Chloramphenicol Clearance Research Articles

Single-helix carbon microcoils prepared via Fe(III)-osmotically induced shape transformation of zucchini (Cucurbita pepo L.) for enhanced adsorption and antibacterial activities

Carbon coils have many significant technological applications; however, most of them were fabricated using either expensive apparatus or complicated procedures. Herein, a versatile and simple method was used for fabricating valuable single-helix carbon microcoils (SHCMs) by Fe(III)-osmotically induced shape transformation of zucchini (Cucurbita pepo L.). This versatile strategy allowed to readily reach high surface area (365m2g−1), large pore volume (0.24cm3g−1) and a narrow average mesoporous size of 5.5nm via a combined impregnation and hydrothermal carbonization process, and to achieve uniform SHCMs in a reasonable system. In addition, the SHCMs showed excellent performance in antibacterial property and the clearance of chloramphenicol, which should be a promising candidate for efficient adsorbent in water purification. The equilibrium data were well fitted to the Langmuir isotherm model with a maximal adsorption capacity of 124.32mgg−1 at ambient temperature. The antibacterial mechanisms was also explored. The findings revealed that the Fe(III)-osmotically induced transformation is a potential route for large-scale preparation of SHCMs from appropriate biomass precursors.

Relationship Between Clinical and Biologic Variables and Chloramphenicol Pharmacokinetic Parameters in Pediatric Patients with Sepsis

OBJECTIVE:To evaluate the influence of several clinical and biologic factors on the disposition kinetics of oral chloramphenicol in pediatric patients and to determine the usefulness of this information to predict chloramphenicol serum concentrations.STUDY DESIGN:The clinical, biologic, and pharmacokinetic data of 30 consecutive pediatric patients diagnosed with sepsis and admitted to a tertiary care center were analyzed retrospectively. The patients were randomly assigned to a study group and a validation group. The model was developed by a three-step approach involving Bayesian estimation of pharmacokinetic parameters, selection of covariates by principal component analysis, and final selection by stepwise multiple linear regression. The model was tested in the study group and compared with a general population model using a prediction error analysis.RESULTS:Regression analysis revealed that weight, albumin, and white blood cell (WBC) count were the most important determinants for chloramphenicol distribution volume, whereas age, WBC count, and serum creatinine were the most important determinants for chloramphenicol clearance. The performance of the constructed population model improved significantly in terms of both bias and precision compared with the general model when tested in the validation group.CONCLUSIONS:Clinical and biologic factors may significantly influence chloramphenicol's disposition in pediatric patients with sepsis and therefore should be considered in programming dosage regimens.

Decreased chloramphenicol clearance in malnourished Ethiopian children

The disposition of chloramphenicol and chloramphenicol monosuccinate has been studied in thirty-four Ethiopian children of varying nutritional status. After a single intravenous dose corresponding to chloramphenicol 25 mg per kg bodyweight, the plasma clearance of chloramphenicol monosuccinate was decreased only in severely malnourished children with kwashiorkor. Seventeen % of the dose (range 0-51%) was recovered in urine as intact prodrug, indicating incomplete and variable bioavailability of chloramphenicol. Compared to underweight children, on average marasmic and kwashiorkor subjects exhibited a 2- and 3-fold increase, respectively, in the AUC of chloramphenicol. Elevated AUCs could be traced to reduced hepatic clearance of the drug. The unbound fraction both of chloramphenicol and its prodrug were slightly elevated in serum from kwashiorkor subjects. The possibility of using a single point measurement of plasma chloramphenicol as a guide to individualized dosage are discussed.

Pharmacokinetics of chloramphenicol in normal andEscherichia coliinfected chickens

1. Disposition kinetics were compared in healthy chickens and in chickens naturally infected with E. coli following the intravenous, intramuscular and oral administration of chloramphenicol in a single dose of 20 mg/kg body weight. 2. Lower serum chloramphenicol concentration in diseased chickens were reported after intravenous injection, but they were higher than normal 30 min after intramuscular and oral administration. Following intravenous injection the volume of distribution was increased in diseased chickens. 3. The biological half-life in normal chickens was 8.32 +/- 0.5 h and was prolonged in diseased birds (26.21 +/- 0.2 h). The body clearance of chloramphenicol was reduced in diseased chickens. 4. The rate of absorption of chloramphenicol was delayed after administration via the oral route but the extent of absorption was increased. The maximum concentration was higher and it was reached after a longer time in diseased than in normal chickens after administration by both intramuscular and oral routes.

