Multidrug-Resistant Staphylococcus epidermidis Ventriculostomy-Related Infection Successfully Treated by Intravenous Ceftaroline after Failure of Daptomycin Treatment.

BACKGROUND: Ventriculostomy-related infection with multidrug-negative strains are challenging to treat. We report the use of new antibiotics in such a case. CASE DESCRIPTION: We report the case of a neurosurgical intensive care unit patient who developed ventriculostomy-related infection with a multidrug-resistant Staphylococcus epidermidis. Vancomycin, recommended in such cases, was not used due to high minimal inhibitory concentrations and concerns for lack of pharmacokinetic/pharmacodynamic target attainment. Daptomycin and ceftaroline remained the only treatment options. Daptomycin was shown microbiologically ineffective after 10 treatment days, with undetectable cerebrospinal fluid (CSF) concentration. Ceftaroline, a novel beta-lactam agent to which the strain showed susceptibility, was thus used. Serum and CSF samples were assessed for antibiotic concentrations. Our results show that CSF bacterial clearance was obtained after 6 days of such treatment. Serum and CSF samplings showed low penetration ratios (2.6%-4.8%), probably due to mild inflammatory CSF profile, with CSF concentration at minimal inhibitory concentration level. CONCLUSIONS: We observed than even in the case of mild meningeal inflammation, ceftaroline penetration in CSF, although moderate, enabled efficient bacterial clearance and clinical efficacy, in adjunction to correct ventriculoperitoneal shunt management.

Efficacy of Ceftaroline Fosamil against Escherichia coli and Klebsiella pneumoniae strains in a rabbit meningitis model.

In this study, the efficacy of ceftaroline fosamil was compared with that of cefepime in an experimental rabbit meningitis model against two Gram-negative strains (Escherichia coli QK-9 and Klebsiella pneumoniae 1173687). The penetration of ceftaroline into inflamed and uninflamed meninges was also investigated. Both regimens were bactericidal, but ceftaroline fosamil was significantly superior to cefepime against K. pneumoniae and E. coli in this experimental rabbit meningitis model (P < 0.0007 against K. pneumoniae and P < 0.0016 against E. coli). The penetration of ceftaroline was approximately 15% into inflamed meninges and approximately 3% into uninflamed meninges.

Evaluation of ceftobiprole activity against a variety of gram-negative pathogens, including Escherichia coli, Haemophilus influenzae (ß-lactamase positive and ß-lactamase negative), and Klebsiella pneumoniae, in a rabbit meningitis model.

Ceftobiprole medocaril, a new cephalosporin, is highly active against a broad spectrum of Gram-positive and Gram-negative clinical pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant pneumococci. In this study, we tested ceftobiprole against various Gram-negative pathogens in a rabbit meningitis model and determined its penetration into the cerebrospinal fluid (CSF). In this animal model, ceftobiprole produced an antibacterial activity similar to that of cefepime against an Escherichia coli strain, a Klebsiella pneumoniae strain, and a ß-lactamase-negative Haemophilus influenzae strain. Against a ß-lactamase-positive H. influenzae strain, ceftobiprole was significantly superior. The penetration of ceftobiprole through inflamed meninges reached about 16% of serum levels compared to about 2% of serum levels through uninflamed meninges.

Blood-brain barrier penetration of cefepime after neurosurgery.

BACKGROUND: It has been confirmed that the concentration of cefepime in cerebrospinal fluid (CSF) could reach the 10% of its concentration in plasma, exceeding the inhibitory concentration to 90% of organisms (MIC(90)) for common bacteria. However, the blood-brain barrier (BBB) penetration ability of cefepime is still unclear. The aim of this study was to measure the CSF concentration of cefepime in patients after neurosurgical operations, and to determine the penetration of the drug through an incomplete BBB. METHODS: Eight patients who received ventricular drainage (VD group) and 5 who underwent lumbar puncture drainage (LPD group) were enrolled into this study. Cefepime (2 g) was injected intravenously in 30 minutes after the neurosurgeries. The concentrations of cefepime in the CSF and plasma were measured by high-pressure liquid chromatography (HPLC) at different time points. RESULTS: The CSF concentrations of cefepime at different time points in the VD group were significantly higher than those in the LPD group (P < 0.05). In the VD group, the concentration of cefepime in CSF reached the peak ((22.54 +/- 14.06) microg/ml) at 1 to 2 hours after the injection, while in the LPD group at 4 hours ((5.61 +/- 3.73) microg/ml). In both groups, the peak was higher than the MIC(90) of most common bacteria in intensive care unit. The ratio of CSF to plasma cefepime concentrations ranged from 0.30 to 2.14 in the VD group and 0.03 to 1.14 in the LPD group. CONCLUSION: After neurosurgeries, CSF concentration of cefepime can reach a therapeutic level. Thus, the drug could be used to prevent and treat postoperative intracranial infection.

