Predicting in vivo absorption of chloramphenicol in frogs using in vitro percutaneous absorption data.

BACKGROUND: Infectious disease, particularly the fungal disease chytridiomycosis (caused by Batrachochytrium dendrobatidis), is a primary cause of amphibian declines and extinctions worldwide. The transdermal route, although offering a simple option for drug administration in frogs, is complicated by the lack of knowledge regarding percutaneous absorption kinetics. This study builds on our previous studies in frogs, to formulate and predict the percutaneous absorption of a drug for the treatment of infectious disease in frogs. Chloramphenicol, a drug with reported efficacy in the treatment of infectious disease including Batrachochytrium dendrobatidis, was formulated with 20% v/v propylene glycol and applied to the ventral pelvis of Rhinella marina for up to 6 h. Serum samples were taken during and up to 18 h following exposure, quantified for chloramphenicol content, and pharmacokinetic parameters were estimated using non-compartmental analysis. RESULTS: Serum levels of chloramphenicol reached the minimum inhibitory concentration (MIC; 12.5 µg.mL- 1) for Batrachochytrium dendrobatidis within 90-120 min of exposure commencing, and remained above the MIC for the remaining exposure time. Cmax (17.09 ± 2.81 µg.mL- 1) was reached at 2 h, while elimination was long (t1/2 = 18.68 h). CONCLUSIONS: The model, based on in vitro data and adjusted for formulation components and in vivo data, was effective in predicting chloramphenicol flux to ensure the MIC for Batrachochytrium dendrobatidis was reached, with serum levels being well above the MICs for other common bacterial pathogens in frogs. Chloramphenicol's extended elimination means that a 6-h bath may be adequate to maintain serum levels for up to 24 h. We suggest trialling a reduction of the currently-recommended continuous (23 h/day for 21-35 days) chloramphenicol bathing for chytrid infection with this formulation.

A two-dimensional zinc(II)-based metal-organic framework for fluorometric determination of ascorbic acid, chloramphenicol and ceftriaxone.

A two-dimensional zinc(II)-based metal-organic framework [Zn • (BA) • (BBI)] was synthesized from 1,2-benzenediacetic acid and 1,1'-(1,4-butanediyl) bis(imidazole) via a solvothermal reaction. The crystal exhibits good chemical stability in the pH range from 2 to 12, and strong fluorescence with excitation/emission maxima of 270/290 nm. The crystal is shown to by a viable fluorescent probe for the detection of ascorbic acid (AA) and the antibiotics chloramphenicol (CHL) and ceftriaxone (CRO). Fluorescence intensity of crystal dispersion is significantly quenched with increasing concentrations of AA/CHL/CRO. Quenching occurs even in the presence of other substances. The assay is fast (5 s) and has a low detection limit (1.6 ppb for AA, 12 ppb for CHL and 3.9 ppb for CRO). The crystal still has a good quenching effect on AA/CHL/CRO after washing and using for five times. The response of the probe is related to the interplay between the MOF and analytes via energy absorption competition. Graphical abstractSchematic diagram of preparing Zn • (BA) • (BBI) and responding to target analytes. BA: 1,2-phenyldiacetic acid; BBI: 1,1'-(1,4-butanediyl)bis(imidazole); Zn • (BA) • (BBI): Crystal chemical formula.

Pharmacokinetics of chloramphenicol base in horses and comparison to compounded formulations.

Chloramphenicol is commonly used in horses; however, there are no studies evaluating the pharmacokinetics of veterinary canine-approved tablets. Studies using different formulations and earlier analytical techniques led to concerns over low bioavailability in horses. Safety concerns about human health have led many veterinarians to prescribe compounded formulations that are already in suspension or paste form. The objective of this study was to evaluate the pharmacokinetics of approved chloramphenicol tablets in horses, along with compounded preparations. The hypothesis was that chloramphenicol has low absorption and a short half-life in horses leading to low serum concentrations and that compounded preparations have lower relative bioavailability. Seven horses were administered chloramphenicol tablets (50 mg/kg orally). In a crossover design, they were administered two compounded preparations to compare all three formulations at the same dose (50 mg/kg). Cmax was 5.25 ± 4.07 µg/ml at 4.89 hr, 4.96 ± 3.31 µg/ml at 4.14 hr, and 3.84 ± 2.96 µg/ml at 4.39 hr for the tablets, paste, and suspension, respectively. Elimination half-life was 2.65 ± 0.75, 3.47 ± 1.47, and 4.36 ± 4.54 hr for tablets, paste, and suspension, respectively. The AUC0→∞ was 17.93 ± 7.69, 16.25 ± 1.85, and 14.00 ± 5.47 hr*µg/ml for the tablets, compounded paste, and compounded suspension, respectively. Relative bioavailability of compounded suspension and paste was 78.1% and 90.6%. Cmax after administration of all formulations did not reach the recommended MIC target of 8 µg/ml set by the Clinical Laboratory Standards Institute (CLSI) for most bacteria. Multidose studies are warranted, but the low serum concentrations suggest that bacteria with MIC values lower than CLSI recommendations should be targeted in adult horses.