Effect of Haemonchus contortus infection on the clearance of antipyrine, sulfobromophthalein, chloramphenicol, and sulfathiazole in lambs

SUMMARY A study was made to determine the effect of Haemonchus contortus parasitic infection in lambs on the clearance of several IV administered drugs. Clearance of sulfobromophthalein or sulfathiazole from the plasma of lambs was unaffected by infection with H contortus. Clearance of antipyrine was enhanced by the infection, and thiabendazole treatment did not alter this effect. Clearance of chloramphenicol (cap), administered as the succinate ester (caps), was not changed by the infection, but it was increased after treatment with thiabendazole. Changes in the mean body residence time and initial plasma concentration of caps and cap after treatment with thiabendazole indicate that hydrolysis of caps to cap was reduced. High concentrations of caps apparently enhanced its own elimination directly rather than via the expected sequence involving hydrolysis, glucuronidation, and excretion of cap-glucuronide. Enhanced clearance of antipyrine following infection of lambs with H contortus can be explained in at least 2 ways. First, it is possible that the lambs did not have mature amounts of hepatic drug metabolizing enzyme activity as reported by other investigators, which may be explained by breed differences or animal husbandry practices. Second, infection of lambs by H contortus may have triggered an inductive response in hepatic cytochrome P- 450-mediated activities, which might result via a generalized enhancement in hepatic protein synthesis associated with the physiologic response to replace plasma proteins and other blood components lost through gastrointestinal hemorrhage caused by the active feeding of adult worms. Other phase-II reactions such as acetylation, glucuronidation, and glutathione-S-transferase apparently were not affected.

Chloramphenicol Clearance is Increased by Paracetamol

Chloramphenicol Clearance is Increased by Paracetamol

Interaction between chloramphenicol and acetaminophen.

Acetaminophen has been reported either to prolong or not to affect the clearance of chloramphenicol. To confirm one of these findings we studied the clearance of chloramphenicol and its metabolites using high pressure liquid chromatography in five patients (ages 2.5 to 5 years) before and during oral treatment with acetaminophen (50 mg/kg/day). Significant differences were observed in mean (SD) peak serum chloramphenicol concentration (-9.7 (3.2) mg/l), mean (SD) apparent volume of distribution (+225 (162) ml/kg), mean (SD) chloramphenicol half life (-1.9 (1.1) hours), mean (SD) chloramphenicol clearance (+236 (94) ml/kg/h), mean (SD) area under the curve (-83.5 (33.0) mg/l/h), and mean (SD) elimination constant (+0.34 (0.13) h-1) between samples obtained before and during treatment with acetaminophen. Acetaminophen, when given orally for several days, increased the clearance of chloramphenicol, perhaps by increased glucuronidation. This report re-emphasises the need for therapeutic drug monitoring whenever these two drugs are used together.

Chloramphenicol dosage and pharmacokinetics in infants and children.

Twenty infants and children receiving intravenous chloramphenicol were studied to examine the pharmacokinetics of the parent compound and its precursor, the succinate ester (CAP-S). Plasma samples were obtained just prior to a 30-minute infusion of chloramphenicol succinate, immediately after or 30 minutes after infusion, and 90, 210, and 330 minutes after infusion. Complete 6-hour urine collections were obtained during 11 studies. Plasma and urine were assayed for chloramphenicol and its succinate ester by high-performance liquid chromatography. Peak plasma concentrations ranged from 11.0 to 51.1 micrograms/ml on doses of 50 to 100 mg/kg/day and were higher in the youngest age group. The elimination half-life of chloramphenicol averaged 4.0 hours. Multilinear regression analysis demonstrated an excellent relationship between body surface area, trough plasma chloramphenicol concentration, and total body chloramphenicol clearance. The hydrolysis of succinate ester to free chloramphenicol may delay the peak free concentration, and its renal elimination (average 21 per cent of the dose administered) significantly affects chloramphenicol pharmacokinetics. The clearance of chloramphenicol exhibited enzyme saturation kinetics in one patient studied at two different doses. Dosage adjustments of intravenous chloramphenicol in children must be made in relation to the trough chloramphenicol plasma concentration, renal elimination of CAP-S, and possible saturation of chloramphenicol metabolism.

