Should we reconsider cefazolin for treating staphylococcal meningitis? A retrospective analysis of cefazolin and cloxacillin cerebrospinal fluid levels in patients treated for staphylococcal meningitis.

OBJECTIVES: To assess the meningeal penetration of cefazolin and cloxacillin in individuals treated for methicillin-susceptible staphylococcal meningitis. METHODS: We retrospectively identified individuals treated for Staphylococcus meningitis with measurements of cefazolin or cloxacillin concentrations in cerebrospinal fluid (CSF) using a validated assay of liquid chromatography coupled with mass spectrometry at the Nantes University Hospital between January 2009 and October 2019. Staphylococcus meningitis was defined by a compatible clinical presentation and a microbiological confirmation (positive CSF culture or positive specific PCR). Medical charts were retrospectively reviewed to collect microbiological and clinical data, and to assess therapeutic success. RESULTS: Among the 17 included individuals, eight (47%) were treated with cefazolin and nine (53%) with cloxacillin. Median daily dosages of cefazolin and cloxacillin were 8 g (range 6-12 g) and 12 g (range 10-13 g), respectively. Cefazolin and cloxacillin were mainly administered by continuous infusion. Eleven individuals (65%) were men, median (interquartile range (IQR)) age was 54 years (50; 70), 14 (82%) had postoperative meningitis and 3 (18%) had haematogenous meningitis. Median (IQR) antibiotic CSF concentrations were 2.8 mg/L (2.1; 5.2) and 0.66 mg/L (0.5; 0.9) for cefazolin and cloxacillin groups, respectively. Cloxacillin was discontinued in two individuals for therapeutic failure. CONCLUSIONS: Patients with staphylococcal meningitis treated with high-dose continuous intravenous infusion of cefazolin achieved therapeutic concentrations in CSF. Cefazolin appears to be a therapeutic candidate that should be properly evaluated in this indication.

Effects of ampicillin, cefazolin and cefoperazone treatments on GLT-1 expressions in the mesocorticolimbic system and ethanol intake in alcohol-preferring rats.

Chronic ethanol consumption is known to downregulate expression of the major glutamate transporter 1 (GLT-1), which increases extracellular glutamate concentrations in subregions of the mesocorticolimbic reward pathway. While ß-lactam antibiotics were initially identified as potent upregulators of GLT-1 expression, only ceftriaxone has been extensively studied in various drug addiction models. Therefore, in this study, adult male alcohol-preferring (P) rats exposed chronically to ethanol were treated with other ß-lactam antibiotics, ampicillin, cefazolin or cefoperazone (100mg/kg) once daily for five consecutive days to assess their effects on ethanol consumption. The results demonstrated that each compound significantly reduced ethanol intake compared to the saline-treated control group. Importantly, each compound significantly upregulated both GLT-1 and pAKT expressions in the nucleus accumbens and prefrontal cortex compared to saline-treated control group. In addition, only cefoperazone significantly inhibited hepatic aldehyde dehydrogenase-2 enzyme activity. Moreover, these ß-lactams exerted only a transient effect on sucrose drinking, suggesting specificity for chronically inhibiting ethanol reward in adult male P rats. Cerebrospinal fluid concentrations of ampicillin, cefazolin or cefoperazone have been confirmed using high-performance liquid chromatography. These findings demonstrate that multiple ß-lactam antibiotics demonstrate efficacy in reducing alcohol consumption and appear to be potential therapeutic compounds for treating alcohol abuse and/or dependence. In addition, these results suggest that pAKT may be an important player in this effect, possibly through increased transcription of GLT-1.

Effect of isoniazid on the pharmacodynamics of cefazolin-induced seizures in rats.

Both isoniazid (INH) and cefazolin (CEZ) can have serious adverse effects on the central nervous system (CNS), causing seizures. In this study, we investigated the effect of INH on the pharmacodynamics of CEZ-induced seizures in rats. Male Wistar rats pretreated with INH (150 mg/kg i.p.) or saline received an intravenous infusion of CEZ at 3.2 g/h/rat until the onset of seizures, then samples of cerebrospinal fluid (CSF), blood (for serum), and brain were obtained immediately. The administration of INH was associated with a reduction in the total dose of CEZ required to produce seizures. The concentrations of CEZ in serum, brain, and CSF in INH-treated rats at the onset of seizures were significantly lower than those in control rats. In rats coadministered with pyridoxine (150 mg/kg s.c.), the concentration of CEZ in CSF at the onset of seizures was significantly higher than that in rats administered INH only. These results suggest that INH potentiates the sensitivity of the CNS to CEZ-induced seizures, and that the increased sensitivity is associated with the inhibition of vitamin B(6) metabolism by INH.

Effect of experimental renal failure and hypotonic hyponatremia on the pharmacodynamics of cefazolin-induced seizures in rats.

