cooled in ice water, ccntrifuged at 5000 rpm for 5 min and separated serum and CSF supernatant were stored at -70°C. All samples were assayed within 10 weeks of collection.
Rlfampidn penetration into CSF
721
Pharmacokinetic analysis Pharmacokinetic calculations were done using standard methods (Rowland & Tozer, 1989). Elimination rate constants (kj) were determined by log-linear regression analysis and half-lives (Tl[2j) as In2/kf. The areas under the concentration-time curves (AUQ were estimated by the linear trapezoidal rule. AUC^,,,,,, and AUQsp were extrapolated to infinity (AUC^,,,)) by dividing the last measurable drug concentration by the kf. No kf could be determined from the CSF data of patients 2 and 6. In these cases AUCop was extrapolated to infinity by dividing the last measurable CSF concentration by the median kf of the otherfivepatients. The total clearance from serum (Cl) was calculated as dose/AUC^nn,,, and the apparent volume of distribution (VJ[) as dose/AXJC^^ • kfl. Results Peak concentrations of rifampicin in serum after the first infusion were 8-6-19-0 mg/L compared with 0-57-1-24 mg/L in CSF. The peak CSF concentrations were observed 0 to 8 h after the end of the infusion. The elimination of rifampicin from serum approximated to a single-exponential decay with Tm of between 2-2 and 5-8 h. In some patients, the CSF concentrations exhibited changes which could not be analysed using conventional pharmacokinetic models, however, in five patients, elimination from CSF was compatible with a first order process as estimated by log-linear regression (r ^ 0-95). The concentration-time curves of rifampicin in serum and CSF of the patients 1 and 7 are shown in the Figure. Patient 1 had the highest, and patient 7 the lowest, CSF rifampicin concentrations. The rifampicin CSF/serum concentration ratio was not constant during the period of observation, but increased with time due to the lag between peak serum and CSF concentrations and the slower elimination from CSF. The overall CSF penetration estimated by the ratio AUCcsp/AUC.^,, was 0-13-0-42 (median = 0-22). The pharmacokinetic parameters in serum and CSF of each patient are shown in Table II. AUCap/AUC,^ did not correlate with the CSF protein content and the CSF/serum albumin ratio (rs = -0-3 and 0-2 (n =« 7)).
Downloaded from http://jac.oxfordjournals.org/ at University of North Carolina at Greensboro on November 6, 2014
bound slightly to the filters in a concentration independent manner, between 0-5 and 20 mg/L rifampicin binding was 0-16-0-24 mg/L (mean 0-2 mg/L). Since the samples were filtered but the calibrators were not 0-2 mg/L was added to all the concentrations measured in patients samples to correct for loss during filtration. Normal injection volume was 20 nL but if concentrations were above 10 mg/L only 5 fiL was injected and if concentrations were between 5 and 10 mg/L 10 /*L was injected. The limit of detection was 0-2 mg/L and, using the 20 yL injection volume, the standard curve was linear between 0-5 and 5-0 mg/L. Within-assay variation was 1-2% and between-assay variation was < 5%. Rifampicin in serum and CSF was stable for at least 24 h at 4°C and three months at — 70°C. However, freezing and thawing resulted in a decline of the rifampicin concentration of approximately 10% in serum and 5% in CSF. Metabolites, in particular desacetyl-rifampicin, did not co-elute with the parent compound. The co-medication of the patients studied did not interfere with the assay as shown by assaying serum and CSF obtained from these patients before starting the rifampicin infusion. Furthermore, ten drugs frequently used in our intensive care ward (promethazine, acetyldigoxin, flunitrazepam, frusemide, acetylcysteine, ranitidine, dexamcthasone, heparin, cefazolin and gentamicin) did not co-elute with rifampicin.
