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At least 19 recordsLinked to original sources
PubMed1991

Alternative binding modes for chloramphenicol and 1-substituted chloramphenicol analogues revealed by site-directed mutagenesis and X-ray crystallography of chloramphenicol acetyltransferase.

Leucine-160 of chloramphenicol acetyltransferase (CAT) has been replaced by site-directed mutagenesis to investigate enzyme-ligand interactions at the 1-hydroxyl substituent of the substrate chloramphenicol. The consequences of the substitution of Leu-160 by glutamine and by phenylalanine were deduced from the steady-state kinetic parameters for acetyl transfer from acetyl-CoA to the 3-hydroxyl of chloramphenicol and its analogues 1-deoxychloramphenicol and 1-acetylchloramphenicol. The acetyl group of the latter, which is a substrate both in vivo and in vitro, could potentially bind in a similar position to the 1-hydroxyl of chloramphenicol, in close proximity to the side chain of Leu-160. In the case of Gln-160 CAT, large increases in Km for the three acetyl acceptors were accompanied by small decreases in kcat and in apparent affinity for acetyl-CoA. Such results are consistent with the introduction of the relatively hydrophilic amide in place of the delta-methyl groups of Leu-160. The kinetic properties of Phe-160 CAT were unexpected in that Km for each of the three acetyl acceptors was unchanged or reduced, compared to the equivalent parameters for the wild-type enzyme, whereas kcat fell significantly (44-83-fold) in each case. The ratios of specificity constants (kcat/Km) for the acetylation of chloramphenicol compared with the alternative acyl acceptors were similar for wild-type and mutant enzymes. As the residue substitutions for Leu-160 do not result in enhanced discrimination against the binding and acetylation of 1-acetylchloramphenicol, it appears unlikely that the 1-acetyl group binds to the CAT active site in the same position as that occupied by the 1-hydroxyl of chloramphenicol.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylation↗
PubMed1980

High-pressure liquid chromatographic assay for chloramphenicol, chloramphenicol-3-monosuccinate, and chloramphenicol-1-monosuccinate.

A high-pressure liquid chromatographic method for the sensitive and rapid determination of chloramphenicol, chloramphenicol-3-monosuccinate, and chloramphenicol-1-monosuccinate is presented. The procedure utilizes a reversed-phase chromatographic column with UV absorption detection. The assay is useful for monitoring patients receiving chloramphenicol, determining the pharmacokinetics of parenteral chloramphenicol sodium succinate, and certifying sterile chloramphenicol sodium succinate.

Blood Proteins↗
PubMedDate not supplied

Clinical pharmacokinetics of chloramphenicol and chloramphenicol succinate.

In recent years there has been a renewal of interest in chloramphenicol, predominantly because of the emergence of ampicillin-resistant Haemophilus influenzae, the leading cause of bacterial meningitis in infants and children. Three preparations of chloramphenicol are most commonly used in clinical practice: a crystalline powder for oral administration, a palmitate ester for oral administration as a suspension, and a succinate ester for parenteral administration. Both esters are inactive, requiring hydrolysis to chloramphenicol for anti-bacterial activity. The palmitate ester is hydrolysed in the small intestine to active chloramphenicol prior to absorption. Chloramphenicol succinate acts as a prodrug, being converted to active chloramphenicol while it is circulating in the body. Various assays have been developed to determine the concentration of chloramphenicol in biological fluids. Of these, high-performance liquid chromatographic and radioenzymatic assays are accurate, precise, specific, and have excellent sensitivities for chloramphenicol. They are rapid and have made therapeutic drug monitoring practical for chloramphenicol. The bioavailability of oral crystalline chloramphenicol and chloramphenicol palmitate is approximately 80%. The time for peak plasma concentrations is dependent on particle size and correlates with in vitro dissolution and deaggregation rates. The bioavailability of chloramphenicol after intravenous administration of the succinate ester averages approximately 70%, but the range is quite variable. Incomplete bioavailability is the result of renal excretion of unchanged chloramphenicol succinate prior to it being hydrolysed to active chloramphenicol. Plasma protein binding of chloramphenicol is approximately 60% in healthy adults. The drug is extensively distributed to many tissues and body fluids, including cerebrospinal fluid and breast milk, and it crosses the placenta. Reported mean values for the apparent volume of distribution range from 0.6 to 1.0 L/kg. Most of a chloramphenicol dose is metabolised by the liver to inactive products, the chief metabolite being a glucuronide conjugate; only 5 to 15% of chloramphenicol is excreted unchanged in the urine. The elimination half-life is approximately 4 hours. Inaccurate determinations of the pharmacokinetic parameters may result by incorrectly assuming rapid and complete hydrolysis of chloramphenicol succinate. The pharmacokinetics of chloramphenicol succinate have been described by a 2-compartment model. The reported values for the apparent volume of distribution range from 0.2 to 3.1 L/kg.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1981

