[Pharmacokinetics of chloramphenicol and tylosin in combined preparations. 2. Pharmacokinetic interaction between chloramphenicol and tylosin in calves and rats].
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Animals↗
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Results for “CHLORAMPHENICOL”
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Chloramphenicol and chloramphenicol succinate concentrations in patients with renal impairment.
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Aged↗
Nitroso-chloramphenicol: possible mediator in chloramphenicol-induced aplastic anemia.
We compared the effects of CAP and its nitroso derivative on DNA synthesis, CFU-C growth, and cell viability in human bone marrow and on mouse CFU-S viability in vitro. As previously reported from this laboratory, CAP inhibited DNA synthesis only when used in high concentrations (greater than 3 x 10(-4)M), and the inhibition was largely reversible. It also caused a reversible concentration-dependent inhibition of CFU-C growth but did not affect marrow cell viability. In sharp contrast, nitroso-CAP inhibited DNA synthesis in much lower concentrations and caused irreversible inhibition of CFU-C growth and cell death at 5 x 10(-5)M as well as irreversible mouse CFU-S damage. In a rapidly growing human lymphoid cell line, nitroso-CAP caused accumulation of cells in the G2M phase and increasing cell death within the arrested population. We have postulated from these and other observations that CAP-induced aplastic anemia occurs in the predisposed host who provides the milieu for the transformation of the p-NO2 group of the drug to toxic intermediates.
Anemia, Aplastic↗
Comparative study of the efficacy of chloramphenicol and a combination of chloramphenicol, broxyquinoline and brobanzoxaldine in the treatment of enteric fever.
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Anti-Infective Agents↗
Effect of chloramphenicol on amino Acid incorporation by chloroplasts and comparison with the effect of chloramphenicol on chloroplast development in vivo.
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Journal Article↗
A permeability barrier as a mechanism of chloramphenicol resistance in Haemophilus influenzae.
Chloramphenicol resistance in Haemophilus influenzae occurs most frequently via plasmid-mediated chloramphenicol acetyltransferase production. We studied four strains with high-level chloramphenicol resistance (MIC greater than 20 micrograms/ml) which did not have detectable chloramphenicol acetyltransferase activity. The chloramphenicol resistance determinant was transformed into a chloramphenicol-susceptible laboratory H. influenzae strain from each of the four wild-type strains, enabling isogenic comparisons. By thin-layer chromatography and a bioassay, there was no evidence of non-chloramphenicol acetyltransferase modification of chloramphenicol. In vitro protein synthesis in the presence of chloramphenicol was equivalently inhibited in the chloramphenicol-resistant transformants and in the susceptible recipient. Chloramphenicol uptake by these strains during logarithmic growth was compared by high-pressure liquid chromatographic quantitation; at chloramphenicol concentrations of 5, 10, and 20 micrograms/ml the four transformants showed a decreased rate of uptake of chloramphenicol compared with the isogenic chloramphenicol-susceptible recipient. Sodium dodecyl sulfate-polyacrylamide gel electrophoretic analysis of outer membrane proteins revealed a markedly diminished 40-kilodalton protein in the resistant transformants. We propose that the mechanism of chloramphenicol resistance in these strains is a relative permeability barrier due to the loss of an outer membrane protein.
Acetyltransferases↗
Chloramphenicol or ceftriaxone, or both, as treatment for meningitis in developing countries?
