Ampicillin Pharmacokinetics During First Week of Life in Preterm and Term Neonates.

BACKGROUND AND AIMS: Ampicillin is 1 of the most commonly used antibiotics for treatment of early onset sepsis, but its pharmacokinetics (PK) is poorly characterized. We aimed to define the dose of ampicillin for late preterm and term neonates by evaluating its PK in serum, cerebrospinal (CSF), and epithelial lining fluid. METHODS: A prospective study included neonates receiving ampicillin for suspected or proven early onset sepsis and pneumonia. PK samples were collected at steady state, at predose and 5 minutes, 1 hour, 3 hours, 8 hours, and 12 hours after ampicillin 3-minute infusion. Ampicillin concentrations were measured by ultra-high-performance liquid chromatography. Noncompartmental anaysis (NCA) and population pharmacokinetic (pop-PK) modeling were performed and probability of therapeutic target attainment was simulated. RESULTS: In 14 neonates (GA of 32-42 wks; mean BW 2873 g), PK parameters (mean ± SD) in NCA were the following: half-life 7.21 ± 7.97 hours; volume of distribution (Vd) 1.07 ± 0.51 L; clearance (CL) 0.20 ± 0.13 L/h; 24-hour area under the concentration-time curve 348.92 ± 114.86 mg*h/L. In pop-PK analysis, a 2-compartmental model described the data most adequately with the final parameter estimates of CL 15.15 (CV 40.47%) L/h/70kg; central Vd 24.87 (CV 37.91%) L/70kg; intercompartmental CL 0.39 (CV 868.56) L/h and peripheral Vd 1.039 (CV 69.32%) L. Peutic target attainment simulations demonstrated that a dosage of 50 mg/kg q 12 hours attained 100% fT > MIC 0.25 mg/L, group B streptococcal breakpoint. CONCLUSIONS: We recommend ampicillin dosage 50 mg/kg q 12 hours for neonates with gestational age ≥32 weeks during the first week of life.

Comparison of the in vitro activity of ampicillin and moxifloxacin against Listeria monocytogenes at achievable concentrations in the central nervous system.

PURPOSE: The aim of this study was to compare the in vitro activity of ampicillin and moxifloxacin against six isolates selected from 154 invasive clinical isolates of Listeria monocytogenes and evaluate their intra- and extracellular activities with achievable central nervous system concentrations obtained using Monte Carlo simulations with conventional and unconventional dosages. METHODOLOGY: The MICs and minimal bactericidal concentrations (MBCs) of ampicillin and moxifloxacin were determined by using the broth microdilution method. The intra- and extracellular activities were compared using time-kill curves and inhibition of intracellular growth assays. RESULTS: The MICs50/90 of ampicillin were 0.125/0.5 mg l-1 and the MBC50/90 was ≥16 mg l-1, while the moxifloxacin MICs50/90 were 0.25/0.5 mg l-1 and the MBC50/90 was 0.5 mg l-1. Ampicillin did not show any extracellular bactericidal activity at 24 h, although bactericidal activity was detected at 48 h. For moxifloxacin, the bactericidal effect was evident after 6 h of incubation. Both antibiotics achieved significant reductions in intracellular inoculum after 1-24 h of incubation; however, moxifloxacin becomes bactericidal more rapidly, producing a much greater reduction in the inoculum in the first hour than ampicillin. There were no differences among the MIC and MBC values of moxifloxacin and ampicillin among the strains belonging to different serotypes and/or epidemic clones. This fact was also found in the intra- and extracellular studies. CONCLUSION: The results of this study demonstrated the faster bactericidal activity of moxifloxacin at achievable central nervous system concentrations against intra- and extracellular forms of L. monocytogenes in comparison with ampicillin.

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.

Trovafloxacin in treatment of rabbits with experimental meningitis caused by high-level penicillin-resistant Streptococcus pneumoniae.