722
R. Nan et aL 100
0-1
10
12
14
16
22
24
26
Timt (h )
Figure. Rifampidn serum and CSF concentration-time curves after rifampidn 600 mg iv over 3 h in two patients. Patient 1, ierura ( + ), CSF (A); patient 7, serum (V), CSF (D)-
Table O. Phannacokinetics of rifampidn in serum and CSF after a single dose of 600 mg given iv infusion over 3 h (1) Serum Patient no. 1 2 3 4 5 6 7 (2) CSF Patient no. 1 2 3 4 5 6 7
(mg/L)
(h)
Cl (mL/min)
(L)
AUC,,).,,, (mg.h/L)
14-8 110 14-5 8-6 13-4 8-8 190
5-8 2-2 4-7 5-6 2-8 2-4 3-6
92-6 137 95-6 131 145 272 104
46-6 257 390 63-2 35-5 55-6 321
108 73-2 105 76-5 69-2 36-8 96-2
CBax (mg/L)
(h)
0>)
AUCpj.,0, (mg-h/L)
1-24 0-99 0-85 0-73 0-71 0-63 0-57
0 0-5 0-5 8 8 1 2
12-8 9-1 19-1 14-5 210
Cma, highest observed concentration; r,,^, time of observation of C
19-2 25-8 140 181 15-4 15-5 17-9
AUQW -»
AUC
0-18 0-35 0-13 0-24 0-22 0-42 0-19
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E o
Rifampidn penetration into CSF
723
Discussion
Downloaded from http://jac.oxfordjournals.org/ at University of North Carolina at Greensboro on November 6, 2014
The peak serum rifampicin concentrations observed in the present study after administration of 600 mg iv were slightly higher than those after 600 mg po (Acocella, 1983). As in previous studies, peak serum concentrations, AUC^,,,,, Tiptma, and Cl displayed a between-patient variability that was not solely related to body weight (Table II) (Acocella, 1983; Kucers & Bennett, 1987). Rifampicin elimination is dependent on hepatic deacetylation and biliary excretion. Enzyme induction by several drugs including rifampicin accelerates elimination, while disturbance of liver function prolongs elimination (Acocella, 1983; Kucers & Bennett, 1987). The low AUC^,,,,,, and the high Cl of patient 6 was probably due to his history of alcoholism. The results of previous studies in humans using bioassays to determine rifampicin concentrations in CSF were in the same range as our results. With uninflamed meninges, Furesz et al. (1967) found CSF levels of 0-33 and 0-83 mg/L in two patients 4 h after a single oral dose of 450 mg. In contrast, Sippel et al. (1974) were unable to detect the drug in CSF 3 h after a single oral dose of 25 mg/kg body weight (maximum: 600 mg). With the same dose in tuberculous meningitis CSF rifampicin concentrations were between 0-23 and 0-33 mg/L (Sippel et al., 1974). In another study in patients with meningeal tuberculosis, after oral administration of rifampicin 300 mg bd, peak CSF concentrations of 0-12—1-37 mg/L were observed 4 h post dose on the second day of treatment (D'Oliveira, 1972). No data on the pharmacokinetics of rifampicin in CSF have been published previously, however, D'Oliveira (1972) wrote that 'the presumptive CSF concentration curve appeared to indicate that the increases in CSF concentrations lagged behind those in plasma, and it was assumed that decreases were also slower'. The rifampicin concentrations in our study were measured by a HPLC method which is more specific for rifampicin than biological assays. Our peak CSF concentrations were higher than those of Sippel et al. (1974), but were similar to the concentrations found by Furesz et al. (1967) with uninflamed meninges and by D'Oliveira (1972) with inflamed meninges. The concentrations observed by us were lower than those measured by HPLC in rabbits that received 10 mg/kg without meningeal inflammation (Chan, 1986). In the present study, serial CSF assays permitted determination of AUCcgp and T]fVCSF. However, since the CSF concentrations were near the detection limit of the HPLC assays those parameters should be regarded as approximations. The ratio of individual CSF and serum concentrations of rifampicin varied with time and therefore was inadequate to characterize CSF penetration. Based on the ratio AUCCSF/AUCiman, the diffusion of rifampicin into CSF was less than that of chloramphenicol and several sulphonamides, but more than that of penicillins, cephalosporins and aminoglycosides (Barling & Selkon, 1978). It was similar to the CSF penetration of ciprofloxacin as estimated by the same method (Nau et al., 1990). The rifampicin concentrations in CSF obtained in this study of uninflamed meninges should be inhibitory to the growth of staphylococci, S. pnewnoniae and L. monocytogenes. They were near the MICs for M. tuberculosis, N. meningitidis and H. mfluenzae. Rifampicin may therefore be a suitable alternative therapy for staphylococcal CNS infections, especially for shunt infections, where meningeal inflammation often is minimal (Gombert et al., 1981). However, rifampicin must be used with another anti-staphylococcal drug, because rifampicin-resistant staphylococcal mutants emerge during monotherapy (Kucers & Bennett, 1987). Possible in-vivo antagonism must be considered in the choice of the second agent (Zinner et al., 1981; Kucers &