AIMS: To determine in children with meningitis whether there is any difference in mortality and neurological sequelae using chloramphenicol as first line treatment, with a change to ceftriaxone if chloramphenicol resistance is shown in vitro, compared to using ceftriaxone as first line treatment, with a change to chloramphenicol if there is no evidence of in vitro resistance. METHODS: An observational study with a retrospective control group nested within a randomised trial of fluid management for bacterial meningitis where clinical care was standardised. Chloramphenicol is standard treatment for bacterial meningitis in Papua New Guinea. In the first 150 cases we used chloramphenicol and only changed treatment to ceftriaxone if chloramphenicol resistance for cerebrospinal fluid isolates was proved. After finding 20% of Haemophilus influenzae were resistant to chloramphenicol, and that most affected children had poor outcomes, we changed to an alternative strategy. In the next 196 cases first line treatment was ceftriaxone and treatment was changed to chloramphenicol if the isolated bacteria were found to be susceptible. RESULTS: When chloramphenicol was used as first line treatment for meningitis followed by ceftriaxone when in vitro resistance was shown, there was invariably a very poor outcome in chloramphenicol resistant disease (71% of children died or had severe neurological complications). Using ceftriaxone as first line treatment was effective in reducing mortality and neurological sequelae from chloramphenicol resistant Haemophilus influenzae type (71% v 9%, relative risk 0.13; 95% CI 0.02 to 0.87; p = 0.013). Changing to chloramphenicol if there was no evidence of in vitro resistance was less than half the cost of empirical use of ceftriaxone for a full course for all children with meningitis. CONCLUSIONS: Using a third generation cephalosporin as first line treatment is effective in dealing with the problem of poor outcomes from meningitis due to Haemophilus influenzae that is resistant to chloramphenicol, and a strategy of changing to chloramphenicol if in vitro susceptibility is shown will reduce the use of expensive third generation cephalosporins without comprising on clinical outcomes. This highlights the urgent need to reduce the costs of third generation cephalosporins, to improve bacteriological services in developing countries, and to introduce effective and affordable vaccines against H influenzae and Streptococcus pneumoniae.
Anti-Bacterial Agents↗
Esterases in serum-containing growth media counteract chloramphenicol acetyltransferase activity in vitro.
The spirochete Borrelia burgdorferi was unexpectedly found to be as susceptible to diacetyl chloramphenicol, the product of the enzyme chloramphenicol acetyltransferase, as it was to chloramphenicol itself. The susceptibilities of Escherichia coli and Bacillus subtilis, as well as that of B. burgdorferi, to diacetyl chloramphenicol were then assayed in different media. All three species were susceptible to diacetyl chloramphenicol when growth media were supplemented with rabbit serum or, to a lesser extent, human serum. Susceptibility of E. coli and B. subtilis to diacetyl chloramphenicol was not observed in the absence of serum, when horse serum was used, or when the rabbit or human serum was heated first. In the presence of 10% rabbit serum, a strain of E. coli bearing the chloramphenicol acetyltransferase (cat) gene had a fourfold-lower resistance to chloramphenicol than in the absence of serum. A plate bioassay for chloramphenicol activity showed the conversion by rabbit, mouse, and human sera but not bacterial cell extracts or heated serum of diacetyl chloramphenicol to an inhibitory compound. Deacetylation of acetyl chloramphenicol by serum components was demonstrated by using fluorescent substrates and thin-layer chromatography. These studies indicate that esterases of serum can convert diacetyl chloramphenicol back to an active antibiotic, and thus, in vitro findings may not accurately reflect the level of chloramphenicol resistance by cat-bearing bacteria in vivo.
Animals↗
Chloramphenicol resistance in vancomycin-resistant enterococcal bacteremia: impact of prior fluoroquinolone use?
