Benzylpenicillin Serum Concentrations in Neonates With Group B Streptococci Sepsis or Meningitis: A Descriptive Cohort Study.

BACKGROUND: Adequate dosage recommendations are imperative for successful treatment of invasive infections. We evaluated the occurrence of sub- and supratherapeutic serum and cerebrospinal fluid (CSF) concentrations of benzylpenicillin (BPEN) in neonates treated for a severe group B streptococci (GBS) sepsis and/or meningitis as well as discrepancies in dosing recommendations provided by pediatric reference sources. METHODS: Retrospective analysis of (pre)term infants treated with BPEN undergoing therapeutic drug monitoring (TDM) between May 2015 and May 2019. Outcomes included numbers of sub- and supratherapeutic concentrations, and dose adjustments, clinical evolution, and dosing recommendations from six pediatric reference sources. RESULTS: A total of 21 TDM samples from 8 neonates were evaluated. Among serum concentrations, 9/21 (43%) were below and 8/21 (38%) above the pre-specified therapeutic target range of 10-20 mg/L. Only 1 patient had BPEN determined in CSF whose concentration was below the lower limit of quantification. TDM identified a need for dose modification in 10/21 (48%) instances. Three of eight patients exhibited complete resolution of clinical, laboratory and radiologic signs of infection. Substantial variation in dosing recommendations (50,000-400,000 IE/kg/d) was present between reference sources. CONCLUSIONS: Our data reveal that under current dosage recommendations, the predefined target serum or CSF concentrations of BPEN are not achieved in all children. In case of clinical failure, serum and/or CSF BPEN concentrations should be determined. Given the wide variation in concentrations and subsequent dose requirements, further exploration of the clinical and pharmacologic characteristics of BPEN in (pre)term neonates is essential to optimize therapeutic efficacy.

[Concentration of benzylpenicillin sodium salt in the cerebrospinal fluid of patients with late neurosyphilis as an indicator of efficacy of specific therapy].

A permeability of crystallized benzylpenicillin sodium salt (CBSS) through a blood-brain barrier (BBB) in patients with late neurosyphilis and experimental animals has been studied. Forty-six patients with vascular and late meningovascular neurosyphilis have been examined. A group of experimental animals included 50 rabbits. The injection of CBSS to patients and animals was followed by the measurement of antibiotic's concentration in the cerebrospinal fluid (CSF) using high performance liquid chromatography. The level of CSF penicillin concentration was estimated as an indicator of efficacy of the treatment. The treponemocide concentration of antibiotics in the CSF was reached only in patients with meningovascular neurosyphilis (0.029+/-0.003 mcg/ml; p<0.05). There was an increase of BBB permeability for CBSS and concentration of the latter in CSF from 0.0012+/-0.001 mcg/ml to 0.02+/-0.0012 mcg/ml (p<0.05) after the injection of mannitol in rabbits.

Mechanism of the reduced elimination clearance of benzylpenicillin from cerebrospinal fluid in rats with intracisternal administration of lipopolysaccharide.

The mechanism responsible for the reduced clearance of benzylpenicillin (BPC) from the cerebrospinal fluid (CSF) was investigated in rats that received an intracisternal administration of lipopolysaccharide (LPS). BPC was intraventricularly injected and its elimination from the CSF studied. During the inflammation created by the LPS administration to the cisterna magna, the clearance of BPC and taurine from the CSF was significantly reduced but reverted to the control level when N-nitro-L-arginine, a nitric oxide (NO) synthase inhibitor, was intracisternally administered. The in vitro uptake of BPC and taurine was significantly reduced in the choroid plexus (CP, the blood-CSF barrier) of rats with experimental inflammation and in control CP that had been pretreated with sodium nitroprusside (SNP, an NO donor). Interestingly, the clearance and CP uptake of formycin B, a substrate for a nucleoside transporter, were not affected by the experimental inflammation or by pretreatement with SNP. These observations suggest that the BPC transporter, and probably other transport systems as well, is functionally sensitive to NO in the blood-CSF barrier. Therefore, functional impairment of BPC transport in the CP by NO may be partly responsible for the increase in BPC concentration in the CSF during inflammation such as that caused by meningitis.

A comparison study of two therapeutic protocols for neurosyphilis.