Comparison of the probability of target attainment between ceftriaxone and cefepime in the cerebrospinal fluid and serum against Streptococcus pneumoniae.

Although the disposition of ceftriaxone and cefepime in the cerebrospinal fluid (CSF) has been described, the ability of these agents to achieve critical pharmacodynamic targets against Streptococcus pneumoniae in CSF has not been reported. Plasma and CSF pharmacokinetic data were obtained from hospital patients with external ventricular drains and receiving ceftriaxone or cefepime. Concentration-time profiles in plasma and CSF were modeled using a 3-compartment model with 0-order infusion and 1st-order elimination and transfer. The model parameters were identified with population pharmacokinetic analysis (Big Non-Parametric Adaptive Grid with adaptive gamma). A Monte Carlo Simulation (9999 subjects) estimated the probability of target attainment (PTA) for total drug CSF concentrations at 50% and 100% T>MIC for ceftriaxone 2G IV Q12H and cefepime 2G IV Q8H. The S. pneumoniae bloodstream infection isolates from the SENTRY Antimicrobial Surveillance Program (USA) provided the distribution of contemporary (2003-2004) MICs. Post-Bayesian measures of bias and precision, observed-predicted plots, and R2 values were highly acceptable for both drugs. The probabilities of achieving 50% and 100% T>MIC in the CSF for ceftriaxone were 76% and 65%, respectively. For cefepime, the PTA at 50% and 100% T>MIC in the CSF were 91.8% and 82%, respectively. The CSF pharmacodynamics against S. pneumoniae for cefepime were superior to that of ceftriaxone. The implications of these findings need to be reexamined in the clinical setting.

Simultaneous determination of cefepime and vancomycin in plasma and cerebrospinal fluid by MEKC with direct sample injection and application for bacterial meningitis.

A simple MEKC with UV detection at 214 nm for simultaneous analysis of cefepime and vancomycin in plasma and in cerebrospinal fluid (CSF) by direct injection without any sample pretreatment is described. The separation of cefepime and vancomycin from biological matrices was performed at 25 degrees C using a BGE consisting of a Tris buffer with SDS and methanol as the electrolyte solution. Under optimal MEKC conditions for biological samples, good separations with high efficiency and short analysis time are achieved. Several parameters affecting the separation of the drugs from biological matrices were studied, including methanol, pH, and concentrations of the Tris buffer and SDS. The linear ranges of the method for the determination of cefepime and vancomycin in plasma and in CSF using imidazole or cefazolin as an internal standard, respectively, were all over the range of 1-30 microg/mL; the detection limits of cefepime and vancomycin in biological matrices (injection 10 kV, 15 s) were 0.3 and 0.5 microg/mL, respectively. The applicability of the proposed method for the determination of cefepime and vancomycin in plasma and CSF collected after intravenous administration of the drugs in patients with meningitis was demonstrated.

Pharmacodynamic profiling of cefepime in plasma and cerebrospinal fluid of hospitalized patients with external ventriculostomies.

Population pharmacokinetic (PK) modeling and Monte Carlo simulation (MCS) were used to describe the pharmacodynamic profile of cefepime in the both plasma and cerebrospinal fluid (CSF). Plasma and CSF cefepime data were obtained from a PK study of 7 hospitalized patients with external ventricular drains. Concentration-time profiles in plasma and CSF were modeled using a 3-compartment model with zero-order infusion and first-order elimination and transfer. Estimates of the PK parameters were identified in the Big Non Parametric Adaptive Grid with adaptive gamma (BigNPAG) program of Leary, Jelliffe, Schumitzky, and Van Guilder. MCS (10,000 subjects) was performed to estimate the probability of attaining the targets of free plasma concentration (20% protein binding) and total drug CSF concentration of 50-100% T>minimal inhibitory concentration (MIC) for MICs 0.06-8 mg/L for cefepime 2 g, iv, every 8 h (0.5-h infusion); cefepime 2 g, iv, every 12 h (0.5-h infusion); and cefepime 2 g (0.5-h infusion) once and 250 mg/h continuous infusion. After the Bayesian step, the observed-predicted regression and r(2) for plasma and CNS were as follows: plasma, observed=0.984 x predicted+2.570, r(2)=0.944; CSF, observed=0.785 x predicted+0.868, r(2)=0.821. The median penetration of cefepime as measured by AUC(CSF)/AUC(plasma) was 7.8%. In the MCS, the target attainment rates in plasma for 60-70% fT>MIC were high at each MIC value between 0.03 and 8 microg/mL for each regimen examined. In CSF, none of the regimens achieved 50-100% T>MIC for>80% of patients for MICs>0.5 mg/L.