724
R. Nan et aL
Acknowledgement We thank Mrs H. Bartels, Borstel Research Institute, for her skilful technical assistance, and J. Buzanoski, MD, for his kind help in preparing the manuscript. References Acocella, G. (1983). Pharmacokinetics and metabolism of rifampcin in humans. Reviews of Infectious Diseases 5, Suppl. 3, S428-32. Barling, R. W. A. & Selkon, J. B. (1978). The penetration of antibiotics into cerebrospinal fluid and brain tissue. Journal of Antimicrobial Chemotherapy 4, 203-27. Chan, K. (1986). Rifampicin concentrations in cerebrospinal fluid and plasma of the rabbit by high performance liquid chromatography. Methods and Findings in Experimental and Clinical Pharmacology 8, 721-6. D'Oliveira, J. J. G. (1972). Cerebrospinal fluid concentrations of rifampin in meningeal tuberculosis. American Review of Respiratory Disease 106, 432-7. Ellard, G. A., Humphries, M. J., Gabriel, M. & Teoh, R. (1987). Penetration of pyrazinamide into the cerebrospinal fluid in tuberculous meningitis. British Medical Journal 294, 284-5. Forgan-Smith, R., Ellard, G. A., Newton, D. & Mitcbison, D. A. (1973). Pyrazinamide and other drugs in tuberculous meningitis. Lancet ii, 374. Furesz, S., Scotti, R., Pallanza, R. & Mapelli, E. (1967). Rifampicin: a new rifamycin. III. Absorption, distribution, and elimination in man. Arzneimittel-Forschung 17, 534-7. Gombert, M. E., Landesman, S. H., Corrado, M. L., Stein, S. C , Melvin, E. T. & Cummings, M. (1981). Vancomycin and rifampin therapy for Staphylococcus epidermidis meningitis associated with CSF shunts: report of three cases. Journal of Newosurgery 55, 633-6. Hof, H. & Emmerling, P. (1984). Murine model for therapy of listeriosis in the compromised host. III. The effect of rifampicin. Chemotherapy (Basel) 30, 125-30. Kucers, A. & Bennett, N. McK. (1987). The Use of Antiobiotics, 4th edn. William Heinemann Medical Books, London. Nau, R., Prange, H. W., Martell, J., Sharifi, S., Kolenda, H. & Birchcr, J. (1990). Penetration of ciprofloxacjn into the cerebrospinal fluid of patients with uninflamed meninges. Journal of Antimicrobial Chemotherapy 25, 965-73. Rowland, M. & Tozer, T. N. (1989). Clinical Pharmacokinetics. Concepts and Applications, 2nd edn. Lea & Febiger, Philadelphia, PA. Sippel, J. E., Mikhail, I. A., Girgis, N. I. & Youssef, H. H. (1974). Rifampin concentrations in cerebrospinal fluid of patients with tuberculous meningitis. American Review of Respiratory Disease 109, 579-80. Van der Auwera, P., Matsumoto, T. & Husson, M. (1988). Intraphagocytic penetration of antibiotics. Journal of Antimicrobial Chemotherapy 22, 185-92. Zinner, S. H., Lagast, H. & Klastersky, J. (1981). Antistaphylococcal activity of rifampin with other antibiotics. Journal of Infectious Diseases 144, 365-71. {Received 27 June 1991; revised version accepted 27 January 1992)
Downloaded from http://jac.oxfordjournals.org/ at University of North Carolina at Greensboro on November 6, 2014
Bennett, 1987). As its CSF concentrations may be close to the MICs for M. tuberculosis and as drug resistance also occurs, rifampicin should be used in tuberculous meningitis in a triple or quadruple regimen (e.g., with isoniazid and pyrazinamide with or without streptomycin) (Ellard et al.. 1987; Kucers & Bennett, 1987; Forgan-Smith et al., 1973). Rifampicin may also be effective in listeriosis; this is of special importance as the conventional therapy with ampicillin is not bactericidal in animal models. The risk of the development of rifampicin resistance in L. monocytogenes during therapy seems to be low (Hof & Emmerling, 1984). From the viewpoint of blood pharmacokinetics, maximal efficacy of rifampicin is achieved using a once daily dosage (Acocella, 1983). The slow elimination of rifampicin from CSF may further support this conclusion.