Relative bioavailability of intravenous chloramphenicol succinate and oral chloramphenicol palmitate in infants and children.

The relative bioavailability of intravenously administered chloramphenicol succinate and orally administered chloramphenicol palmitate was compared in 18 children, age 2 months to 14 years. The area under the serum concentration vs time curve of chloramphenicol and urinary excretion of chloramphenicol succinate were determined in each child under steady-state conditions while receiving chloramphenicol succinate and again while receiving chloramphenicol palmitate. The mean AUC was significantly greater during oral therapy compared to intravenous therapy (110 vs 78 mg hr/L, P less than 0.001). The relative bioavailability of chloramphenicol succinate was 70% compared to chloramphenicol palmitate. This could be explained by the mean loss of 36% of the intravenous dose in the urine as unhydrolyzed chloramphenicol succinate. The intravenous dose of chloramphenicol succinate did not correlate with AUC (r = 0.193). However, there was a significant correlation between the oral dose of chloramphenicol palmitate and AUC (r = 0.429, P = 0.025). The bioavailability of orally administered chloramphenicol palmitate is superior to that of chloramphenicol succinate given intravenously. Furthermore, there is a greater correlation between dose and amount of active drug in the body when the oral preparation is used. Oral administration of chloramphenicol palmitate appears to offer significant therapeutic advantages in patients who can tolerate medication given orally.

Administration, Oral↗
PubMed1977

Studies on the concentrations of chloramphenicol in the serum and cerebrospinal fluid of neonates, infants, and small children. Reciprocal reactions between chloramphenicol, penicillin and phenobarbitone.

The interactions between chloramphenicol, penicillin and phenobarbitone were investigated in 383 children (premature and neonate children, infants and small children). As expected, the chloramphenicol concentrations in the serum of the newborns was considerably higher than that of infants and small children with the same dosage of chloramphenicol. In the age group of the premature and newborn children and infants there was significantly higher total chloramphenicol concentrations with the chloramphenicol-penicillin combination than with chloramphenicol monotherapy. Addition of phenobarbitone to the combination significantly reduced the chloramphenicol concentrations in the neonates. Lowering of the serum chloramphenicol concentrations by phenobarbitone could not be statistically confirmed in the infant age group. Combinations of chloramphenicol with ampicillin, gentamycin or cephalosporin derivatives showed no influence on serum chloramphenicol concentrations. Transference of chloramphenicol from the serum to the cerebrospinal fluid was about twice as high in the acute inflammatory stage as when the meninges were no longer acutely diseased (60 and 30% respectively of the serum concentrations). The passage of chloramphenicol to the cerebrospinal fluid showed no dependence on age.

Age Factors↗
PubMed1981

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.

Adolescent↗
PubMed1983

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.

Adolescent↗
PubMed1983

Comparative bioavailability and pharmacokinetics of chloramphenicol after intravenous chloramphenicol succinate in premature infants and older patients.

The bioavailability of chloramphenicol and the pharmacokinetics of chloramphenicol and chloramphenicol succinate were studied in 5 premature infants (group A), 8 full-term infants (group B) and 4 children (group C) receiving intravenous chloramphenicol succinate at steady-state. Although the total body clearances of chloramphenicol succinate were similar in the three groups, its renal clearance, 0.78 +/- 1.13 ml/min/kg, in group A was markedly lower than 4.11 +/- 2.41 ml/min/kg in group B (p less than 0.05) and 7.31 +/- 2.85 ml/min/kg in group C (p less than 0.05). The bioavailability of chloramphenicol, 0.93 +/- 0.10, in group A was considerably higher as compared to 0.71 +/- 0.14 in group B (p = 0.06) and 0.64 +/- 0.13 in group C (p less than 0.05). The elimination half-life of chloramphenicol, 10.08 +/- 6.88 h, in group A was longer than 3.48 +/- 1.52 h in group B (p less than 0.05) and 4.86 +/- 2.41 h in group C (p = 0.06). The increased bioavailability of chloramphenicol in premature infants was a result of the decreased renal clearance of chloramphenicol succinate causing a greater fraction of the chloramphenicol succinate dose to be hydrolyzed to chloramphenicol.