The pharmacokinetics of chloramphenicol in the neonate and young infant.

The peak and trough serum concentrations and total body clearance of chloramphenicol were determined by microbiological assay in a multicentre investigation of 90 babies. Chloramphenicol was administered by the intravenous, intramuscular or oral route and dosage ranged between 12 and 210 mg/kg/day. A wide variation in both serum levels and clearance amongst babies receiving the same dose was observed. Neonates (64) had significantly higher serum concentrations (P less than 0.001) and slower clearance (P less than 0.0001) than infants (26). Oral administration in neonates resulted in lower steady state serum levels (P less than 0.02) than those following intravenous administration. Term neonates cleared chloramphenicol more rapidly than their preterm contemporaries (P less than 0.005). Forty-one per cent of subjects had potentially toxic serum levels; subtherapeutic peak serum levels (less than 15 mg/l) were recorded in 39/90 babies. Concomitant penicillin therapy resulted in higher serum concentrations (P less than 0.05); phenobarbitone was not associated with increased clearance or lower steady state serum levels of chloramphenicol. Postnatal age and gestational age accounted for some of the variability in pharmacokinetic response to chloramphenicol. Although many babies receiving the recommended dose had serum levels within the accepted range (15-25 mg/l), others did not. Routine monitoring of chloramphenicol in every baby receiving this antibiotic is essential: the regimens of 18% babies in the present study were altered after assay.

Chloramphenicol pharmacokinetics in Ethiopian children of differing nutritional status.

The pharmacokinetics of i.v. chloramphenicol succinate and oral chloramphenicol palmitate were studied in Ethiopian children with different nutritional states. In children with kwashiorkor the plasma clearance of chloramphenicol was significantly lower than in children of normal weight (4.16 ml/min/kg versus 7.53 ml/min/kg). In consequence the mean half-life was prolonged (3.76 h versus 2.85 h) and this led to somewhat higher plasma levels in the kwashiorkor children. The influence of the pathophysiological changes offset one another so that plasma concentrations within the therapeutic range were obtained in children with kwashiorkor given recommended standard i.v. doses. The absorption of chloramphenicol after oral administration in severely malnourished children was erratic, which suggests that this route should be avoided in such patients.

Chloramphenicol pharmacokinetics in the newborn.

We studied pharmacokinetics of chloramphenicol in 9 neonates having a mean gestational age of 31.2 +/- 1.9 weeks (mean +/- SEM). The studied dose was the final dose of treatment in 8 of these and the first dose in 2 of these. 1 neonate was studied twice. Concentrations of chloramphenicol and its 3-monosuccinate and 1-monosuccinate esters were measured in serum by high performance liquid chromatography. Apparent total body clearance of chloramphenicol correlated with postnatal age (r = 0.81, p less than 0.01). Mean apparent clearance was 1.1 ml X min-1 X kg-1. Serum concentrations of succinate esters were below assay sensitivity after 6 h postdose. Factors leading to excessive chloramphenicol concentrations (greater than 25.0 mg/l) were evaluated in another 44 newborns. Instability of the patient's clinical condition was an important cause of excessive serum concentrations during ongoing therapy.

Chloramphenicol: new perspectives on an old drug.

Chloramphenicol is an old antibiotic being used with increasing frequency in serious childhood infections largely due to the emergence of ampicillin-resistant Hemophilus influenzae type b. Because of this renewed popularity and the recent availability of accurate analytical techniques for measurement of chloramphenicol, there have been many recent articles examining the pharmacokinetics of chloramphenicol and its two major prodrug esters, chloramphenicol succinate and chloramphenicol palmitate. New data from these studies include the incomplete bioavailability of chloramphenicol succinate, the possible superior bioavailability of chloramphenicol palmitate vs. chloramphenicol succinate, and the wide interpatient variability in chloramphenicol clearance. These observations, coupled with the known serious hematologic toxicity (reversible bone marrow suppression or irreversible aplastic anemia) and metabolic toxicity (gray baby syndrome) associated with chloramphenicol use, require that initial antibiotic doses be selected by age and be carefully individualized by measurement of peak serum chloramphenicol concentrations.