The fluoroquinolone trovafloxacin was bactericidal (0.47 +/- 0.23 delta log10 CFU/ml x h after 10 mg/kg of body weight and 0.78 +/- 0.15 delta log10 CFU/ml x h after 30 mg/kg) in the treatment of experimental meningitis caused by a highly penicillin-resistant (MIC and minimum bactericidal concentration = 4 and 4 microg/ml) strain of Streptococcus pneumoniae. Combinations with ampicillin and rifampin were indifferent compared to single drugs.

Use of ampicillin-sulbactam for treatment of experimental meningitis caused by a beta-lactamase-producing strain of Escherichia coli K-1.

We evaluated the pharmacokinetics and therapeutic efficacy of ampicillin combined with sulbactam in a rabbit model of meningitis due to a beta-lactamase-producing strain of Escherichia coli K-1. Ceftriaxone was used as a comparison drug. The MIC and MBC were 32 and greater than 64 micrograms/ml (ampicillin), greater than 256 and greater than 256 micrograms/ml (sulbactam), 2.0 and 4.0 micrograms/ml (ampicillin-sulbactam [2:1 ratio, ampicillin concentration]) and 0.125 and 0.25 micrograms/ml (ceftriaxone). All antibiotics were given by intravenous bolus injection in a number of dosing regimens. Ampicillin and sulbactam achieved high concentrations in cerebrospinal fluid (CSF) with higher dose regimens, but only moderate bactericidal activity compared with that of ceftriaxone was obtained. CSF bacterial titers were reduced by 0.6 +/- 0.3 log10 CFU/ml/h with the highest ampicillin-sulbactam dose used (500 and 500 mg/kg of body weight, two doses). This was similar to the bactericidal activity achieved by low-dose ceftriaxone (10 mg/kg), while a higher ceftriaxone dose (100 mg/kg) produced a significant increase in bactericidal activity (1.1 +/- 0.4 log10 CFU/ml/h). It appears that ampicillin-sulbactam, despite favorable CSF pharmacokinetics in animals with meningitis, may be of limited value in the treatment of difficult-to-treat beta-lactamase-producing bacteria, against which the combination shows only moderate in vitro activity.

Antibiotic concentrations in liquor compared to the minimal inhibitory concentrations of isolates in paediatric bacterial meningitis. The Finnish Study Group.

The susceptibilities of 171 bacteria which caused meningitis in 200 children were tested for their susceptibility as minimal inhibitory concentrations (MICs) for the antibiotics used in therapy. These antibiotics were chloramphenicol, ampicillin, cefotaxime and ceftriaxone. The MICs were compared to the minimal concentrations of the drugs seen in the cerebrospinal fluid (CSF) samples. The minimal bacteriostatic capacity (lowest concentration in CSF/MIC) of both cephalosporins was superior to that of chloramphenicol and ampicillin. The correlation of the finding with the speed of liquor sterilization in the treatment groups is discussed.

Delayed cerebrospinal fluid sterilization in infants with Hemophilus influenzae type b meningitis.

Cerebrospinal fluid (CSF) sterilization after greater than 24 h of intravenous antibiotic therapy (delayed CSF sterilization) was noted in two infants treated with ceftizoxime and ceftazidime for bacterial meningitis. A case-control study was conducted of children between 6 w and 6 y of age treated between 1975 and 1985 at one institution for bacterial meningitis to determine risk factors for delayed CSF sterilization. Hemophilus influenzae type b was isolated from all children (n = 5) with delayed CSF sterilization, compared with only 78% of all children in the study (n = 83). In children with H. influenzae type b disease, children less than 6 mo of age were at higher risk than older children for delayed CSF sterilization (odds ratio = 7.5, 95% confidence limits = 1.4, 40.0). Factors not associated with delayed CSF sterilization included time of follow-up lumbar puncture, CSF total or differential white blood cell count, and CSF protein and glucose concentrations. Despite the in vitro antimicrobial susceptibility of H. influenzae type b to ceftizoxime and ceftazidime, delayed CSF sterilization may occur in infants receiving these antibiotics for bacterial meningitis.

Concentrations of ceftazidime, tobramycin and ampicillin in the cerebrospinal fluid of newborn infants.