Penetration of rifampicin into the cerebrospinal fluid of adults with tminflamed meninges
Department of Neurology" and Newosurgery1, University of Gdttingen, Institute of Experimental Biology and Medicine, Research Institute Borstelb, Germany The penetration of rifampicin into CSF was studied in seven patients who had undergone external ventriculostomy for occlusive hydrocephalus without major disturbance of the blood-CSF barrier. After the first dose of rifampicin 600 mg iv over 3 h, blood and CSF concentrations were determined serially by HPLC. Peak CSF concentrations obtained 0-8 h (median = 1 h) after the end of the infusion ranged from 0-57 to 1-24 mg/L (median =• 0-73 mg/L). Elimination from CSF was slower than from serum (Tintaf: 9-1-21-0 h (median - 14-5 h, n - 5); Tl/2/mm: 2-2-5-8 h (median - 3-6 h, n - 7)). Based on the ratios of the areas under the concentration-time curves in CSF and serum, the overall penetration of rifampicin into CSF was 0-13-042 (median = 0-22). These results demonstrate effective CSF penetration and favourable pharmacokinetics of rifampicin in the absence of meningeal inflammation. They support the use of rifampicin as part of a combination therapy not only for tuberculosis of the central nervous system (CNS), but also for staphylococcal and listerial infections of the CNS in which there may be little meningeal inflammation.
Introduction
Rifampicin is highly active against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus, multiresistant Streptococcus pneumoniae and Listeria monocytogenes and Mycobacterium tuberculosis. Neisseria meningitidis and Haemophilus mfluenzae are also sensitive (Zinner, Lagast & Klastersky, 1981; Hof & Emmerling, 1984; Kucers & Bennett, 1987). Unlike many other antibiotics it is lipid soluble, penetrates cell membranes and kills intracellular bacteria (Van der Auwera, Matsumoto & Husson, 1988). These properties may qualify rifampicin for the treatment of tuberculous meningitis (D'Oliveira, 1972) and for other conditions such as meningitis caused by S. pneumoniae and H. mfluenzae resistant to conventional chemotherapy, CNS infections in immunocompromised hosts and listeria meningoencephalitis and ventriculitis (Gombert et al., 1981; Hof & Emmerling, 1984). Because there is little meningeal inflammation in some CNS infections, particularly in listeria brain stem encephalitis and ventricular shunt infections, we studied the diffusion of rifampicin into the CSF of 7 patients with uninflamed meninges. Correspondence to: Dr Roland Nau, Dept of Neurology, University of Gdttingen, Robert-Koch-StraBe 40, D-3400 G6tungen, Germany. 719 0305-7453/92/060719+06 S02.00/0
© 1992 The Britiih Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at University of North Carolina at Greensboro on November 6, 2014
Roland Nan*, Hflmar W. Prange', SyMa Menck*, Herbert Kolenda', Hans Vfaser* and Joachim K. Seydd*
720
R. Nan et aL
Patients and methods
HPLC assay Serum and CSF samples were deproteinized with acetonitrile and filtered through disposable 25 mm syringe filters of pore size 0-2 fim (Nalge Comp., Rochester, NY, USA). The samples were assayed on Chromosphere C,8 (10 cm column length) with a mobile phase of 62-65% methanol in phosphate buffered saline pH 7-4 pumped at a flow rate of 0-6 mL/min. Detection was by UV absorption at 280 nm. The retention time of rifampicin was 4-2-4-8 min. Quantitation was by multipoint calibration and peak area comparison using a model 760 integrator (Nelson Analytical). The calibrator solutions were not filtered because of a shortage of control CSF although rifampicin Table I. Characterization of investigated patients in the sequence of descending peak CSF rifampicin concentrations after an iv infusion of 600 nig over 3 h
no.