Transfer of vaginal chloramphenicol to circulating blood in pregnant women and its relationship with their maternal background and neonatal health.

Few clinical studies have determined the quantitative transfer of vaginal chloramphenicol to circulating blood in pregnant women. This study aimed to evaluate the plasma concentration of chloramphenicol in pregnant women treated with trans-vaginal tablets and its relationship with maternal background and neonatal health. Thirty-seven pregnant women treated with 100 mg of trans-vaginal chloramphenicol once daily for bacterial vaginosis and its suspected case were enrolled. The plasma concentration of chloramphenicol was determined using liquid chromatography coupled to tandem mass spectrometry at day 2 or later after starting the medication. The correlations between the maternal plasma concentration of chloramphenicol and the background and neonatal health at birth were investigated. Chloramphenicol was detected from all maternal plasma specimens and its concentration ranged from 0.043 to 73.1 ng/mL. The plasma concentration of chloramphenicol declined significantly with the administration period. The plasma concentration of chloramphenicol was lower at the second than the first blood sampling. No correlations were observed between the maternal plasma concentration of chloramphenicol and background such as number of previous births, gestational age at dosing, and clinical laboratory data. Neonatal infant health parameters such as birth-weight, Apgar score at birth, and gestational age at the time of childbearing were not related to the maternal plasma concentration of chloramphenicol. Vaginal chloramphenicol transfers to circulating blood in pregnant women. The maternal plasma concentration of chloramphenicol varied markedly and was associated with the administration day, but not with maternal background or her neonatal health.

Anti-Biofouling Isoporous Silica-Micelle Membrane Enabling Drug Detection in Human Whole Blood.

Direct electrochemical detection in human whole blood remains challenging due to electrode surface fouling and passivation by abundant biological substances. In this work we report that the isoporous silica-micelle membranes (designated as iSMM) can effectively function as antibiofouling layer for electrochemical detection of drug molecules in human whole blood without pretreatment. The iSMM possesses molecular sieving capacity, charge/lipophilicity selectivity, and preconcentration ability. Only small and neutral/lipophilic analytes can permeate the iSMM, be concentrated, and subsequently be detected at the underlying electrode. It is however impermeable to big sized substances and those small but charged and hydrophilic. We first investigated the molecular permeability of iSMM by electrochemical impedance spectroscopy (EIS) and then demonstrated its application in the quantitative determination of chloramphenicol (CAP) in the unprocessed human whole blood. The analytical sensitivity and long-term stability of iSMM based electrochemical sensors are apparently better than bare electrodes.

Label-free and sensitive aptasensor based on dendritic gold nanostructures on functionalized SBA-15 for determination of chloramphenicol.

A highly sensitive and low-cost electrochemical aptasensor was developed for the determination of chloramphenicol (CAP). The system was based on a CAP-binding aptamer, a molecular recognition element, and 1,4-diazabicyclo[2.2.2]octane (DABCO)-supported mesoporous silica SBA-15 on the surface of a screen-printed graphite electrode for formation of dendritic gold nanostructures and improving the performance and conductivity of the biosensor. Hemin has been applied as an electrochemical indicator which interacted with the guanine bases of the aptamer. In the absence of CAP, hemin binds to the aptamer and produces a weak differential pulse voltammetric (DPV) signal. The presence of CAP led to stabilization of the folded aptamer, which generated an amplified DPV signal. The peak current of hemin increased linearly with the concentration of CAP. Under optimal conditions, two linear ranges were obtained from 0.03 to 0.15 µM and 0.15 to 7.0 µM, respectively, and the detection limit was 4.0 nM. The prepared biosensor has good selectivity against other non-target drugs. Thus, the sensor could provide a promising platform for the fabrication of aptasensors. The feasibility of using this aptasensor was demonstrated by determination of CAP in a human blood serum sample.