In Morocco, neurosyphilis is a serious public health problem. In the neurology service at the specialist hospital in Rabat, two drug treatments were used. Treatment A consisted of infusion over a period of 4 h of 20 MUI of penicillin G per day for 3 weeks. Treatment B consisted of infusion over a period of 6 h of 30 MUI of penicillin G per day for 10 days. Each treatment was tested on a group of eight neurosyphilitic patients as first-line treatment. On the first day of treatment, both blood and CSF pharmacokinetics were sampled for each patient. Blood and CSF were taken within 24 h. Penicillin G concentrations were determined by a microbiological method. The results obtained showed that perfusions of either 20 MUI or 30 MUI of penicillin allowed the achievement of high serum concentrations. These increased progressively until reaching their maximum at T4 h for treatment A (from 92.33 to 106.38 micrograms/ml). For treatment B, maximal concentration is obtained at T6 h (from 108 to 141.52 micrograms/ml). Penicillin concentrations decreased immediately after stopping the perfusion. At CSF levels, penicillin G concentrations were identical to serum concentrations. However, one difference was observed: a one-hour difference between the serum and CSF peaks. The CSF peak was achieved at T5 h for treatment A (0.063 to 2.25 micrograms/ml) and at T7 h for treatment B (0.92 to 2.94 micrograms/ml). The concentrations obtained were largely superior to the CMI of Treponema pallidum for both treatment A and treatment B, at 47 times and 82 times higher respectively. The recovery time of the patients was 14 h for treatment A and 24 h for B treatment. These results have shown that therapeutic method B was more efficient than A. Moreover, the evolution of penicillin G's diffusion in the CSF during treatment, of cell counts of protein level, of the VDRL test and of the gamma-globulin rate was studied.

[A patient with Streptococcus intermedius brain abscess treated with high dose penicillin G--susceptibility of the isolate to penicillin G and the concentration of penicillin G in cerebrospinal fluid].

We report here a 2-year-old boy with a Streptococcus intermedius brain abscess and bilateral ventriculitis successfully treated with a high dose penicillin G (200,000 U/kg/dose, 6 times a day, 1 hour continuous infusion). Although hydrocephalus residuced, the high dose penicillin G therapy cured his brain abscess and bilateral ventriculitis. The minimal inhibitory concentration of penicillin G to the isolate was 0.008 microgram/ml. The penicillin G concentration in the cerebrospinal fluid after 2 hours from the infusion was about 5 micrograms/ml. S. intermedius must be considered as one of the causative agents for brain abscess. High dose penicillin G therapy is one choice of treatment for brain abscess due to penicillin-susceptible streptococci.

Concentrations of doxycycline and penicillin G in sera and cerebrospinal fluid of patients treated for neuroborreliosis.

Concentrations of doxycycline and penicillin G in serum and cerebrospinal fluid (CSF) were analyzed in 46 patients during treatment for neuroborreliosis. Twenty patients were treated intravenously with penicillin G at 3 g every 6 h (q6h), and 26 patients were treated orally with doxycycline at 200 mg q24h. All samples were collected on day 13 of treatment. The median concentrations of penicillin G in serum were 0.5, 37, and 5.6 micrograms/ml before and 1 and 3 h after drug administration, and that in CSF was 0.5 (range, 0.3 to 1.6) microgram/ml after 2 to 3 h. The median concentrations of doxycycline in serum were 2.1, 6.1, and 4.7 micrograms/ml before and 2 and 6 h after drug administration, and that in CSF was 0.6 (range, 0.4 to 2.5) microgram/ml after 4 h. All patients had concentrations of penicillin G or doxycycline in CSF above the lowest reported MICs of penicillin G (0.003 microgram/ml) and doxycycline (0.12 microgram/ml) for Borrelia burgdorferi. However, no patients had a drug concentration in CSF above the highest reported MIC of penicillin G (8 micrograms/ml), and only one had a drug concentration in CSF above the highest reported MIC of doxycycline (2 micrograms/ml), despite good clinical response to treatment. No treatment failure or relapse was observed during a 1-year follow-up, although one patient treated with penicillin G and one treated with doxycycline were retreated because of residual pain. The chosen dosages of penicillin G and doxycycline seem to give sufficient concentrations in serum and CSF for the treatment of neuroborreliosis.

beta-lactam antibiotics in the treatment of neuroborreliosis in children: preliminary results.