Body weight (kg)
1
100
Patient
2 3 4 5 6 7
70 80 70 70 95 55
CSF
CSF
WBC/
xlO"'
mm1
RBC/
313
8-4
4
1112
618
15-9
45
none
353
1-5
8
1149
768
10-4
28
1153
812
9-2
28
8021
308
09
1
512
1113
3-3
7
4941
CSF Age (sex)
Diseases
54 (M) Intracerebral haemorrhage, 66 (F) Subarachnoid haemorrhage, ventriculitis 57 (M) Intracerebral haemorrhage, 61 (M) Subarachnoid haemorrhage, 48 (F) Subarachnoid haemorrhage, 46 (M) Intracerebral haemorrhage, 70 (F) Intra cerebral haemorrhage,
protein (mg/L)
QAM
mm5
RTI RTI, UTI RTI, TBC RTI, UTI RTI, UTI RTI
RTI, Respiratory tract infection; UTI, urinary tract infection; TBC, history of tuberculosis; g A t l , CSF/serum albumin ratio.
Downloaded from http://jac.oxfordjournals.org/ at University of North Carolina at Greensboro on November 6, 2014
The study protocol was approved by the Hospital Ethics Commission. Informed consent for participation was obtained from the nearest relative of each patient. Seven patients with cerebrovascular diseases (four males, three females, age 48-70 years), who had undergone external ventriculostomy for occlusive hydrocephalus, were treated with rifampicin because of extracerebral infections. Co-medication varied according to clinical necessities but did not include barbiturates. The permeability of the blood-CSF barrier was assessed by determining the CSF protein content and the CSF/serum albumin ratio. Further details on the patients are shown in Table I. Rifampicin 600 mg (Rifa®, Griinenthal, Stolberg, Germany) was administered iv over 3 h once daily. Simultaneous blood and CSF samples were drawn 1, 2 and 3 h after the start, and 0-5, 1, 2, 4, 6, 8, 10, 12, 14 and 22 h after termination of the first rifampicin infusion. Samples were cooled in ice water, ccntrifuged at 5000 rpm for 5 min and separated serum and CSF supernatant were stored at -70°C. All samples were assayed within 10 weeks of collection.