Rapid elimination of cefaclor from the cerebrospinal fluid is mediated by a benzylpenicillin-sensitive mechanism distinct from organic anion transporter 3.

The purpose of this study was to investigate the carrier-mediated elimination of cephalosporins from the cerebrospinal fluid (CSF) via the choroid plexus. Cefaclor and cefalexin are structural analogs with similar lipophilicity, differing by only one functional group (cefaclor, -Cl; cephalexin, -CH(3)), and they are substrates of rat peptide transporter PEPT2 with similar transport activities. However, cefaclor was cleared from the CSF more rapidly than cefalexin after intracerebroventricular administration (the elimination rate constants were 0.11 and 0.050 min(-1), respectively). The elimination of cefaclor from the CSF was inhibited by benzylpenicillin, but not by glycylsarcosine (GlySar), whereas GlySar, but not benzylpenicillin, had an inhibitory effect on the elimination of cefalexin from the CSF. The uptake of cefaclor by the freshly isolated rat choroid plexus was saturable, with a K(m) value of 250 muM, and the uptake clearance corresponding to saturable components accounts for the major part of the in vivo clearance from the CSF (17 versus 26 mul/min, respectively). The uptake of cefaclor by the choroid plexus was inhibited by benzylpenicillin, but not by GlySar. However, the inhibitory effect of benzylpenicillin was weaker than expected from its own K(m) value, and furthermore, organic anion transporter (Oat)3 substrates (cimetidine or p-aminohippurate) had no effect. These results suggest that cefaclor and cefalexin are eliminated from the CSF by different transporters, and rapid elimination of cefaclor from the CSF is accounted for by a benzylpenicillin-sensitive mechanism distinct from Oat3. A slight modification of a single chemical group of cephalosporins can greatly affect the contribution of the transporters involved, and their duration in the CSF.

Determination of ceftriaxone in cerebrospinal fluid by ion-pair liquid chromatography.

An ion-pair liquid chromatographic assay was developed and validated for the determination of ceftriaxone in cerebrospinal fluid. Chromatographic separation was achieved on a C18 column (125 x 4 mm, 5 microm) with detection at 270 nm, a 1 mL/min flow rate and a 50 microL loop. The mobile phase consisted of 300 mL acetonitrile, 50 mL 0.1M phosphate buffer (pH 7.4), 3.2 g tetrabutylammonium bromide as the ion-pairing agent, and dilution with distilled deionized water to 1 L. Cephradine was used as the internal standard. The assay was linear for ceftriaxone concentrations of 0.5-50 microg/mL. The coefficients of variation for precision were <4.61%. The accuracy ranged from 96.07 to 102.42%. The detection and quantitation limits were 0.019 and 0.065 microg/mL, respectively. This method was used to quantify ceftriaxone in the cerebrospinal fluid of children with meningitis. The results showed that the method described here is useful for the determination of ceftriaxone in cerebrospinal fluid.

Determination of cefepime in plasma and cerebrospinal fluid by micellar electrokinetic chromatography with direct sample injection.

A simple micellar capillary electrokinetic chromatography (MEKC) with UV detection is described for analysis of cefepime in plasma and cerebrospinal fluid by direct injection without any sample pretreatment. The separation of cefepime from biological matrix was performed at 25 degrees C using a background electrolyte consisting of tris(hydroxymethyl)aminomethane (Tris) buffer with sodium dodecyl sulfate (SDS) as the electrolyte solution. Under optimal MEKC condition, good separation with high efficiency and short analyses time is achieved. Several parameters affecting the separation of the drug were studied, including the pH and concentrations of the Tris buffer and SDS. Using cefazolin as an internal standard, the linear ranges of the method for the determination of cefepime in plasma and cerebrospinal fluid were 1-50 and 1-20 microg/mL, respectively; the detection limits of plasma (signal-to-noise ratio = 3; injection, 5 kV, 5 s) and cerebrospinal fluid (signal-to-noise ratio = 3; injection, 0.5 psi, 3 s) were 0.2 microg/mL and 0.3 microg/mL, respectively. Application of the proposed method for determination of cefepime in plasma and cerebrospinal fluid collected after intravenous administration of 2 g cefepime in patients with meningitis was demonstrated.