In vitro beta-lactam antibiotics like ceftriaxone and penicillin G sodium have been shown to be active against Borrelia burgdorferi. Results of quantitative determinations of both antibiotic substances in the CSF for children are limited. Seventy-five children (median age 96 months, range 10 to 176 months) with probable or definite neuroborreliosis were treated with ceftriaxone (1 x 50-90 mg/kg/day) or penicillin G sodium (4 x 80,000-120,000 IU/kg/day) intravenously. On day 10 of therapy levels of penicillin G sodium (1,1.5,2,3,4, 5, or 6 h after i.v. administration), and ceftriaxone (1,2,4,6,12 or 24 h after i.v. administration) in serum and CSF were measured with a micro agar diffusion bioassay. Results demonstrate that after 5 h penicillin G sodium in CSF was above the minimal inhibitory concentration (MIC) but after 6 h penicillin G sodium levels were below the determination limit in 60% of the cases. All ceftriaxone results in CSF-even after 24 h-were above MIC. Penicillin G sodium serum values ranged from 46.6 to 0.1 mg/L (1 to 6 h post dose) and ceftriaxone serum values from 261 to 5 mg/l (1 to 24 h post dose). The role of penicillin G sodium and ceftriaxone and administration intervals of both antibiotics in the therapy of neuroborreliosis in children are discussed.

Concentrations of procaine and aqueous penicillin in the cerebrospinal fluid of infants treated for congenital syphilis.

Penicillin concentrations in cerebrospinal fluid (CSF) were measured at various hours and days of treatment in 163 infants undergoing therapy for congenital syphilis. The CSF levels were compared for three treatment regimens. Aqueous penicillin G (A-PEN), 100,000 U/kg per day, was used in 23 infant, and a dosage of 200,000 U/kg per day was used in 40 patients; procaine penicillin G (P-PEN), 50,000 U/kg per day, was used in 100 children. Mean CSF penicillin levels were 0.416, 0.493, and 0.077 microgram/ml, respectively, in the three treatment groups. The mean CSF penicillin concentration among the 63 infants treated with either of the A-PEN regimens (0.465 microgram/ml) was significantly greater than the mean concentration (0.077 microgram/ml) among those treated with P-PEN (p < 0.001). Among those who received A-PEN, the difference in dosage was not associated with a significant difference in mean CSF penicillin concentration (p = 0.68). All the specimens obtained from patients who received A-PEN, but only 82% of those from patients who received P-PEN, had treponemicidal concentrations (> or = 0.018 microgram/ml). However, 33.3% (9/27) of specimens from infants who received P-PEN, tested between 18 and 24 hours after a dose, had CSF penicillin concentrations < 0.018 microgram/ml. These data suggest that administration of A-PEN may be the preferred therapy if CSF levels > 0.018 microgram/ml are desired, especially for infants with severe disease or congenital neurosyphilis.

Effect of active transport on distribution and concentration gradients of [3H]benzylpenicillin in the cerebrospinal fluid.

After application of [3H]benzylpenicillin ([3H]BP) in lateral brain ventricle in dogs, the distribution of [3H]BP to contralateral ventricle and cisterna magna was much higher when its active transport from cerebrospinal fluid (CSF) was blocked by probenecid than under control conditions. Analysis of [3H]BP concentrations in both lateral ventricles and cisterna magna over time indicates that active transport restricts distribution of substances along CSF spaces and contributes to the maintenance of their concentration gradients between CSF compartments. This suggests that biochemical changes in a part of the brain and the adjacent CSF compartment may not be reflected into remote compartments of CSF such as lumbar CSF if substances in question are removed from CSF by active transport.

Kinetics of active efflux via choroid plexus of beta-lactam antibiotics from the CSF into the circulation.

To examine the role of the choroid plexus in eliminating organic anions from the cerebrospinal fluid (CSF), a kinetic study was performed both in in vivo and in vitro experiments using [3H]benzylpenicillin (PCG) as a model compound. In vivo, after intracerebroventricular administration, [3H]PCG was eliminated from the CSF much more rapidly than [14C]mannitol. Analysis of the elimination clearance from the CSF revealed that 12 and 24% of the disappearance of [3H]PCG can be accounted for by convective loss at a rate equivalent to CSF turnover, and by diffusional loss across the ependymal surface into the brain extracellular space, respectively. Approximately two-thirds of [3H]PCG elimination was due to a saturable process [Michaelis constant (Km) = 43.0 +/- 17.8 microM, maximum velocity (Vmax) = 619 +/- 286 pmol.min-1 x rat-1]. These kinetic parameters obtained in vivo were comparable to those determined previously in vitro, i.e., [3H]PCG was accumulated by the isolated rat choroid plexus via an active transport mechanism (Km = 58 microM, Vmax = 504 pmol.min-1 x rat-1; H. Suzuki, Y. Sawada, Y. Sugiyama, T. Iga, and H. Hanano, J. Pharmacol. Exp. Ther. 242: 660-665, 1987). Furthermore, other organic anions (probenecid, ampicillin, cefodizime, cefotaxime, and ceftriaxone) reduced the transport of [3H]PCG in a dose-dependent manner both in vivo and in vitro. A good correlation was observed between the log inhibition constant (Ki) values obtained for these ligands in vivo and in vitro (r = 0.94, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

[Effect of electrophoresis of the head region on benzylpenicillin penetration across the blood-brain barrier]. / Vliianie élektroforeza oblasti golovy na perenos benzilpenitsillina cherez gematoéntsefalicheskii bar'er.