Rlfampidn penetration into CSF
721
Pharmacokinetic analysis Pharmacokinetic calculations were done using standard methods (Rowland & Tozer, 1989). Elimination rate constants (kj) were determined by log-linear regression analysis and half-lives (Tl[2j) as In2/kf. The areas under the concentration-time curves (AUQ were estimated by the linear trapezoidal rule. AUC^,,,,,, and AUQsp were extrapolated to infinity (AUC^,,,)) by dividing the last measurable drug concentration by the kf. No kf could be determined from the CSF data of patients 2 and 6. In these cases AUCop was extrapolated to infinity by dividing the last measurable CSF concentration by the median kf of the otherfivepatients. The total clearance from serum (Cl) was calculated as dose/AUC^nn,,, and the apparent volume of distribution (VJ[) as dose/AXJC^^ • kfl. Results Peak concentrations of rifampicin in serum after the first infusion were 8-6-19-0 mg/L compared with 0-57-1-24 mg/L in CSF. The peak CSF concentrations were observed 0 to 8 h after the end of the infusion. The elimination of rifampicin from serum approximated to a single-exponential decay with Tm of between 2-2 and 5-8 h. In some patients, the CSF concentrations exhibited changes which could not be analysed using conventional pharmacokinetic models, however, in five patients, elimination from CSF was compatible with a first order process as estimated by log-linear regression (r ^ 0-95). The concentration-time curves of rifampicin in serum and CSF of the patients 1 and 7 are shown in the Figure. Patient 1 had the highest, and patient 7 the lowest, CSF rifampicin concentrations. The rifampicin CSF/serum concentration ratio was not constant during the period of observation, but increased with time due to the lag between peak serum and CSF concentrations and the slower elimination from CSF. The overall CSF penetration estimated by the ratio AUCcsp/AUC.^,, was 0-13-0-42 (median = 0-22). The pharmacokinetic parameters in serum and CSF of each patient are shown in Table II. AUCap/AUC,^ did not correlate with the CSF protein content and the CSF/serum albumin ratio (rs = -0-3 and 0-2 (n =« 7)).
Downloaded from http://jac.oxfordjournals.org/ at University of North Carolina at Greensboro on November 6, 2014
bound slightly to the filters in a concentration independent manner, between 0-5 and 20 mg/L rifampicin binding was 0-16-0-24 mg/L (mean 0-2 mg/L). Since the samples were filtered but the calibrators were not 0-2 mg/L was added to all the concentrations measured in patients samples to correct for loss during filtration. Normal injection volume was 20 nL but if concentrations were above 10 mg/L only 5 fiL was injected and if concentrations were between 5 and 10 mg/L 10 /*L was injected. The limit of detection was 0-2 mg/L and, using the 20 yL injection volume, the standard curve was linear between 0-5 and 5-0 mg/L. Within-assay variation was 1-2% and between-assay variation was < 5%. Rifampicin in serum and CSF was stable for at least 24 h at 4°C and three months at — 70°C. However, freezing and thawing resulted in a decline of the rifampicin concentration of approximately 10% in serum and 5% in CSF. Metabolites, in particular desacetyl-rifampicin, did not co-elute with the parent compound. The co-medication of the patients studied did not interfere with the assay as shown by assaying serum and CSF obtained from these patients before starting the rifampicin infusion. Furthermore, ten drugs frequently used in our intensive care ward (promethazine, acetyldigoxin, flunitrazepam, frusemide, acetylcysteine, ranitidine, dexamcthasone, heparin, cefazolin and gentamicin) did not co-elute with rifampicin.
722
R. Nan et aL 100
0-1
10
12
14
16
22
24
26
Timt (h )
Figure. Rifampidn serum and CSF concentration-time curves after rifampidn 600 mg iv over 3 h in two patients. Patient 1, ierura ( + ), CSF (A); patient 7, serum (V), CSF (D)-
Table O. Phannacokinetics of rifampidn in serum and CSF after a single dose of 600 mg given iv infusion over 3 h (1) Serum Patient no. 1 2 3 4 5 6 7 (2) CSF Patient no. 1 2 3 4 5 6 7
(mg/L)
(h)
Cl (mL/min)
(L)
