Journal of Antimicrobial Chemotherapy (1990) 25, 965-973

Penetration of ciprofloxacin into the cerebrospinal fluid of patients with tminflamed meninges R. Nan', H. W. Prange", J. MarteD*, S. Sharifi', H. Kolenda'' and J. Birched

Nine patients with external ventriculostomy and suffering from hydrocephalus, due to non-inflammatory central nervous system diseases,' were given ciprofloxacin (200 mg twice daily iv). Ciprofloxacin concentrations in serum and CSF were measured by HPLC. Single-dose pharmacokinetics were determined in three patients, and 60 and 600 min post-dose levels after repeated administration in six patients. CSF concentrations were maximal 60-120 min after the end of the infusion. The CSF elimination half-life was 260-430 min compared with 145-170 in serum. Post-dose levels at 60 min ranged from 0-042 to 0-223 mg/1 (median = 0-110). Repeated administration did not lead to substantial increases in serum and CSF concentrations. With respect to MIC* values reported for bacteria involved in CNS infections, the CSF concentrations of ciprofloxacin obtained under our experimental conditions would be considered subtherapeutic. Thus ciprofloxacin therapy of CNS infections may be inadequate when only minor impairment of the blood-CSF barrier exists.

Introduction Many antibiotics achieve therapeutic cerebrospinal fluid (CSF) concentrations in the presence of inflamed meninges. Penetration of the majority of antibiotics is insufficient, when the blood-CSF barrier is intact (Barling & Selkon, 1978; Simon & Stille, 1985). Subtherapeutic CSF levels may complicate therapy of central nervous system (CNS) infections when only minor impairment of the blood-CSF barrier is present, as in encephalitis or with a brain abscess, and may provoke relapse in the course of meningitis when the blood-CSF barrier begins to recover (Barling & Selkon, 1978; Schaad, Nelson & McCracken, 1981). To ensure successful therapy any antibiotic suggested for the treatment of CNS infections should be evaluated not only for therapeutic concentrations during meningeal inflammation but also when the meninges are uninflamed. Ciprofloxacin has a broad range of in-vitro antibacterial activity, against most organisms responsible for purulent meningitis (Chin & Neu, 1984). It may have therapeutic potential in CNS infections caused by Gram-negative bacteria (Hackbarth et al., 1986; Isaacs et al., 1986; Millar et al., 1986). Because of its broad spectrum against Gram-positive and Gram-negative bacteria, ciprofloxacin may be of use in the Correspondence: Prof. Dr H. W. Prange, Department of Neurology, Univenity of Gdttingen, RobertKoch-Str. 40, D-3400 Gdttingen, FRG. 0305-7453/90/060965+09 $02.00/0

965 © 1990 The British Society for Antimicrobia] Chemotherapy

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Departments of'Neurology, bSurgery, 'Clinical Pharmacology and'Neurosurgery, University of Gottingen, FRG

966

R. Nao et aL

prevention of infections in CSF shunt surgery, particularly in external ventriculostomies, which have high infection rates (Wyler & Kelly, 1972; Haines, 1986). In neurological patients treated with ciprofloxacin for respiratory or urinary tract infection we evaluated its ability to penetrate into CSF in the absence of inflamed meninges and prevent infections of external ventriculostomies.