Determination of chloramphenicol in biological matrices by solid-phase membrane micro-tip extraction and capillary electrophoresis.

Solid-phase membrane micro-tip extraction (SPMMTE) and capillary electrophoresis (CE) methods were developed and validated for analysis of chloramphenicol in human plasma and urine samples. Iron composite nanoparticles were prepared using green technology. CE was carried out using a silica capillary (60 cm × 50 µm i.d.), phosphate buffer (50 mm, 8.0 pH)-acetonitrile (95:5, v/v) as the background electrolyte, 10 kV voltage, 280 nm detection, 20 s injection time and 27 ± 1°C temperature. Frusemide was used as an internal standard. The values of migration time, electrophoretic mobility, electrophoretic velocity and theoretical plates of chloramphenicol were 12.254 min, 4.44 × 10, 7.41 × 10 and 11,227. The limits of detection and quantitation of chloramphenicol were 0.1 and 1.0 µg/mL. Recovery of chloramphenicol in the standard solution was 95%. Solid-phase membrane micro-tip extraction and capillary electrophoresis methods may be used to analyze chloramphenicol in human plasma and urine samples of any patient.

Pharmacokinetics of chloramphenicol following administration of intravenous and subcutaneous chloramphenicol sodium succinate, and subcutaneous chloramphenicol, to koalas (Phascolarctos cinereus).

Clinically normal koalas (n = 19) received a single dose of intravenous (i.v.) chloramphenicol sodium succinate (SS) (25 mg/kg; n = 6), subcutaneous (s.c.) chloramphenicol SS (60 mg/kg; n = 7) or s.c. chloramphenicol base (60 mg/kg; n = 6). Serial plasma samples were collected over 24-48 h, and chloramphenicol concentrations were determined using a validated high-performance liquid chromatography assay. The median (range) apparent clearance (CL/F) and elimination half-life (t(1/2)) of chloramphenicol after i.v. chloramphenicol SS administration were 0.52 (0.35-0.99) L/h/kg and 1.13 (0.76-1.40) h, respectively. Although the area under the concentration-time curve was comparable for the two s.c. formulations, the absorption rate-limited disposition of chloramphenicol base resulted in a lower median C(max) (2.52; range 0.75-6.80 µg/mL) and longer median tmax (8.00; range 4.00-12.00 h) than chloramphenicol SS (C(max) 20.37, range 13.88-25.15 µg/mL; t(max) 1.25, range 1.00-2.00 h). When these results were compared with susceptibility data for human Chlamydia isolates, the expected efficacy of the current chloramphenicol dosing regimen used in koalas to treat chlamydiosis remains uncertain and at odds with clinical observations.

Pharmacokinetics of multiple doses of chloramphenicol in fed adult horses.

To the authors' knowledge, there have been no studies evaluating the pharmacokinetics of chloramphenicol administered orally to horses at the currently recommended dose of 50 mg/kg PO q6 h for multiple days. The published antimicrobial susceptibility breakpoint is 8.0 ug/mL; it is unknown if this concentration is achievable at the recommended dose rate in horses. The aim of this prospective multi-dose pharmacokinetic study was to perform pharmacokinetic analysis of chloramphenicol after multiple doses. The authors hypothesize that the antimicrobial susceptibility breakpoint will not be reached. Seven healthy adult horses were administered 50 mg/kg chloramphenicol base tablets PO q6 h for 4 days. Blood was collected via venipuncture daily at 4 and 6 h after administration for the first 15 doses. After the 16th dose, an IV catheter was aseptically placed in the right jugular vein and blood was collected at regular intervals for pharmacokinetic analysis. Maximum chloramphenicol concentration was variable between horses (2.1-42.7 µg/mL). The highest average chloramphenicol concentration was just below the susceptibility breakpoint at 7.7 ug/mL while the lowest was well below the breakpoint at 1.5 ug/mL. On average, the time above 8.0 µg/mL was 75 min, considerably less than the recommended 50% of the dosing interval. When chloramphenicol is administered at a dose of 50 mg/kg PO q6 h in horses, the highest reliably achievable steady state concentration for at least half of the dosing interval is 2.0 µg/mL. The established susceptibility breakpoint of 8.0 ug/mL is not achievable in adult horses, and should be re-evaluated.