AUC,,).,,, (mg.h/L)
14-8 110 14-5 8-6 13-4 8-8 190
5-8 2-2 4-7 5-6 2-8 2-4 3-6
92-6 137 95-6 131 145 272 104
46-6 257 390 63-2 35-5 55-6 321
108 73-2 105 76-5 69-2 36-8 96-2
CBax (mg/L)
(h)
0>)
AUCpj.,0, (mg-h/L)
1-24 0-99 0-85 0-73 0-71 0-63 0-57
0 0-5 0-5 8 8 1 2
12-8 9-1 19-1 14-5 210
Cma, highest observed concentration; r,,^, time of observation of C
19-2 25-8 140 181 15-4 15-5 17-9
AUQW -»
AUC
0-18 0-35 0-13 0-24 0-22 0-42 0-19
Downloaded from http://jac.oxfordjournals.org/ at University of North Carolina at Greensboro on November 6, 2014
E o
Rifampidn penetration into CSF
723
Discussion
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The peak serum rifampicin concentrations observed in the present study after administration of 600 mg iv were slightly higher than those after 600 mg po (Acocella, 1983). As in previous studies, peak serum concentrations, AUC^,,,,, Tiptma, and Cl displayed a between-patient variability that was not solely related to body weight (Table II) (Acocella, 1983; Kucers & Bennett, 1987). Rifampicin elimination is dependent on hepatic deacetylation and biliary excretion. Enzyme induction by several drugs including rifampicin accelerates elimination, while disturbance of liver function prolongs elimination (Acocella, 1983; Kucers & Bennett, 1987). The low AUC^,,,,,, and the high Cl of patient 6 was probably due to his history of alcoholism. The results of previous studies in humans using bioassays to determine rifampicin concentrations in CSF were in the same range as our results. With uninflamed meninges, Furesz et al. (1967) found CSF levels of 0-33 and 0-83 mg/L in two patients 4 h after a single oral dose of 450 mg. In contrast, Sippel et al. (1974) were unable to detect the drug in CSF 3 h after a single oral dose of 25 mg/kg body weight (maximum: 600 mg). With the same dose in tuberculous meningitis CSF rifampicin concentrations were between 0-23 and 0-33 mg/L (Sippel et al., 1974). In another study in patients with meningeal tuberculosis, after oral administration of rifampicin 300 mg bd, peak CSF concentrations of 0-12—1-37 mg/L were observed 4 h post dose on the second day of treatment (D'Oliveira, 1972). No data on the pharmacokinetics of rifampicin in CSF have been published previously, however, D'Oliveira (1972) wrote that 'the presumptive CSF concentration curve appeared to indicate that the increases in CSF concentrations lagged behind those in plasma, and it was assumed that decreases were also slower'. The rifampicin concentrations in our study were measured by a HPLC method which is more specific for rifampicin than biological assays. Our peak CSF concentrations were higher than those of Sippel et al. (1974), but were similar to the concentrations found by Furesz et al. (1967) with uninflamed meninges and by D'Oliveira (1972) with inflamed meninges. The concentrations observed by us were lower than those measured by HPLC in rabbits that received 10 mg/kg without meningeal inflammation (Chan, 1986). In the present study, serial CSF assays permitted determination of AUCcgp and T]fVCSF. However, since the CSF concentrations were near the detection limit of the HPLC assays those parameters should be regarded as approximations. The ratio of individual CSF and serum concentrations of rifampicin varied with time and therefore was inadequate to characterize CSF penetration. Based on the ratio AUCCSF/AUCiman, the diffusion of rifampicin into CSF was less than that of chloramphenicol and several sulphonamides, but more than that of penicillins, cephalosporins and aminoglycosides (Barling & Selkon, 1978). It was similar to the CSF penetration of ciprofloxacin as estimated by the same method (Nau et al., 1990). The rifampicin concentrations in CSF obtained in this study of uninflamed meninges should be inhibitory to the growth of staphylococci, S. pnewnoniae and L. monocytogenes. They were near the MICs for M. tuberculosis, N. meningitidis and H. mfluenzae. Rifampicin may therefore be a suitable alternative therapy for staphylococcal CNS infections, especially for shunt infections, where meningeal inflammation often is minimal (Gombert et al., 1981). However, rifampicin must be used with another anti-staphylococcal drug, because rifampicin-resistant staphylococcal mutants emerge during monotherapy (Kucers & Bennett, 1987). Possible in-vivo antagonism must be considered in the choice of the second agent (Zinner et al., 1981; Kucers &