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Patients and methods Nine patients with occlusive hydrocephalus who underwent external ventriculostomy for more than three days and who did not suffer from major impairment of renal function were included in the study. Patients with inflammatory CNS diseases and with serum creatinine levels > 0-015 g/1 were not considered. In eight cases cerebrovascular accidents (four cerebral ischaemic infarctions, four intracranial haemorrhages) and in one patient tuberous sclerosis were the underlying diseases. For further details see Table I. Written consent to participate in the study was obtained from the nearest relative. Other medication varied according to clinical necessity and consisted of catecholamines, diuretics, antihypertensives, sedatives, glycerol H2-receptor-blockers. Patient E received treatment with cefazolin. Chemicals structurally related to theophylline were avoided, because of the mutual inhibition of the metabolism of theophylline and quinoloncs (Bergan, Dalhoff & Rohwedder, 1988). No adverse effects attributable to ciprofloxacin were observed. The rise of serum creatinine in patient W to 0056 g/1 on day 3 was due to neurogenic shock by vasomotor paralysis. In the other patients serum creatinine remained unchanged. Ciprofloxacin (Bayer Leverkusen) 200 mg was infused intravenously (iv) within 30 min every 12 h for three to nine days. Single dose pharmacokinetics were determined in patients G and D after the first and in patient E after the last infusions. In the other six patients serum and CSF samples were obtained 60 and 600 min after the end of ciprofloxacin infusion. To attain steady-state conditions measurements were begun after the third dose. Ciprofloxacin serum and CSF concentrations were determined by HPLC as previously described (Gau, Ploschke & Weber, 1986; Behrens-Baumann & Martell, 1988) using an isocratic system (buffer 3X10~ 2 M H3PO4 in H2O, neutralized with tetrabutylammonium hydroxide to pH 3, 5% acetonitrile). Separation of 50-/J samples was performed at 50°C on a Lichrosphere RP 18250 x 4 mm analytical column (Merck). Ciprofloxacin eluted at 41 ±0-1 min and was detected by fluorescence (Shimadzu RF-530, excitation wave length 281 nm, emission wave length 455 nm). Peak areas obtained by means of a CR3A Shimadzu integrator were compared with peak areas of standard solutions. Sensitivity was 0-003 mg ciprofloxacin/1; linear detection ranged from 0005 to 1 mg/1. The coefficient of variation on replicated determinations at several concentrations within the linear detection range was below 3%. Ciprofloxacin metabolites and control sera from ICU patients treated with a variety of drugs did not interfere with the assay. Serum and CSF distribution and elimination half-lives (Tir3a and Tll2fT), total areas under the concentration-time curves (AUC), apparent volumes of distribution (yjl) and total body clearances (Cl) were calculated according to standard methods (Rowland & Tozer, 1980). The permeability of the blood-CSF barrier was characterized by the ratio albumin concentration in CSF/albumin concentration in serum (Q/jbi Reiber & Felgenhauer, 1987).

45 75 105 75 95 65 90 100

M R A H E W K D 59, m

53, m

61, m

62, m

58, m

64, m

68, f

20, f

54, f

sex

Age/ ICB RTI, UT1 tuberous sclerosis UTI cerebellar infarction, RTI cerebellar ICB, RTI pontine ICB, RTI, UTI cerebellar infarction, RTI cerebellar infarction, RTI cerebral infarction, RTI cerebellar ICB, RTI

Diseases'

3

8

4

9

5

5

9

6

9

Duration of CPX administration (days)

15 31

171

1

44

129

81

1

3-8

2-8

7-3

10-5

10-5

15-4

6-9

88-7

12-6

11 6

CAlb* xl0"J

WBC mm'

163

357

404

560

1193

345

6329

858

CSF protein (mg/1)

*ICB, Intracerebral bleeding; RTI, respiratory tract infection; UTI, urinary tract infection. *CSF/serum albumin ratio (normal values below 8 x 10"5).

75

G

Patient

Body weight (kg)

20

20

90

40

600

4500

20

4000

12000

mm3

RBC/

Table I. Characterization of investigated patients in the sequence of descending 60 min after a dose of ciprofloxacin (CPX) concentrations in CSF

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R,

§o

a

g o

8 1

R. Nan et aL

968

Results

001 001

Strum (mg/1)

Fignc 1. Double-logarithmic graph of ciprofloxacin serum vt CSF concentrations determined in the present study. Concentrations measured in patients E (Q). D (A), and G ( • ) , after end of ciprofloxacin (200 rag iv) infusion. Arrows indicate measurement sequence. Note the increase of the CSF/serum ratio during the period of observation. Concentrations 60 min post-dote ( # ) and 600 min post-dose (O) in six patients after repeated administration of ciprofloxacin (200 mg iv); medians of n measurements (see Table III).