Chloramphenicol clearance in infants.

Chloramphenicol clearance was evaluated over one dosing interval in 10 infants after at least 24 hours of therapy to evaluate dosage guidelines using a specific chemical assay. Serum samples were obtained prior to and at 1, 2, 4, and 6 hours after the start of a 20-minute infusion of 24 mg/kg chloramphenicol as the sodium succinate. The chemical assay used is technically simple and is specific for unesterified chloramphenicol. Peak serum concentrations ranged from 20.9 to 94.0 microgram/ml and occurred from 1 to 4 hours after infusion. Clearances ranged from 0.058 to 0.236 l./kg . hr and paralleled previously reported results using different assay methodology. The 4-hour serum chloramphenicol concentrations were significantly lower (P less than 0.05) in infants on phenobarbital. The currently recommended dose of chloramphenicol for severe infections, 100 mg/kg per day, is excessive in some infants. Widely divergent clearance rates prohibit uniform dosage guidelines so that serum level monitoring with an assay specific for chloramphenicol is essential.

Bioavailability and clearance of chloramphenicol after intravenous chloramphenicol succinate.

Bioavailability of chloramphenicol and kinetics of chloramphenicol succinate and chloramphenicol were studied in 12 patients. Chloramphenicol succinate, 25 mg/kg, was injected intravenously every 6 hr over 0.5 to 1 hr. Both the drug and the prodrug were analyzed by high-pressure liquid chromatography. Bioabailability of chlorampenicol ranged from 0.55 to 0.92 and total, renal, and nonrenal clearance from 6.81 to 98.22, 2.54 to 26.90, and 3.73 to 87.38 ml/m2/min, while clearances of chloramphenicol succinate ranged from 84.75 to 916.00 28.40 to 312.00, and 26.06 to 760.93 ml/m2/min. Urinary recovery of chloramphenicol was 3% to 25% and that of chloramphenicol succinate was 7% to 45%. Mean apparent volumes of distribution were 0.71 l/kg for chloramphenicol and 2.10 l/kg for chloramphenicol succinate and elimination half-lifes were 4.03 and 2.65 hr, respecitively. There were relationships between patient age and clearance of both drugs. Incomplete bioavailability of chloramphenicol and the more than 10-fold variability in clearance of both chloramphenicol and chloramphenicol succinate explain the need for individualizing doses to achieve thrapeutic effect and minimize the risk to toxicity.

Rapid estimation of chloramphenicol clearance in infants and children.

A method is presented by which chloramphenicol clearance (CL) can be estimated from a single serum sample obtained 6 hours after the initial intravenous dose. The method was evaluated prospectively in 20 infants and children who received intravenous chloramphenicol sodium succinate. Agreement between predicted and observed clearance was excellent (r = 0.914, p less than 0.001). The equation of the observed regression line was: observed 0.886x predicted + 0.019. The method appears to provide reasonably accurate estimates of clearance which can be used for rapid clinical adjustment of dose.

Effect of hemodiaiysis on total body ciearance of chloramphenicol

The effect of hemodialysis on the total body clearance (ClTB) of chloramphenicol was studied in two patients with renal failure and hepatic dysfunction. Chloramphenicol sodium succinate was administered intravenously eight hours before dialysis in doses of 20 and 26.1 mg/kg/day to Patients 1 and 2, respectively. Serum samples were taken at 48 hours after initiation of the drug, 2.5 hours after the last dose and 5 minutes into dialysis for Patient 1, and before dosing and at 0.5, 1, 2, 4, 6, 8 and 11 hours after dosing for Patient 2. Serum levels of chloramphenicol were measured by high-performance liquid chromatography. Chloramphenicol ClTB values on dialysis (162.2 and 118 ml/min for Patients 1 and 2, respectively) were 58% and 72% higher than off-dialysis ClTB values (102.9 and 69 ml/min) for Patients 1 and 2, respectively. Dialysis extraction ratios for chloramphenicol were 0.52 and 0.31 for Patients 1 and 2, respectively. Although the increased clearance of chloramphenicol that occurred during dialysis may be important only in patients with hepatic dysfunction, it is recommended that the normal maintenance dose of the drug be administered after dialysis to avoid the possibility of increased clearance.