A procedure for administration of sodium benzylpenicillin (SB) to the brain was developed and tested on 22 rabbits. SB was administered drop-like intravenously in a dose of 200,000 units/kg body weight in combination with electrophoresis of the head area. It was shown spectrophotometrically that a single administration of SB increased its concentration in the liquor and brain tissues by 366.7 and 500 per cent respectively as compared to the control values. Practically no shifts in the EEG and ECG were observed which was indicative of safety of SB administration by that route. The procedure for intraorgan administration of SB in combination with electrophoresis may be recommended for clinical use.

Possibilities of perfecting antimicrobial therapy. Dynamics of penicillin G concentrations in the cerebro-spinal fluid in purulent meningitis.

In 43 adult patients with purulent meningitis receiving daily doses of 1-4,000,000 IU penicillin G i.v. in bolus, determinations were made, 1-6 hrs after administration, in 153 samples of cerebrospinal fluid (CSF), to ascertain the concentrations of penicillin that have reached the CSF. After 1 hour maximum levels of penicillin were noted, exceeding by far the meningococcus and pneumococcus minimum inhibitory concentration (MIC). Generally, high penicillin concentrations persisted in the CSF, in most of the cases at least for the following 6 hours. The advantages of using penicillin G i.v. in doses of 1-3,000,000 IU in bolus at 12 hour intervals are discussed. All the 36 patients with meningococcal meningitis and 3 of the 5 with pneumococcal meningitis recovered with this therapeutic scheme, under daily control of the CSF.

Transport of imipenem, a novel carbapenem antibiotic, in the rat central nervous system.

The transport of imipenem, a novel carbapenem antibiotic, in the rat central nervous system (CNS) was studied using in vivo, in situ and in vitro experimental techniques. After i.v. bolus administration, the imipenem concentration in the cerebrospinal fluid (CSF) rose to a peak within 30 min and declined with time. The CSF/serum unbound concentration ratio of imipenem was 0.22 at 2 hr after i.v. administration, substantially higher than that reported for benzylpenicillin. By using an in situ brain perfusion technique, we found that imipenem was transported through the blood-brain barrier principally via passive diffusion with a permeability-surface area product comparable to that of mannitol. In vitro, imipenem was accumulated by the isolated choroid plexus via an active organic anion transport system, although much less rapidly than benzylpenicillin. In vivo, after i.c.v. administration, imipenem was cleared from the CNS in a manner comparable to that of mannitol with only a small probenecid-sensitive process. Imipenem thus has minimal affinity for the organic anion transport system in the choroid plexus, resulting in the slow elimination of this drug from the CNS. These results suggest that the difference between imipenem and benzylpenicillin in the ratio of CSF to unbound serum drug concentration is determined principally by the efflux process in the choroid plexus rather than the influx process through the blood-brain barrier.

Penicillin concentrations in cerebrospinal fluid (CSF) during repository treatment regimen for syphilis.

Penicillin concentrations in cerebrospinal fluid (CSF) were measured in 40 asymptomatic patients with syphilis, 10 of whom had neurosyphilis. The patients were treated with 2.4 MIU procaine penicillin a day intramuscularly in combination with 500 mg probenecid every six hours orally. This intramuscular treatment regimen did not consistently yield treponemicidal penicillin concentrations in the CSF (subtreponemicidal CSF concentrations were found in 17 patients, four of whom had neurosyphilis). These data provide additional evidence that the cure of asymptomatic neurosyphilis is not guaranteed by intramuscular penicillin treatment.

Neurotoxicity of benzylpenicillin: correlation to concentrations in serum, cerebrospinal fluid and brain tissue fluid in rabbits.

The neurotoxic potential of benzylpenicillin, administered as continuous intravenous infusion, was studied in rabbits. Thirteen animals were killed at the onset of epileptogenic EEG activity (seven) or convulsions (six). Benzylpenicillin levels were determined in serum, cerebrospinal fluid (CSF) and brain tissue fluid. High doses of benzylpenicillin were required to induce neurotoxicity; epileptogenic (EEG) changes were seen at serum levels of 510-960 mg/l and convulsions at 920-1902 mg/l. Neurotoxicity correlated well with levels of benzylpenicillin in brain tissue fluid, calculated as 10 x the concentration in whole brain tissue. The correlation of neurotoxic reactions to levels of benzylpenicillin in CSF was poor and the CSF levels were consistently lower than those in brain tissue fluid. The technique used was found to be a satisfactory, though laborious, way to study neurotoxicity of drugs.