[Nano-titania-coated modified magnetic graphene oxide for pass-through cleanup of chloramphenicol, thiamphenicol, and florfenicol in human blood].

To develop a rapid, effective, and accurate method for the simultaneous determination of chloramphenicol, thiamphenicol, and florfenicol in human blood by pass-through cleanup solid-phase extraction combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS), novel nano-titania-coated modified magnetic graphene oxide (TiO2-Mag-GO) is used as the PRiME pass-through cleanup solid-phase extraction sorbent for the cleanup of blood phospholipids. The chromatographic separation was performed on an Eclipse Plus C18 column (100 mm×2.1 mm, 1.8 µm) using 0.08% (v/v) aqueous ammonia solution and acetonitrile having aqueous ammonia (0.08%, v/v) as mobile phases. The tandem mass spectrometer was operated using electrospray ion source (ESI) in the multiple reaction monitoring (MRM) mode. The results showed that the linearities were in the range of 0.1-10.0 µg/L with the determination coefficients (r2) greater than 0.9990 for chloramphenicol, thiamphenicol, and florfenicol. The limits of quantification (LOQs) (S/N>10) in the blood samples were between 0.056 and 0.082 µg/L and the recoveries ranged from 90.0% to 105% at three spiked levels. Precision values expressed as relative standard deviations (RSDs) were in the range of 1.2%-6.6%. The developed method can be used for routine analyses to determine chloramphenicol, thiamphenicol, and florfenicol in clinical studies.

Bactericidal versus bacteriostatic antibiotic therapy of experimental pneumococcal meningitis in rabbits.

A rabbit model of pneumococcal meningitis was used to examine the importance of bactericidal vs. bacteriostatic antimicrobial agents in the therapy of meningitis 112 animals were infected with one of two strains of type III Streptococcus pneumoniae. Both strains were exquisitely sensitive to ampicillin, minimum inhibitory concentration (MIC)/minimum bactericidal concentration (MBC)<0.125 mug/ml. The activity of chloramphenicol against the two strains varied: strain(1)-MIC 2 mug/ml, MBC 16 mug/ml; strain(2)-MIC 1 mug/ml, MBC 2 mug/ml. Animals were treated with either ampicillin or chloramphenicol in dosages that achieved a peak bactericidal effect in cerebrospinal fluid (CSF) for ampicillin against both strains. Two different dosages were used for chloramphenicol. The first dosage achieved a peak CSF concentration of 4.4+/-1.1 mug/ml that produced a bacteriostatic effect against strain(1) and bactericidal effect against strain(2). The second dosage achieved a bactericidal effect against both strains (mean peak CSF concentration 30.0 mug/ml). All animals were treated intramuscularly three times a day for 5 d. CSF was sampled daily and 3 d after discontinuation of therapy for quantitative bacterial cultures. Results demonstrate that only antimicrobial therapy that achieved a bactericidal effect in CSF was associated with cure. Over 90% of animals treated with one of the bactericidal regimens (i.e., animals in which the bacterial counts in CSF dropped >5 log(10) colony-forming units [cfu]/ ml after 48 h) had sterile CSF after 5 d of treatment. On the other hand, the regimen that achieved bacteriostatic concentrations (CSF drug concentrations between the MIC and MBC) produced a drop of 2.4 log(10) cfu/ml by 48 h; however, none of the animals that survived had sterile CSF after 5 d. These studies clearly demonstrate in a strictly controlled manner that maximally effective antimicrobial therapy of experimental pneumococcal meningitis depends on achieving a bactericidal effect in CSF.

Development of an improved method for trace analysis of chloramphenicol using molecularly imprinted polymers.

A confirmatory method is described for the determination of the illegal antibiotic chloramphenicol using a specifically developed molecularly imprinted polymer (MIP) as the sample clean-up technique. The newly developed MIP was produced using an analogue to chloramphenicol as the template molecule. Using an analogue of the analyte as the template avoids a major traditional drawback associated with MIPs of residual template leeching or bleeding. The MIP described was used as a solid-phase extraction phase for the extraction of chloramphenicol from various sample matrices including honey, urine, milk and plasma. A full analytical method with quantification by LC-MS/MS is described. The method was fully validated according to the European Union (EU) criteria for the analysis of veterinary drug residues.