Biological Availability↗
PubMed1980

A study of the enzymatic inactivation of chloramphenicol by highly purified chloramphenicol acetyltransferase.

We report the purification of chloramphenicol acetyltransferase (acetyl-CoA:chloramphenicol 3-O-acetyltransferase, EC 2.3.1.28) by a two-step procecdure involving chromatography on a Sepharose 4B-reduced chloramphenicol matrix and DEAE-Sephadex A-50. This procedure resulted in a 120-fold purification with 50% recovery of the enzyme. Only one band of enzyme activity was present after electrophoresis on polyacrylamide gel. The enzyme is active over a broad pH range, maximal activity being observed near pH 7.6. Both chloramphenicol 1-acetate of chloramphenicol 3-acetate were found to be very stable in Tris-maleate buffer at pH 6.09 with negligible interconversion. The incubation at pH 6.0 of chloramphenicol 1-acetate with the purified chloramphenicol acetyltransferase yielded chloramphenicol 1,3-diacetate. These data indicate that the enzyme acetylates specifically at the 3-hydroxy position and the diacetylation is possible only because of non-enzymatic interconversion of chloramphenicol 3-acetate to chloramphenicol 1-acetate at higher pH values.

Acetylation↗
PubMed1990

Initial treatment of bacterial meningitis in Yaounde, Cameroon: theoretical benefits of the ampicillin-chloramphenicol combination versus chloramphenicol alone.

A prospective 6-month study in Yaounde evaluated 49 children aged from 2 months to 8 years, hospitalized with bacterial meningitis. They were randomly assigned to one of two initial treatment groups, either an ampicillin-chloramphenicol combination (group A) or chloramphenicol alone (group B). The majority of patients were infected with Haemophilus influenzae, and the majority of deaths were caused by Streptococcus pneumoniae. Altogether, 17.9% of Haemophilus influenzae isolates were ampicillin-resistant and 3.6% chloramphenicol-resistant. We found no isolate resistant to both antibiotics. Response to both treatments was similar in both groups. The theoretical risk of treatment failure with ampicillin was higher than with the ampicillin-chloramphenicol combination (p less than 0.05). There was no statistically significant difference between the risk of treatment failure with the ampicillin-chloramphenicol combination and the risk with chloramphenicol alone (p less than 0.05), but the latter was increased by the occurrence of chloramphenicol-resistant isolates of Streptococcus pneumoniae (11.1%). Although treatment with an ampicillin-chloramphenicol combination is four times more expensive than treatment with chloramphenicol alone, costwise it is also one-quarter the price of a third-generation cephalosporin (moxalactam). At present, the ampicillin-chloramphenicol combination can be suggested as the first choice for initial treatment considering both the epidemiological data and the cost/efficiency ratio in the area of Yaounde.

Ampicillin↗
PubMed2002

Inactivation of the acrA gene is partially responsible for chloramphenicol sensitivity of Escherichia coli CM2555 strain expressing the chloramphenicol acetyltransferase gene.

An Escherichia coli CM2555 strain, sensitive to chloramphenicol when expressing the cat gene and producing active chloramphenicol acetyltransferase (CAT), was described recently. It was proposed that this sensitivity is due to decreased levels of acetyl coenzyme A (Acetyl CoA) in cat-expressing CM2555 cells in the presence of chloramphenicol. CAT catalyzes transfer of the acetyl moiety from Acetyl CoA to a chloramphenicol molecule. Thus, a very efficient acetylation of chloramphenicol may cause deprivation of Acetyl CoA and cell death. A specific mutation causing the chloramphenicol sensitivity phenotype of CM2555 was not reported to date. Therefore, we aimed to identify a genetic defect causing this phenotype. Here, we found that overexpression of the acrEF genes, encoding a transmembrane pump, or the acrE gene alone, results in restoration of chloramphenicol-resistance of cat-expressing CM2555 strain. Although no mutation exists in the CM2555 acrE locus, a nonsense mutation in the 67th codon of the acrA gene, which encodes a component of another transmembrane pump, has been found. Although introduction of the deltaacrAB allele into CM732, a parental strain of CM2555, and into some other commonly used E. coli strains led to their chloramphenicol sensitivity in the presence of CAT, the same genetic manipulation did not result in such a phenotype in other genetic backgrounds, including "wild-type" E. coli MG1655. These results suggest that the acrA dysfunction is one of more mutations responsible for chloramphenicol sensitivity of cat-expressing CM2555 strain.