Chloramphenicol disposition in infants and children

We studied the pharmacokinetics of chloramphenicol following its intravenous administration as the sodium succinate ester to 54 infants and children. The mean "apparent t 1/2" of chloramphenicol clearance from the plasma was 5.94 hours (range 0.87 to 17.8 hours). The t 1/2 of patients who weighed less than 10 kg was significantly longer than that of those who weighed more than 10 kg (9.02 vs 4.55 hours; P less than 0.0001). There was a discrepancy between the plasma levels of chloramphenicol and total aromatic nitro compounds in four patients; these compounds were cleared at different rates. Repeated dosing (eight to 30 doses) did not produce a consistent effect on the t 1/2. The CSF concentrations of chloramphenicol in 13 patients were 67% (range 45 to 99%) of the simultaneous serum concentrations. We conclude that the marked individual variation in chloramphenicol pharmacokinetics in infants and children requires monitoring of blood concentrations during therapy.

Drug residues in food animals. I. Plasma and tissue kinetics of chloramphenicol in young cross‐bred swine

Eighteen non‐fasted, 12–16 week old pigs weighing between 20 and 40 kg were dosed with chloramphenicol intravenously at a dose rate of 22 mg/kg body weight. The pharmacokinetics of chloramphenicol were determined in blood plasma and sixteen selected organs and body fluids. The elimination half‐life in plasma was estimated to be 2.66pL1.06 h and volume of distribution was 1.39pL0.32 I/kg. The body clearance of chloramphenicol was estimated to be 6.64pL1.52 ml/kg/min. The elimination half‐life in tissue was found to range from 1.25 h in kidney to 5.89 h in fat. Most major organs ranged from 2.0 to 5.0 h. Significant correlations were found to exist between plasma concentrations and most major organ concentrations. Chloramphenicol concentrations in muscle, spleen, lung, stomach content, and large intestine content were found to exist slightly beyond the time when concentrations were negative in plasma. However, urine levels exceeded tissue levels at the last slaughter interval. It appears that serum or urine would be a good body fluid for monitoring chloramphenicol residues in tissues, whereas stomach content might be used as an indicator for chloramphenicol treatment for many days after therapy with the drug.

Induction of chloramphenicol metabolism by phenobarbital.

The induction of hepatic microsomal enzymes leading to more rapid metabolism of antibiotics has been demonstrated in only a few prior studies. We have studied the induction of chloramphenicol metabolism in an isolated rat liver perfusion model and in intact dogs. Using these methods, we have demonstrated that the clearance of chloramphenicol from serum is markedly increased after treatment of animals with phenobarbital. This was demonstrated to be a function of increased clearance of the drug by the liver, accompanied but not paralleled by increases in liver weight and biliary excretion by the rat liver. In intact dogs, small doses of chloramphenicol were not sufficient to demonstrate this fact, whereas a large test dose of 100 mg/kg showed markedly enhanced clearance after 1 week of oral phenobarbital administration. Prolongation of phenobarbital treatment or increased dose did not further increase the clearance, and chloramphenicol could not be demonstrated to enhance its own clearance. Human data on induction of enzymes is to date inconclusive.

Delayed Clearance of Chloramphenicol from Serum in Patients with Hematologic Toxicity

Abstract The clearance of chloramphenicol from serum was studied in 18 patients. A significantly impaired clearance was found in all patients who manifested erythropoietic toxicity. Seven of the 18 patients were tested before chloramphenicol therapy was started. From these results it was possible to predict the patients who would subsequently develop hematologic toxicity. Therefore, prior testing with chloramphenicol may be valuable in screening adults susceptible to hematologic toxicity when the use of this drug is contemplated.