Determination of chloramphenicol residues in meat, seafood, egg, honey, milk, plasma and urine with liquid chromatography-tandem mass spectrometry, and the validation of the method based on 2002/657/EC.

A simple and rapid method for the determination and confirmation of chloramphenicol in several food matrices with LC-MS/MS was developed. Following addition of d5-chloramphenicol as internal standard, meat, seafood, egg, honey and milk samples were extracted with acetonitrile. Chloroform was then added to remove water. After evaporation, the residues were reconstituted in methanol/water (3+4) before injection. The urine and plasma samples were after addition of internal standard applied to a Chem Elut extraction cartridge, eluted with ethyl acetate, and hexane washed. Also these samples were reconstituted in methanol/water (3+4) after evaporation. By using an MRM acquisition method in negative ionization mode, the transitions 321-->152, 321-->194 and 326-->157 were used for quantification, confirmation and internal standard, respectively. Quantification of chloramphenicol positive samples regardless of matrix could be achieved with a common water based calibration curve. The validation of the method was based on EU-decision 2002/657 and different ways of calculating CCalpha and CCbeta were evaluated. The common CCalpha and CCbeta for all matrices were 0.02 and 0.04 microg/kg for the 321-->152 ion transition, and 0.02 and 0.03 microg/kg for the 321-->194 ion transition. At fortification level 0.1 microg/kg the within-laboratory reproducibility is below 25%.

Distribution of chloramphenicol to tissues, plasma and urine in pigs after oral intake of low doses.

Toxic effects of chloramphenicol in humans caused the ban for its use in food-producing animals in the EU. A minimum required performance level (MRPL) was specified for chloramphenicol at 0.3 µg kg(-1) for various matrices, including urine. In 2012, residues of chloramphenicol were found in pig urine and muscle without signs of illegal use. Regarding its natural occurrence in straw, it was hypothesised that this might be the source, straw being compulsory for use as bedding material for pigs in Sweden. Therefore, we investigated if low daily doses of chloramphenicol (4, 40 and 400 µg/pig) given orally during 14 days could result in residues in pig tissues and urine. A dose-related increase of residues was found in muscle, plasma, kidney and urine (showing the highest levels), but no chloramphenicol was found in the liver. At the lowest dose, residues were below the MRPL in all tissues except in the urine. However, in the middle dose, residues were above the MRPL in all tissues except muscle, and at the highest dose in all matrices. This study proves that exposure of pigs to chloramphenicol in doses occurring naturally in straw could result in residues above the MRPL in plasma, kidney and especially urine.

In situ solvothermal growth of metal-organic framework-ionic liquid functionalized graphene nanocomposite for highly efficient enrichment of chloramphenicol and thiamphenicol.

Here we report a facile in situ solvothermal growth method for immobilization of metal-organic framework-ionic liquid functionalized graphene (MOF-5/ILG) composite on etched stainless steel wire. The X-ray diffraction spectra, scanning electron microscopy and transmission electron microscopy images showed that the metal organic framework possessed good crystal shape and its structure was not disturbed by the introduction of ILG. Moreover, the covalent bond established between the amino group of ILG and the carboxylic group of the metal organic framework improved the mechanical stability and structure uniformity of the microcrystals. The obtained material combined the favorable attributes of both metal-organic framework and ILG, having high surface area (820 m(2)/g) and good adsorption capability. Its adsorption properties were explored by preconcentrating chloramphenicol and thiamphenicol from aqueous solutions prior to gas chromatography-flame ionization detection. The MOF-5/ILG exhibited high enrichment capacity for the analytes as they could interact through π-π and H-bonding interaction. Under the optimum conditions, good linearity (correlation coefficients higher than 0.9981), low limits of detection (14.8-19.5 ng/L), and good precision (relative standard deviations less than 6.0% (n=5)) were achieved. The MOF-5/ILG composite displayed durable property. The method was applied to the determination of two antibiotics in milk, honey, urine and serum samples with acceptable relative recoveries of 82.3-103.2%.

Chloramphenicol serum concentration falls during chloramphenicol succinate dosing.