Thirty-five neonates with suspected septicaemia were randomized to treatment with tobramycin or ceftazidime, both in combination with ampicillin. Concentrations of antibiotics in the CSF were measured 1 h after the third, fourth or fifth injection. In 13 of 17 neonates tobramycin CSF concentrations were below 0.5 mg/l. Ceftazidime CSF concentrations ranged from 2.5 to 17 mg/l, which should be sufficient for treatment of infections with group B streptococci and most aerobic gram-negative bacilli but not all strains of Staphylococcus aureus. Ampicillin CSF concentrations ranged from 1 to 80 mg/l, which should be sufficient for treatment of meningitis caused by enterococci and Listeria monocytogenes, the most important neonatal pathogens not covered by ceftazidime.

[Experimental study on transferability to cerebrospinal fluid of cefodizime in combination with ampicillin].

A study was done on cefodizime (THR-221, CDZM) in combination with ampicillin (ABPC) for its transferability to cerebrospinal fluid (CSF) of rabbits with experimental meningitis caused by Staphylococcus aureus. Blood and CSF were collected at 15, 30, 45, 60, 90, 120 and 180 minutes after intravenous administration of CDZM at 100 mg/kg to 6 rabbits, ABPC at 100 mg/kg to 4 rabbits and simultaneous administration of both drugs at 100 mg/kg each to 5 rabbits. Drug concentrations were assayed with an high performance liquid chromatography method, and pharmacokinetic parameters were calculated. The comparison revealed no significant difference in concentrations achieved among different groups. Therefore, the mutual transferability of these drugs to CSF was not considered to interact adversely due to the simultaneous administration of both drugs. Accordingly, CDZM may be a candidate of chemotherapeutics in the therapy of purulent meningitis, and it is worthy of further investigations.

Influence of antibiotic dose, dosing interval, and duration of therapy on outcome in experimental pneumococcal meningitis in rabbits.

We examined the influence of several pharmacokinetic parameters on cure rates in rabbits with experimental pneumococcal meningitis. When the duration of treatment was kept constant, cure rates improved as the individual dose of ampicillin was increased. On the other hand, when four doses of ampicillin at 60 mg/kg of body weight, producing peak concentrations in cerebrospinal fluid (CSF) of approximately 40 times the MBC, were administered at intervals of 24 instead of 4 h and the duration of therapy was thus prolonged from 12 to 72 h, cure rates also increased (85 versus 25%; P less than 0.01). These high cure rates were achieved even though bacterial titers in CSF 24 h after the first dose had reached levels similar to those present at the beginning of therapy. Cure in these animals was explained by the fact that the second ampicillin dose reduced bacterial titers in CSF significantly more than did the first dose (5.2 versus 2.5 log10 CFU/ml; P less than 0.02). The clinical relevance of these observations remains to be determined.

[Cerebrospinal fluid levels of sulbactam/ampicillin in rabbits with staphylococcal meningitis].

Concentrations of sulbactam (SBT) and ampicillin (ABPC) in the blood and cerebrospinal fluid (CSF) following an intravenous administration of SBT/ABPC at a dose of 150 mg/kg (SBT/ABPC = 1:2) were determined in 12 rabbits with staphylococcal meningitis. Drug concentrations were measured 9 times, 6 times each with intervals of 15 minutes and thereafter with intervals of 30 minutes. The results were compared with those of a group of 9 rabbits given 100 mg/kg of ABPC alone. 1. The maximum concentration of SBT in the CSF and the percentages of both the maximum concentration and the area under the concentration-time curve (AUC) of SBT in CSF vs. those in serum of the SBT/ABPC group were higher than those of ABPC and the half-life of SBT in the CSF was also longer than that of ABPC, all with significant difference. When these parameters for SBT of SBT/ABPC groups were compared with those of ABPC of the ABPC group, not much differences existed between the 2 groups except that the CSF half-life of SBT was much longer than that of ABPC. 2. The percentages of both the maximum concentration and AUC of ABPC in CSF vs. those in serum of the SBT/ABPC group were significantly lower than those of ABPC of the ABPC group. The CSF half-life of ABPC of the former group was longer than that of the latter. 3. The above results suggest that when SBT and ABPC are administered simultaneously, the penetration of ABPC into the CSF is inhibited.