Bacterial Proteins↗
PubMed1981

Pharmacokinetics of chloramphenicol and chloramphenicol succinate in infants and children.

The metabolism and elimination of chloramphenicol-3-monosuccinate was studied in 45 infants and children, ages 3 days to 16 years, during intravenous administration. The apparent half-life of chloramphenicol was extremely variable, ranging from 1.7 to 12.0 hours with a mean of 5.1 hours. Apparent half-lives were inversely correlated with age. Chloramphenicol-S serum concentration declined biexponentially in most patients, with an estimated mean initial half-life of 0.7 hours and a subsequent longer mean half-life of 2.2 hours. Chloramphenicol-S persisted in serum up to six hours after a dose, and comprised a significantly larger fraction of total chloramphenicol in the serum of infants under one month of age than in older infants and children. A widely variable fraction of the administered chloramphenicol-S dose, with a mean of 33%, was excreted in the urine unchanged and was, therefore, not bioavailable in active form. Mean renal clearance of chloramphenicol-S was 259.5 ml/minute/1.73 M2, four times the mean creatinine clearance, indicating active tubular secretion. Variable hydrolysis and renal elimination of nonhydrolyzed chloramphenicol-S reduces the bioavailability of the antibiotic and appears to contribute substantially to the wide variation in apparent half-life and poor correlation between dose and serum concentration of free chloramphenicol.

Adolescent↗
PubMed1985

Resistance to chloramphenicol in Proteus mirabilis by expression of a chromosomal gene for chloramphenicol acetyltransferase.

Proteus mirabilis PM13 is a well-characterized chloramphenicol-sensitive isolate which spontaneously gives rise to resistant colonies on solid media containing chloramphenicol (50 micrograms ml-1) at a plating efficiency of 10(-4) to 10(-5). Such chloramphenicol-resistant colonies exhibit a novel phenotype with respect to chloramphenicol resistance. When a single colony grown on chloramphenicol agar is transferred to liquid medium and grown in the absence of antibiotic for 150 generations, a population of predominantly sensitive cells arises. This mutation-reversion phenomenon has been observed in other Proteus species and Providencia strains, wherein resistance has been shown to be mediated in each case by the enzyme chloramphenicol acetyltransferase. The cat gene responsible for the phenomenon is chromosomal and can be cloned from P. mirabilis PM13 with DNA prepared from cells grown in the absence or the presence of chloramphenicol. Recombinant plasmids which confer resistance to chloramphenicol carry an 8.5-kilobase PstI fragment irrespective of the source of host DNA. The location of the cat gene within the PstI fragment was determined by Southern blotting with a cat consensus oligonucleotide corresponding to the expected amino acid sequence of the active site region of chloramphenicol acetyltransferase, and the direction of transcription was deduced from homology with the type I cat variant.

Acetyltransferases↗
PubMed1983

Chloramphenicol-mediated DNA damage and its possible role in the inhibitory effects of chloramphenicol on DNA synthesis.

Studies were undertaken to examine the interaction of chloramphenicol and some of its analogs with DNA in an effort to elucidate the mechanism by which high levels of the drug cause inhibition of DNA synthesis. Chloramphenicol at concentrations of 1 mM and above was found to mediate the degradation of double-stranded DNA in the presence of copper and a reducing agent. Similarly, the L-threo steroisomer of chloramphenicol was equally potent at causing strand scissions in DNA. Nitroso-chloramphenicol, which inhibits DNA synthesis at much lower concentrations, also causes DNA damage at levels 100-fold lower than chloramphenicol. In contrast, thiamphenicol, which has a methyl-sulfonyl group in place of the nitro group at the para position, neither affects DNA synthesis nor causes DNA degradation under the conditions tested. The good correlation between the inhibition of DNA synthesis and the generation of strand-scissions by this series of analogs suggests that damage to DNA may be responsible for the inhibition of DNA synthesis seen with chloramphenicol, rather than an interaction of chloramphenicol with DNA polymerase. This proposal is further substantiated by studies with a DNA polymerase in a cell-free system. There was no inhibition of DNA synthesis when any of the analogs were added directly to the polymerase reaction mixture. However, a significant, time-dependent reduction in DNA synthesis was seen when the DNA template used for the polymerase assay was preincubated with chloramphenicol or nitroso-chloramphenicol prior to its use in the assay, again suggesting damage to DNA as the mechanism involved.