Chloramphenicol succinate and chloramphenicol kinetics were examined on two occasions at steady state, separated by 2 to 17 days, in 10 pediatric patients on the same intravenous dose of chloramphenicol succinate. The steady-state peak serum concentration of chloramphenicol succinate fell from an average of 77.1 micrograms/ml during the first study to 42.2 micrograms/ml during the second. The steady-state peak serum concentration of chloramphenicol also decreased from an average of 27.8 micrograms/ml to 24.9 micrograms/ml. There was a marked decrease in the steady-state trough serum concentration of chloramphenicol, which averaged 8.4 micrograms/ml during the first and 5.3 micrograms/ml at the time of the second study. Mean area under the serum concentration-time curve (AUC) of chloramphenicol succinate decreased from 59.7 micrograms . hr/ml to 24.0 micrograms . hr/ml. The AUC of chloramphenicol averaged 105.7 micrograms . hr/ml at the time of the first and decreased to 79.5 micrograms . hr/ml during the second study. Mean percent decrease in the AUC of chloramphenicol was about 28% and occurred most substantially in patients with high AUCs during the first study. Mean elimination chloramphenicol half-life was 3.0 hr during the first study and fell to 2.3 hr at the time of the second study. Our data indicate that chloramphenicol serum concentration should be monitored frequently, especially in patients not responsive to a set dose.

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.

Chloramphenicol sodium succinate kinetics in critically ill patients.

Chloramphenicol sodium succinate (SCAP) kinetics were studied in 10 critically ill patients. High-performance liquid chromatography was used to assay SCAP and chloramphenicol (CAP) in serum and urine. Total body (ClTB), metabolic (ClM), and renal (ClR) clearances of SCAP were variable. Correlations were found between creatinine clearance (Clcr) and ClTB, ClM, and ClR of SCAP (r = 0.92, p less than 0.001; r = 0.84, p less than 0.005; and r = 0.84, p less than 0.005). Recovery of SCAP in the urine also demonstrated large interpatient variability. Between 6.5% and 43.5% of the SCAP dose was recovered in the urine of 6 patients. This variability could not be explained by incomplete urine collection or by differences in renal function. Renal excretion of SCAP was shown to influence CAP serum levels. CAP ClTB was diminished, but no relationship was found between routine liver function studies and CAP ClTB. Therefore we caution the use of such relationships in using CAP in critically ill patients.

Pharmacokinetic comparison of intravenous and oral chloramphenicol in patients with Haemophilus influenzae meningitis.

The pharmacokinetics of chloramphenicol following intravenous and oral administration were studied in 14 infants with Haemophilus influenzae meningitis. Following five days of treatment with intravenous chloramphenicol (100 mg/kg/day every six hours), oral chloramphenicol was substituted at the same dose. Multiple serum levels of chloramphenicol were determined after an intravenous dose on day 4 and after an oral dose on day 10. CSF levels were measured six hours after intravenous or oral chloramphenicol dose on those days (CSF trough). Following intravenous administration, the mean peak serum level of 15.0 micrograms/ml was reached at 45 minutes. In comparison, after oral chloramphenicol in the same dosage, the mean peak serum level of 18.5 micrograms/ml was achieved at two to three hours. The mean serum half-life of the drug (6.5 hours) was significantly longer after oral administration than after intravenous chloramphenicol (4.0 hours) (P less than .001). The increased serum half-life following orally administered chloramphenicol was occasionally associated with drug accumulation. In addition, mean trough CSF levels were somewhat higher when the patient received oral medication (6.6 micrograms/ml) compared to intravenous administration (4.2 micrograms/ml) (P less than .001). For any treatment regimen for H influenzae meningitis that includes a period of oral chloramphenicol therapy the patient should be hospitalized to ensure compliance. Because of the wide range of individual variation in serum half-life that may result in accumulation, periodic monitoring of serum chloramphenicol levels is also recommended.

Prediction of maintenance dose required to attain a desired drug concentration at steady-state from a single determination of concentration after an initial dose.

Strong correlations have been reported between drug concentrations at steady-state and a single drug concentration determined sometime after an initial dose for lithium, nortriptyline, imipramine, desipramine, choramphenicol and theophylline. The mathematical basis of these relationships suggests that a one point method for predicting steady-state drug concentrations and individual dosing requirements should be widely applicable to most drugs and should be valid for patients having a wide range of drug half-lives. A method is presented for evaluating the optimum time of blood sampling to determine a drug concentration in serum of plasma that best correlates with steady-state levels and for defining the range of drug half-lives beyond which the predictive approach is likely to give poor results.