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After single dose administration in three patients, ciprofloxacin in serum and CSF reached the concentrations shown in Figure 1. Maximal CSF concentrations (0-223, 0101 and 0-045 mg/1) were observed 60min (patients G, E) and 120 min (patient D) after the end of iv infusion. Ciprofloxacin kinetics in serum and CSF were adequately described by a linear pharmacokinetic model (Table II). On the basis of A U C ^ and A U Q S F overall penetration of ciprofloxacin into CSF was 238, 21-3 and 33-5% respectively. CSF TI/2/? were about twice as long as serum Ti/2fi. Multiple ciprofloxacin administration did not result in substantial increases of 60 min and 600 min post-dose levels in serum and CSF (Table 111). Sixty minute post-dose ciprofloxacin concentrations in CSF after single or multiple administration ranged from 0-042 to 0-223 mg/1. They were close to the minimal inhibitory concentrations (MIC) for the majority of bacteria isolated from CSF in our hospital from January 1986 until June 1988: 45 isolates were highly susceptible—their growth being inhibited by concentrations of 0-125 mg/1 or less, 15 isolates had MICs from 0-25 to 0-5 mg/1 and 16 were moderately susceptible or resistant (MIC > 0-5mg/l). Despite the low CSF levels no ventricular shunt infection emerged during ciprofloxacin treatment. In patients whose CSF was sterile before starting the infusions, it remained so until the end of the study period. In patient E, ventricular CSF grew Staphylococcus epidermidis (MIC 4 mg/1) and a Corynebacterium sp. (MIC 16 mg/1). S. epidermidis (MIC 0-125 mg/1) was isolated from the CSF of patient H. In both patients

CSF penetration of dprofloxadn

969

Table IL Single dose pharmacokinetics of ciprofloxacin in serum and CSF G

Patient Pharmacokinetics in serum Tipct (min) TlJ2fi (min) AUC (mg min/1) Cfc (ml/min)

10 170 3821 523 125-6

15 165 312-0 641 152-6

5 260 90-8 0-223 60 23-8

9 430 66-4 0-101 60 21-3

10 145 123-6 1620 337-5 40 420 41-4 0045 120 33-5

Table HL Simultaneous dprofloxadn concentrations in serum and CSF, 60 and 600 min after drug administration

Patient C M R A H W K D*

Concentrations, Serum H» (mg/1)

60 min' CSF Ratio (mg/1) (%)

1 1198 5 0-940 (0-855-2-273) 4 1-623 (0-936-2-633) 4 0-963 (0774-1157) 10 1-238 (0781-1-982) 1 0934 3 1-477 (1-216-1-907) 4 1104 (O785-1-570) 1 0422

0223 18-6 0139 14-8 (0098-0-275) 0139 8-6 (0132-0145) 0112 11-6 (0047-0161) 0110 8-9 (0075-0317) 0101 108 0076 5-1 (0071-0089) 0047 4-3 (0025-0070) 0042 100

7i*

(mg/1)

600minc CSF Ratio (mg/1) (%)

1 1

0150 O400

0051 O096

Concentrations, Serum

4

0224 (0129-0267) 3 0210 (0205-0216) 5 0316 (O211-O-610) 1 0072 3 0386 (0205-0413) 3 0138 (0116-0-169) 1 0032

33-5 24-0

O045 200 (0033-0068) O074 35-2 (0046-0094) 0060 19-0 (0048-0083) O043 59-7 O026 6-7 (0O24-O-030) 0O47 341 (0023-0051) 0020 62-5

"Concentrations after a single dose of dprofloxadn. Median (range) in CSF after single dose administration: 0-101 (0042-0-223) (60min

Penetration of ciprofloxacin into the cerebrospinal fluid of patients with uninflamed meninges.

Nine patients with external ventriculostomy and suffering from hydrocephalus, due to non-inflammatory central nervous system diseases, were given cipr...
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