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Acknowledgement We thank Mrs H. Bartels, Borstel Research Institute, for her skilful technical assistance, and J. Buzanoski, MD, for his kind help in preparing the manuscript. References Acocella, G. (1983). Pharmacokinetics and metabolism of rifampcin in humans. Reviews of Infectious Diseases 5, Suppl. 3, S428-32. Barling, R. W. A. & Selkon, J. B. (1978). The penetration of antibiotics into cerebrospinal fluid and brain tissue. Journal of Antimicrobial Chemotherapy 4, 203-27. Chan, K. (1986). Rifampicin concentrations in cerebrospinal fluid and plasma of the rabbit by high performance liquid chromatography. Methods and Findings in Experimental and Clinical Pharmacology 8, 721-6. D'Oliveira, J. J. G. (1972). Cerebrospinal fluid concentrations of rifampin in meningeal tuberculosis. American Review of Respiratory Disease 106, 432-7. Ellard, G. A., Humphries, M. J., Gabriel, M. & Teoh, R. (1987). Penetration of pyrazinamide into the cerebrospinal fluid in tuberculous meningitis. British Medical Journal 294, 284-5. Forgan-Smith, R., Ellard, G. A., Newton, D. & Mitcbison, D. A. (1973). Pyrazinamide and other drugs in tuberculous meningitis. Lancet ii, 374. Furesz, S., Scotti, R., Pallanza, R. & Mapelli, E. (1967). Rifampicin: a new rifamycin. III. Absorption, distribution, and elimination in man. Arzneimittel-Forschung 17, 534-7. Gombert, M. E., Landesman, S. H., Corrado, M. L., Stein, S. C , Melvin, E. T. & Cummings, M. (1981). Vancomycin and rifampin therapy for Staphylococcus epidermidis meningitis associated with CSF shunts: report of three cases. Journal of Newosurgery 55, 633-6. Hof, H. & Emmerling, P. (1984). Murine model for therapy of listeriosis in the compromised host. III. The effect of rifampicin. Chemotherapy (Basel) 30, 125-30. Kucers, A. & Bennett, N. McK. (1987). The Use of Antiobiotics, 4th edn. William Heinemann Medical Books, London. Nau, R., Prange, H. W., Martell, J., Sharifi, S., Kolenda, H. & Birchcr, J. (1990). Penetration of ciprofloxacjn into the cerebrospinal fluid of patients with uninflamed meninges. Journal of Antimicrobial Chemotherapy 25, 965-73. Rowland, M. & Tozer, T. N. (1989). Clinical Pharmacokinetics. Concepts and Applications, 2nd edn. Lea & Febiger, Philadelphia, PA. Sippel, J. E., Mikhail, I. A., Girgis, N. I. & Youssef, H. H. (1974). Rifampin concentrations in cerebrospinal fluid of patients with tuberculous meningitis. American Review of Respiratory Disease 109, 579-80. Van der Auwera, P., Matsumoto, T. & Husson, M. (1988). Intraphagocytic penetration of antibiotics. Journal of Antimicrobial Chemotherapy 22, 185-92. Zinner, S. H., Lagast, H. & Klastersky, J. (1981). Antistaphylococcal activity of rifampin with other antibiotics. Journal of Infectious Diseases 144, 365-71. {Received 27 June 1991; revised version accepted 27 January 1992)
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Bennett, 1987). As its CSF concentrations may be close to the MICs for M. tuberculosis and as drug resistance also occurs, rifampicin should be used in tuberculous meningitis in a triple or quadruple regimen (e.g., with isoniazid and pyrazinamide with or without streptomycin) (Ellard et al.. 1987; Kucers & Bennett, 1987; Forgan-Smith et al., 1973). Rifampicin may also be effective in listeriosis; this is of special importance as the conventional therapy with ampicillin is not bactericidal in animal models. The risk of the development of rifampicin resistance in L. monocytogenes during therapy seems to be low (Hof & Emmerling, 1984). From the viewpoint of blood pharmacokinetics, maximal efficacy of rifampicin is achieved using a once daily dosage (Acocella, 1983). The slow elimination of rifampicin from CSF may further support this conclusion.