Drug transfer into cerebrospinal fluid after simultaneous administration of ampicillin with ceftriaxone or ceftazidime in rabbits with Staphylococcus aureus meningitis.

Meningitis was induced in white rabbits with a non beta-lactamase producing strain of Staphylococcus aureus. There was no significant difference in the CSF level of ceftazidime after simultaneous administration of ceftazidime with ampicillin or after ceftazidime alone. In contrast the percentage CSF penetration of ampicillin decreased from 8.81% after administration of ampicillin alone to 2.77% after the simultaneous administration of ampicillin with ceftazidime. The ratio of AUC in CSF and serum was 19.4% after ampicillin alone and 7.71% after simultaneous administration with ceftazidime. When ceftriaxone was combined with ampicillin there was no effect on the CSF penetration of either drug. Cephalosporins have unpredictable effects on the CSF concentration of ampicillin, probably due to variable effects on the penetration of ampicillin from blood to CSF.

Penetration of sulbactam and ampicillin into cerebrospinal fluid of infants and young children with meningitis.

Infusions of 50 mg of sulbactam per kg per day and 400 mg of ampicillin per kg per day in divided doses to infants and children with bacterial meningitis produced levels in cerebrospinal fluid approximately one-third those in serum. Concentrations in cerebrospinal fluid of 5.5 micrograms of sulbactam per ml and 16.0 micrograms of ampicillin per ml declined within a few days of therapy to 1.9 microgram of sulbactam per ml and 5.2 micrograms of ampicillin per ml.

Penetration of sulbactam into the cerebrospinal fluid of patients with bacterial meningitis receiving ampicillin therapy.

Concentrations of sulbactam in the CSF of 18 patients with bacterial meningitis who were undergoing treatment with intravenous (iv) ampicillin were determined. Six patients received single doses of sulbactam (1 g) and 12 patients received multiple doses (four times daily) by the iv route at various intervals before lumbar punctures were performed to monitor their condition. Concentrations of sulbactam up to 12 micrograms/ml were detected in the CSF between 1 and 4 hr after dosing, the higher levels being present in the CSF of patients with the most severe meningeal inflammation. There were no significant differences in the concentrations achieved after single or multiple doses of sulbactam, and the concentrations were generally similar to the concurrent concentrations of ampicillin. It is concluded that these results as well as the antibacterial properties of sulbactam plus ampicillin support the evaluation of this combination as an alternative in the treatment of bacterial meningitis.

Sulbactam/ampicillin vs. chloramphenicol/ampicillin for the treatment of meningitis in infants and children.

Eighty-one patients ages one month to 14 years with meningitis were randomized to receive either sulbactam (50 mg/kg per day) and ampicillin (400 mg/kg per day; 41 patients) or chloramphenicol and ampicillin (40 patients). The groups were comparable in terms of sex and degree of illness; however, more patients treated with chloramphenicol/ampicillin than patients treated with sulbactam/ampicillin were younger than 12 months of age (78% vs. 56%). Pathogens were isolated from the cerebrospinal fluid (CSF) of 65 (80%) of the 81 patients. In the sulbactam/ampicillin group, there were 18 Haemophilus influenzae isolates (one resistant to ampicillin), five Streptococcus pneumoniae, five Neisseria meningitidis, one Klebsiella pneumoniae, one Pseudomonas aeruginosa, and one Listeria. In the chloramphenicol/ampicillin group, there were 19 H. influenzae isolates, 10 S. pneumoniae, three N. meningitidis, one Haemophilus parainfluenzae, and one Citrobacter. Of 63 patients with assessable CSF pathogens, one (3%) of 29 treated with sulbactam/ampicillin died (S. pneumoniae) and six (18%) of 34 treated with chloramphenicol/ampicillin died (two, H. influenzae; three, S. pneumoniae; and one, Citrobacter). Twelve percent in the sulbactam/ampicillin group and 18% in the chloramphenicol/ampicillin group had neurologic sequelae. No clinically significant reactions or toxicities were noted. Sulbactam/ampicillin was as effective as chloramphenicol/ampicillin in the treatment of meningitis.