PURPOSE: The purpose of this study was to investigate the effect of experimental renal failure and hypotonic hyponatremia on the pharmacodynamics of cefazolin (CEZ)-induced seizures. METHODS: Rats received an intravenous infusion of CEZ until the onset of seizures. Renal failure was produced by bilateral ureteral ligation (UL) or uranyl nitrate (UN) injection. Hypotonic hyponatremia was produced by intravenous infusion of 5% dextrose in water or intraperitoneal infusion of distilled water after arginine vasopressin injection. RESULTS: The serum and brain concentrations of CEZ at the onset of seizures increased with increasing infusion rate, but the CSF concentration of CEZ at the onset of seizures was not affected by the infusion rate. The concentration of CEZ in CSF at the onset of seizures was significantly lower in UL rats than control rats, whereas there was no difference between UN rats and their controls. Serum concentrations of Na+ and serum tonicity were lower in UL rats than UN rats. Hypotonic hyponatremia had no apparent effect on the CSF concentration of CEZ. The CSF concentration of CEZ at the onset of seizures was significantly lower in UN rats with hypotonic hyponatremia than their controls. CONCLUSION: Renal failure with severe hypotonic hyponatremia is associated with increased central nervous system sensitivity to CEZ-induced seizures.

Influence of lipophilicity on the diffusion of cephalosporins into the cerebrospinal fluid.

The aim of this quantitative structure-activity relationship (QSAR) study was to investigate the influence of lipophilicity on the diffusion of cephalosporins into the cerebrospinal fluid (CSF). The lipophilicity was expressed as the chromatographic capacity factor (log k'w) determined by high-performance liquid chromatography in a reversed-phase system. The penetration of eight cephalosporins into CSF was studied in male Wistar rats receiving the drugs intramuscularly (1.5 mg/kg). One hour after administration, CSF and blood samples were collected, and concentrations of free drug were measured in CSF (CCSF) and in plasma (CP). A significant parabolic relationship was sought between lipophilicity (log k'w) and the capacity of diffusion across the blood-brain barrier expressed as log (CCSF/CP). The cephalosporins exhibiting a moderate lipophilicity diffused well into CSF. A pharmacokinetic study was performed at 1, 2 and 4 h after administration of three cephalosporins: cefazolin, ceftriaxone and cefsulodin. These compounds were choosen according to their lipophilicities (low, moderate and high values, respectively). The AUC0-4h for both free plasma (AUCP) and cerebrospinal fluid (AUCCSF) concentrations were determined. The AUCCSF/AUCP ratio presented a maximum value for a strongly albumin bound cephalosporin, ceftriaxone. In our experimental conditions, the ideal lipophilicity (log k'w) range for diffusion of cephalosporins from plasma into CSF was between 1.6 and 1.8.

Effect of multidose therapy on cerebrospinal fluid penetration of cefazolin.

The relationship between serum concentrations and cerebrospinal fluid (CSF) concentrations of cefazolin, and the association between these concentrations and neurotoxic reactions, were investigated. Samples of serum and spinal fluid were drawn simultaneously from six patients at the steady state on various dosages of cefazolin sodium for different conditions. The dose, dosing interval, number of doses, results of renal function tests, and signs of neurotoxicity, such as muscle twitches, confusion, and seizures, were recorded. The concentrations of cefazolin in the serum and CSF, total serum protein, and percent albumin were determined. Five of the six patients given multiple doses of cefazolin sodium had notable CSF accumulation of the drug (11.3 +/- 2.7% of the serum concentration). Three patients experienced generalized focal-motor seizures during their therapy. Neurotoxicity was found to be associated with renal dysfunction and multiple-dose therapy leading to serum concentrations greater than 360 micrograms/ml and CFS concentrations greater than 34 micrograms/ml. Cefazolin will penetrate into the CSF in patients receiving multiple-dose therapy of the drug. To avoid neurotoxicity, careful attention should be paid to the recommended dosage regimens, the impact of renal dysfunction on drug clearance should be recognized, and serum assays should be performed when necessary.

Seizures associated with high cerebrospinal fluid concentrations of cefazolin.

Three cases of generalized seizures in patients with high cerebrospinal fluid (CSF) concentrations of cefazolin are reported. Patient 1, a 60-year-old woman with impaired renal function and a Klebsiella pneumoniae infection, was treated with 70 mg every eight hours of i.v. gentamicin sulfate and 1.5 g every four hours of i.v. cefazolin sodium. Gentamicin was discontinued on day 11. On day 12, the patient had a generalized tonic-clonic seizure. Serum and CSF concentrations of cefazolin one day later were 470 and 64 micrograms/ml, respectively. Patient 2, a 70-year-old man with impaired renal function, was given i.v. cefazolin, 1 g every 12 hours; the dosage interval was shortened later to every six hours. Two days later, the patient had two tonic-clonic seizures. Serum and CSF concentrations eight hours after the last dose of cefazolin were 360 and 34 micrograms/ml, respectively. Patient 3, a 67-year-old woman with renal vein thrombosis, received 55 mg every eight hours of i.v. gentamicin and 2 g every six hours of i.v. cefazolin. The antibiotics were discontinued after eight days when the patient had two tonic-clonic seizures. Serum and CSF concentrations of cefazolin measured 28 hours later were 1000 and 106 micrograms/ml, respectively. Previous reports of cefazolin-associated seizures are reviewed. In patients with renal failure, cefazolin may obtain high CSF concentrations. To avoid seizures, cefazolin doses should be adjusted in these patients.