Ceftriaxone acts synergistically with levofloxacin in experimental meningitis and reduces levofloxacin-induced resistance in penicillin-resistant pneumococci.

Ceftriaxone acted synergistically with levofloxacin in time-killing assays in vitro over 8 h against two penicillin-resistant pneumococcal strains (WB4 and KR4; MIC of penicillin: 4 mg/L). Synergy was confirmed with the chequerboard method, showing FIC indices of 0.25. In the experimental rabbit meningitis model, ceftriaxone (1x 125 mg/kg) was slightly less bactericidal (-0.30 Deltalog(10) cfu/mL(.)h) compared with levofloxacin (-0.45 Deltalog(10) cfu/mL(.)h) against the penicillin-resistant strain WB4. The combination therapy (levofloxacin and ceftriaxone) was significantly superior (-0.64 Deltalog(10) cfu/mL(.)h) to either monotherapy. In cycling experiments in vitro, the addition of ceftriaxone at a sub-MIC concentration (1/16 MIC) reduced levofloxacin-induced resistance in the two strains KR4 and WB4. After 12 cycles with levofloxacin monotherapy, the MIC increased 64-fold in both strains versus a 16-fold increase with the combination (levofloxacin + ceftriaxone 1/16 MIC). In both strains, levofloxacin-induced resistance was confirmed by mutations detected in the genes parC and gyrA, encoding for subunits of topoisomerase IV and gyrase, respectively. The addition of ceftriaxone suppressed mutations in parC but led to a new mutation in parE in both strains.

[Experience with maxipime in neurosurgical clinic]. / Opyt primeneniia preparata Maksipima v neirokhirurgicheskoi klinike.

Cefepime (Maxipime, Bristol-Myers Squibb), a 4th generation cephalosporin was used in the postoperative treatment of 121 patients of Anesthesiology and Intensive Care Unit of Neurosurgical Clinics. The patients were divided into groups by the risk factor of pyoseptic complications. The results were estimated by the number and nature of the complications such as increasing liquor neutrophilic cytosis, systemic inflammations and others. The findings (increasing liquor neutrophilic cytosis only in 2 patients and endobronchitis in 4 patients) and good tolerance of cefepime (Maxipime) were in favour of its use in a dose of 1 g administered intravenously dropwise during initial narcosis and in 12 hours as an efficient agent for perioperative prophylaxis in neurosurgical patients.

Adsorptive stripping voltammetric determination of cefepime at the mercury electrode in human urine and cerebrospinal fluid, and differential pulse polarographic determination in serum.

The cephalosporin cefepime has been studied by adsorptive stripping voltammetric on the hanging mercury drop electrode, followed by linear sweep voltammetry (staircase). The adsorptive stripping response was evaluated with respect to preconcentration dependence and other variables. The drug is strongly adsorbed in acid media, with maximum adsorption at pH 5.8. The detection limit found was 4.8 x 10(-10) M, with 120-s preconcentration. The relative standard deviation at the 10(-7) M level was 0.93%. This method was applied to the determination of cefepime in human urine and cerebrospinal fluid. Differential pulse polarography has been applied to determination in human serum.

Cefotaxime acts synergistically with levofloxacin in experimental meningitis due to penicillin-resistant pneumococci and prevents selection of levofloxacin-resistant mutants in vitro.

Cefotaxime, given in two doses (each 100 mg/kg of body weight), produced a good bactericidal activity (-0.47 Deltalog(10) CFU/ml. h) which was comparable to that of levofloxacin (-0.49 Deltalog(10) CFU/ml. h) against a penicillin-resistant pneumococcal strain WB4 in experimental meningitis. Cefotaxime combined with levofloxacin acted synergistically (-1.04 Deltalog(10) CFU/ml. h). Synergy between cefotaxime and levofloxacin was also demonstrated in vitro in time killing assays and with the checkerboard method for two penicillin-resistant strains (WB4 and KR4). Using in vitro cycling experiments, the addition of cefotaxime in sub-MIC concentrations (one-eighth of the MIC) drastically reduced levofloxacin-induced resistance in the same two strains (64-fold increase of the MIC of levofloxacin after 12 cycles versus 2-fold increase of the MIC of levofloxacin combined with cefotaxime). Mutations detected in the genes encoding topoisomerase IV (parC and parE) and gyrase (gyrA and gyrB) confirmed the levofloxacin-induced resistance in both strains. Addition of cefotaxime in low doses was able to suppress levofloxacin-induced resistance.

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.

Disposition of cefepime in the central nervous system of patients with external ventricular drains.