[Penetration of aztreonam and ampicillin to cerebrospinal fluid in the concomitant administration to rabbits with Staphylococcus aureus meningitis].

Aztreonam (AZT) and ampicillin (ABPC) were independently administered to 6 and 7 rabbits respectively, with S. aureus meningitis. Additionally, AZT and ABPC were concomitantly given to 6 rabbits with S. aureus meningitis. Concentrations of AZT and ABPC in cerebrospinal fluid (CSF) and serum were determined by HPLC method, and the results in concomitant treatment were compared with those for single treatment of each agent. Results were as follows: Maximum serum concentrations of AZT in concomitant treatment of AZT and ABPC were higher than those in single treatment of AZT. However, there was no significant difference between the 2 treatment groups with regard to maximum CSF concentration, percentage of AUC of CSF to serum, and T1/2 of the CSF and serum concentrations of AZT. ABPC in the concomitant treatment did not influence the CSF concentration of AZT. There was no significant difference in serum concentration of ABPC between concomitant treatment and the single one. However, the values of maximum CSF concentration, percentage of maximum CSF to serum concentration and percentage of AUC of CSF to serum in the concomitant treatment were lower than those in the single treatment of ABPC. With regard to T1/2 of CSF concentration of ABPC, there was no remarkable difference between the 2 treatment groups. The above results suggest that the distribution of ABPC into CSF is suppressed in the concomitant treatment of AZT and ABPC. AZT has no antimicrobial activity against Gram-positive bacteria. The CSF concentration of ABPC is suppressed in the concomitant treatment. Those facts suggest that AZT should be administered for meningitis cases after the identification of causative pathogens.

[Factors of meningeal diffusion of amoxicillin and ampicillin at the acute phase of purulent meningitis in children]. / Facteurs de pénétration méningée de l'amoxicilline et de l'ampicilline à la phase aiguë des méningites purulentes de l'enfant.

Amoxicillin and ampicillin levels were comparatively studied in blood and CSF of children with purulent meningitis. Thirty one children aged 2 months to 11 years were treated by one of two beta lactams by monotherapy in a daily dose of 200 mg/kg (Group 1: amoxicillin, n = 17; group 2: ampicillin, n = 14). Samples were collected on day 2 one hour after administration of 50 mg/kg IV of the chosen antibiotic. The mean levels observed in serum (69.5 and 53.4 micrograms/ml) and in CSF (7.74 and 7.96) were not significantly different. Beyond these levels we studied different biologic parameters in CSF: leucocytes, polymorphonuclears, protein, glucose and lactic acid. Multiple linear correlations were found, for the two groups and for the whole population between the CSF antibiotic level and the 6 other parameters (group 1: R1 = 0.82; group 2: R2 = 0.88; group 1 + 2: R3 = 0.78). The best correlated parameters with antibiotic CSF level are serum antibiotic level and CSF lactic acid. With these two parameters we can also estimate antibiotic level in CSF with good correlations (R1 = 0.78; R2 = 0.72 and R3 = 0.72).

Cerebrospinal fluid penetration after combined administration of cefotaxime and ampicillin to rabbits with staphylococcal meningitis.

The pharmacokinetics of cefotaxime and ampicillin in the cerebrospinal fluid (CSF) were studied by a HPLC method after administering each of the antibiotics singly or as a mixture to rabbits with experimental meningitis caused by Staphylococcus aureus. The half-lives of cefotaxime and desacetyl-cefotaxime in the serum and of ampicillin in the CSF were found to be significantly shorter in the mixture group than in the respective single administration groups. No other statistically significant differences were observed between the mixture and single administration groups with respect to the maximum concentrations (Cmax) of the antibiotics in the serum and the CSF, to the relative percentage of the Cmax of each antibiotic in the CSF to the Cmax in the serum, and to the relative percentage of the AUC of each antibiotic in the CSF to that in the serum. These results differ from earlier findings that the concentration of ampicillin in the CSF of rabbits was significantly lower in animals concomitantly dosed with latamoxef (moxalactam) and ampicillin than in a group dosed only with ampicillin.