[Experimental studies on the passage of antibiotics into cerebrospinal fluid in staphylococcal meningitis in rabbits. II. Cephaloridine, cephalothin and cefazolin (author's transl)].

Passage of cephaloridine, cephalothin and cefazolin into cerebrospinal fluid (CSF) was evaluated in Staphylococcus aureus meningitis in rabbits and the following results were obtained. 1. Concentration in CSF (microgram/ml) [CSF/serum ratio (%)] was determined 1/2, 1 and 2 hours after a single intravenous injection of 100 mg/kg of each antibiotic, respectively; cephaloridine-7.5 [8.9], 9.7 [13.8], 9.1 [22.6]; cephalothin-0.42 [3.6], 0.23 [6.4], not detectable [0]; cefazolin-7.5 [11.8], 5.2 [19.3], 2.0 [17.5]. 2. When results with cefazolin after an intravenous injection 100 mg/kg and 200 mg/kg were compared, a definite dose response was noted in blood concentration but not in CSF concentration. 3. A standard error of CSF concentrations of each antibiotic was larger than that of penicillins, and "Unpredictability" of their passage into CSF was considered to be one of the characteristics common to these three drugs in respect of their passage into CSF. 4. There was no significant difference noted in antibiotic passage into CSF between cephaloridine of low protein binding rate and cefazolin of very high binding rate. Cephalothin, of which binding rate was intermediate, showed a remarkably lower passage into CSF. These results indicate that a correlation does not always exist between protein binding rate of the antibiotics and their passage into CSF. 5. Based on the above results, a review of the literature was made on clinical applicability of these three antibiotics in the treatment of bacterial meningitis. Low transport rate of cephalothin into CSF and nephrotoxicity of cephaloridine make them to be unsuitable for bacterial meningitis. Cefazolin is considered to be suitable in the treatment of ampicillin-resistant Escherichia coli meningitis and Gram-positive coccal meningitis in which penicillins are not applicable.

[Investigation of the c. s. fluid levels of two newer antibiotics; cefazolin and sisomicin (author's transl)]. / Liquorspiegeluntersuchung zwei neuerer Antibiotika Cefazolin und Sisomicin.

In ten patients continuous estimations of the C.S.F. and serum levels were performed after the administration of a Cephalosporin derivative (Cefazolin - 4 cases) and a new alpha-amino-glycoside antibiotic (Sisomicin - 6 cases). After the evaluation of the results some doubts must be cast on the value of both these antibiotics for the treatment of meningitis or for per-operative chemo-prophylaxis in neurosurgical procedures. The values found were compared with those well-known in the literature, regarding the cephalosporins and the alpha-amino-glycoside Gentamycin.

[Chemotherapy of purulent meningitis in children (author's transl)].

Purulent meningitis in patients admitted to the pediatric department of Kyoto University Hospital and affiliated institutions from 1951 through 1973 were studied with emphasis on the kinds of the causative organisms and the susceptibility of these organisms to antibiotics. The findings in this study have served to help select antibiotics most likely to be effective against this disease. The overall incidence of purulent meningitis was 0.68%. This figure decreased little throughout the period. As for the frequency of causative organisms, Neisseria meningitidis led the list, and Diplococcus pneumoniae ranked just behind. Haemophilus influenzae was rare. The frequency of N. meningitidis, however, decreased sharply in spite of the essentially unchanged overall incidence of this disease. The probable reason for the poor prognosis of this disease in spite of the remarkable strides in chemotherapy is the decreased frequency of N. meningitidis and the inversely increased organisms that are resistant to usual chemotherapy. The therapeutic effectiveness of cefazolin against this disease was studied in 15 children including eight newborns and four infants. The daily per kg bodyweight dose was 50 mg or less in four, 50 approximately 100 mg in five, and more than 100 mg in the remaining six. The route of administration was either intramuscular or intravenous. No deaths occurred. The rate of effectiveness was as high as 80%. Residual symptoms were recorded in six and, in as many as five of them, the cause was a-tributable to the delayed detection of the disease. Neither side effects nor aberrent laboratory findings attributable to large doses of cefazolin were recorded. Diffusibility of cefazolin into the CSF was studied in nine subjects. The CSF concentration of this antibiotic was shown to be somewhat lower than that of ampicillin or cephaloridine and to account on an average for 13% of the mean peak serum level. This relatively low diffusibility will be offset by its high serum concentration and safe large-dose therapy. These findings have clearly shown that the therapeutic effectiveness of cefazolin is as high as that of ampicillin, and that this excellent effectiveness holds true even when the causative organism happens to be Escherichia coli, Klebsiella, etc. that are resistant to ampicillin. The authors have furthermore scrutinized much literature on the frequency of the causative organisms, emergence of resistant strains, and the diffusibility of antibiotics into the CSF, and arrived at the conclusion that cefazolin is a promising antibiotic of choice for the treatment of purulent meningitis in newborn. The daily dose is preferably 150 mg/kg or more given in three divided intravenous doses. Meanwhile ampicillin proved to be useful as the antibiotic of choice for the treatment of purulent meningitis in infants and children.