STUDY OBJECTIVE: To assess central nervous system (CNS) penetration of cefepime in adults with external ventricular drains and to compare the achieved cerebrospinal fluid (CSF) concentrations with the usual minimum inhibitory concentrations (MICs) of common pathogens. DESIGN: Open-label, prospective study. SETTING: University-affiliated medical center. PATIENTS: Seven patients with external ventricular drains and normal renal function (documented creatinine clearance > 60 ml/min) who received cefepime 2 g intravenously every 12 hours for treatment of nosocomial pneumonia. INTERVENTION: Serial serum and CSF samples were obtained concurrently after the fourth dose during one dosing interval. MEASUREMENTS AND MAIN RESULTS: The concentration-time profiles in serum and CSF were comodeled by using a two-compartment model with zero-order infusion to the central compartment. The CSF concentration-time profiles of the individual patients were compared with published MIC90 of common pathogens isolated in nosocomial meningitis. Our model reasonably characterized the disposition of cefepime in serum and CSF. Penetration into the CNS was 4-34% based on area under the curve and was 5-58% based on minimum concentration. CONCLUSION: Penetration of cefepime into the CNS was variable among the patients (4-34%) but appeared similar to that reported for other cephalosporins given to treat meningitis. The concentrations attained by most patients in this study were above the MIC90 of many common nosocomial organisms.

Determination of cefotaxime and desacetylcefotaxime in cerebrospinal fluid by solid-phase extraction and high-performance liquid chromatography.

A high-performance liquid chromatographic procedure has been developed for the measurement of cefotaxime and desacetylcefotaxime in cerebrospinal fluid. Both compounds were isolated from cerebrospinal fluid samples using solid-phase extraction (SPE). LiChrolut RP-18 (200 mg; 3 ml) columns and a mixture of methanol-phosphate buffer pH 7 (1:1) were applied to elute cefotaxime and its desacetyl metabolite. The separation was performed on a LiChrospher 100RP-18 (5 microm; 250 x 4 mm I.D.) column. The mobile phase consisted of 0.01 M acetate buffer pH 4.8-methanol (85:15), flow-rate was 1.5 ml/min. Cefotaxime and desacetylcefotaxime were detected at a wavelength of 254 nm by UV-Vis detector. The range of concentrations for method calibration and for analytical studies was 1.56-100 microg/ml. The quantitation limit in cerebrospinal fluid was 0.39 microg/ml for cefotaxime and 0.78 microg/ml for desacetylcefotaxime. The extraction recovery from cerebrospinal fluid spiked with cefotaxime and desacetylcefotaxime was 90.4-100.1% and 97.4-102.9%, respectively. The RSDs were below 10.7% for cefotaxime and 6.8% for desacetylcefotaxime. The developed SPE-HPLC method was applied for cefotaxime and desacetylcefotaxime determination in cerebrospinal fluid of children with hydrocephalus after intraventricular administration.

Cefepime-induced neurotoxicity: an underestimated complication of antibiotherapy in patients with acute renal failure.

OBJECTIVES: To describe five new cases of life-threatening cefepime-induced neurotoxicity observed in a 2-year period. SETTING: A university intensive care unit. PATIENTS: Five patients recently treated with cefepime, admitted for seizures and coma. All suffered from acute renal failure, induced by sepsis and combined aminoside therapy, or by cefepime itself in one case. INTERVENTIONS: All patients underwent hemodialysis, which led to complete neurological improvement in four of them. One patient remained comatose and subsequently died. MEASUREMENTS: Blood and CSF cefepime levels were measured by high performance liquid chromatography before and after hemodialysis. CONCLUSION: The frequency of cefepime-induced neurotoxicity is probably underestimated. Monitoring of renal function and close neurological survey in treated patients should allow an early diagnosis of this complication. Urgent hemodialysis seems the best therapeutic method to obtain a rapid neurological improvement.

Cefepime is efficacious against penicillin- and quinolone-resistant pneumococci in experimental meningitis.

In experimental rabbit meningitis, cefepime given at a dose of 100 mg/kg was associated with concentrations in the cerebrospinal fluid of between 5.3 and 10 mg/L and a bactericidal activity of -0.61 +/- 0.24 Delta log(10) cfu/mL x h, similar to the standard regimen of ceftriaxone combined with vancomycin (-0.58 +/- 0.14 Delta log(10) cfu/mL x h) in the treatment of meningitis due to a penicillin- and quinolone-resistant pneumococcal mutant strain (MIC 4 mg/L). Compared with the penicillin-resistant parental strain, the penicillin- and quinolone-resistant mutant was killed more slowly by cefepime and ceftriaxone in time-killing assays in vitro over 8 h.