Neurotoxicity of beta-lactam antibiotics. Experimental kinetic and neurophysiological studies.

The neurotoxic potential of intravenous administered benzylpenicillin (BPC) was studied in rabbits with intact blood-CNS barriers and rabbits with experimental E. coli meningitis. At onset of epileptogenic EEG activity or seizures, serum, CSF and brain tissue were collected for assay of BPC. Based on the fact that, in tissues, BPC seems to remain extracellularly, brain concentrations of BPC were expressed as brain tissue fluid (BTF) levels, calculated as 10x the concentration in whole brain tissue. Neurotoxicity could be precipitated in all rabbits. In normal rabbits BTF levels of BPC were considerably higher than those in CSF indicating a better penetration across the blood-brain barrier (BBB). BPC penetrated better to CSF and BTF in meningitic rabbits than in normal controls, suggesting some degree of damage of the BBB concomitant with meningeal inflammation. E. coli meningitis did not increase the neurotoxicity of BPC. In control rabbits the intracisternal injection of saline resulted in some degree of pleocytosis. Unmanipulated animals are therefore preferable as controls. Epileptogenic EEG-changes was the most precise of the two variables used for demonstration of neurotoxicity. EEG-changes were therefore used as neurotoxicity criterion in the following rabbit experiments. To evaluate the effect of uraemia alone and uraemia plus meningitis on the neurotoxity of BPC in rabbits, cephaloridine was used to induce uraemia. Meningitis was induced by intracisternal inoculation of a cephalosporin resistant strain of E. cloacae. Untreated rabbits were used as controls. Uraemia resulted in increased BTF penetration of BPC, possibly explained by permeability changes in the BBB and/or decreased binding of BPC to albumin. Uraemia did not result in increased penetration of BPC into the CSF of non-meningitic rabbits. Uraemic non-meningitic rabbits had the highest BTF levels of BPC at the criterion, indicating that cephaloridine-induced renal failure increased the epileptogenic threshold in these rabbits. The combination of uraemia and meningitis increased the neurotoxicity of BPC since the criterion was reached at considerably lower BTF levels of BPC. Meningitis, either alone or together with uraemia, did not increase the neurotoxicity in comparison to control rabbits. Higher BTF levels of BPC were found in meningitic rabbits than in controls with intact blood-CNS barriers at onset of EEG-changes. In all groups of rabbits there was a pronounced variability of BPC levels in the CSF while the intra-group variations in BTF levels were much smaller. Thus, BTF and not CSF levels were decisive for the neurotoxicity of BPC.(ABSTRACT TRUNCATED AT 400 WORDS)

Treatment of neurosyphilis. A comparison of penicillin regimens.

Recommendations for treatment of neurosyphilis and reasons for renewed debate are briefly reviewed and discussed. Experience with 11 patients with neurosyphilis who were treated with different preparations of penicillin by different routes of administration is recorded. The concentration of penicillin was measured in the serum and cerebrospinal fluid in each case. Very high levels were attained by the intravenous administration of penicillin G, but in the follow-up period of 1 year this has not been shown to confer any advantage. The administration of procaine penicillin 1.2 million U intramuscularly daily for 20 days is as effective as a dosage schedule which requires admission to hospital for intravenous administration.

Efficacy of teicoplanin in experimental group B streptococcal bacteremia and meningitis.

We evaluated the activity of teicoplanin against a type-III group B streptococcal strain in vitro and in vivo and compared the results with those of penicillin G. In vitro, the minimal inhibitory and minimal bactericidal concentrations of teicoplanin were 2- to 4-fold greater than those of penicillin G. In vivo studies were carried out with an experimental bacteremia and meningitis model in newborn rats. Eighty-one infected animals were randomized to receive teicoplanin 5, 10 or 20 mg/kg, twice daily, or penicillin G 50 or 200 mg/kg, twice daily, or saline (0.05 ml), twice daily. The mean serum levels of teicoplanin were maintained above 100 X the minimal bactericidal concentration for 7-8 h even with a dose of 5 mg/kg. The mean penetration of teicoplanin into the cerebrospinal fluid was estimated as 2.4-8.2% of those of concomitant levels in serum. The overall efficacy of teicoplanin was similar to that of penicillin G as judged by mortality rates. However, two bacteremic animals which were free of meningitis at the beginning of therapy developed this complication during 4 days of teicoplanin therapy, in contrast with none in the penicillin group. Further studies are needed to understand the reason(s) for these failures with teicoplanin therapy.