Chloramphenicol↗
PubMed1986

Analysis of the regulatory sequences needed for induction of the chloramphenicol acetyltransferase gene cat-86 by chloramphenicol and amicetin.

Induction of the chloramphenicol acetyltransferase gene cat-86 in Bacillus subtilis results from the activation of translation of cat-86 mRNA. The inducers, chloramphenicol and amicetin, are thought to enable ribosomes to destabilize a stem-loop structure in cat-86 mRNA that sequesters the ribosome binding site for the cat-86 coding sequence, designated RBS-3. The region of cat-86 mRNA which is 5' to the stem-loop contained two additional ribosome binding sites, RBS-1 and RBS-2, located 84 and 56 nucleotides, respectively, upstream from RBS-3. RBS-1 and RBS-2 were each followed by a potential translation initiation codon and a short open reading frame. Bal 31-generated deletions into the 5' end of the regulatory region that removed RBS-1 but did not enter RBS-2 caused a fourfold decrease in the uninduced and chloramphenicol-induced level of cat-86 expression and a more than 10-fold reduction in the amicetin-induced level of expression. Deletions that removed both RBS-1 and RBS-2 but did not enter the stem-loop abolished both chloramphenicol- and amicetin-inducible expression. These data indicate that RBS-2 and sequences 3' to RBS-2 are minimally essential to chloramphenicol induction. However, the presence of RBS-1 in the mRNA elevated the maximum level of expression obtained during chloramphenicol induction. These studies also demonstrate that induction of cat-86 by amicetin is highly dependent on RBS-1. To determine whether a correlation existed between RBS-1 and amicetin inducibility, we examined the sequence of the regulatory regions for two natural variants of cat-86, cat-66 and cat-57, which are chloramphenicol inducible but are very poorly induced by amicetin. Both contained nucleotide sequence differences from cat-86 in the vicinity of RBS-1 that would prevent translation of the leader peptide associated with RBS-1 in cat-86. In contrast, the regulatory regions got the three genes were virtually identical in the vicinity of RBS-2. These data indicate that efficient induction by amicetin requires sequences that are not essential for induction by chloramphenicol.

Acetyltransferases↗
PubMed1984

Chloramphenicol-inducible gene expression in Bacillus subtilis is independent of the chloramphenicol acetyltransferase structural gene and its promoter.

cat-86 specifies chloramphenicol acetyltransferase and is the indicator gene on the Bacillus subtilis promoter cloning plasmid pPL703. Insertion of promoters from various sources into pPL703 at a site ca. 144 base pairs upstream from cat-86 activates expression of cat-86, and the expression is characteristically inducible by chloramphenicol. Thus, chloramphenicol inducibility of cat-86 is independent of the promoter that is used to activate the gene. To determine whether cat-86 or its products were involved in chloramphenicol inducibility, gene replacement studies were performed. cat-86 consists of 220 codons. The lacZ gene from Escherichia coli was inserted into a promoter-containing derivative of pPL703, plasmid pPL603E, at two locations within cat-86. pPL3lac2 contains lacZ inserted in frame after codon 2 of cat-86. pPL3lac30 contains lacZ inserted in frame after codon 30 of cat-86. In both constructions, all cat coding sequences 3' to the site of the lacZ insertion were deleted. Both plasmids exhibited chloramphenicol inducibility of beta-galactosidase in B. subtilis. These studies provide the first direct demonstration that the transcription and translation products of a chloramphenicol-inducible cat gene are uninvolved in chloramphenicol inducibility of gene expression. The results localize the region essential to inducibility to the 144-base pair segment that intervenes between the site of promoter insertion and the cat-86 gene.

Acetyltransferases↗