OBJECTIVE: The prevalence of vancomycin-resistant enterococci (VRE) has increased markedly during the past decade. Few data exist regarding the epidemiology of resistance of VRE to chloramphenicol, one of the few therapeutic options. DESIGN: Survey and case-control study. SETTING: A 725-bed, tertiary-care academic medical center and a 344-bed urban community hospital. PATIENTS: Hospitalized patients with blood cultures demonstrating VRE. METHODS: We examined the trends in the prevalence of chloramphenicol resistance in VRE blood isolates at our institution from 1991 through 2002 and conducted a case-control study to identify risk factors for chloramphenicol resistance among these isolates. RESULTS: From 1991 through 2002, the annual prevalence of chloramphenicol-resistant VRE increased from 0% to 12% (P < .001, chi-square test for trend). Twenty-two case-patients with chloramphenicol-resistant VRE bloodstream isolates were compared with 79 randomly selected control-patients with chloramphenicol-susceptible VRE. Independent risk factors for chloramphenicol-resistant VRE were prior chloramphenicol use (odds ratio [OR], 10.9; 95% confidence interval [CI95], 1.72-68.91; P = .01) and prior fluoroquinolone use (OR, 4.74; CI95, 1.15-19.42; P = .03). Chloramphenicol-resistant VRE isolates were more likely to be susceptible to beta-lactams and resistant to tetracycline than were chloramphenicol-susceptible VRE isolates. CONCLUSIONS: Significant increases in the prevalence of chloramphenicol-resistant VRE may limit the future utility of chloramphenicol in the treatment of VRE infections, and close monitoring of susceptibility trends should continue. The association between fluoroquinolone use and chloramphenicol-resistant VRE, reflecting possible co-selection of resistance, suggests that recent dramatic increases in fluoroquinolone use may have broader implications than previously recognized.
Bacteremia↗
Pharmacologic interactions among chloramphenicol, phenytoin and phenobarbital.
Bioactive chloramphenicol was measured in the sera of 34 infants and children receiving intravenous chloramphenicol succinate (25 mg/kg/dose) as therapy for meningitis, pneumonia, brain abscess or Rocky Mountain spotted fever. In 17 children receiving chloramphenicol succinate alone, mean peak and trough serum concentrations of chloramphenicol were 25.3 and 13.4 micrograms/ml, respectively. Concurrent administration of chloramphenicol succinate and phenobarbital in six patients resulted in reduced peak and trough concentrations of chloramphenicol of 16.6 and 7.5 micrograms/ml, respectively (P less than 0.05). Concurrent administration of chloramphenicol succinate and phenytoin in six patients resulted in an elevated mean peak serum concentration of chloramphenicol of 41.7 micrograms/ml (P less than 0.05). Five other patients treated with phenytoin had indeterminate serum chloramphenicol half-lives with chloramphenicol concentrations of 29 to 90 micrograms/ml. Potentially toxic chloramphenicol concentrations occurred in 9 of 17 controls, 0 of 6 patients who had received phenobarbital (P = 0.001) and 11 of 11 patients who had received phenytoin (P = 0.008). Patients receiving combined chloramphenicol succinate and anticonvulsant therapy require monitoring of serum concentrations of drug and adjustments in the dose of chloramphenicol succinate administered.
Biological Availability↗
A competitive enzyme-linked immunosorbent assay for determination of chloramphenicol.
Chloramphenicol is a broad-spectrum antibiotic shown to have specific activity against a wide variety of organisms that are causative agents of several disease conditions in domestic animals. Chloramphenicol has been banned for use in food-producing animals for its serious adverse toxic effects in humans. Due to the harmful effects of chloramphenicol residues livestock products should be free of any traces of these residues. Several analytical methods are available for chloramphenicol analysis but sensitive methods are required in order to ensure that no traces of chloramphenicol residues are present in edible animal products. In order to prevent the illegal use of chloramphenicol, regulatory control of its residues in food of animal origin is essential. A competitive enzyme-linked immunosorbent assay for chloramphenicol has been locally developed and optimized for the detection of chloramphenicol in sheep serum. In the assay, chloramphenicol in the test samples and that in chloramphenicol-horseradish peroxidase conjugate compete for antibodies raised against the drug in camels and immobilized on a microtitre plate. Tetramethylbenzidine-hydrogen peroxide (TMB/H2O2) is used as chromogen-substrate system. The assay has a detection limit of 0.1 ng/mL of serum with a high specificity for chloramphenicol. Cross-reactivity with florfenicol, thiamphenicol, penicillin, tetracyclines and sulfamethazine was not observed. The assay was able to detect chloramphenicol concentrations in normal sheep serum for at least 1 week after intramuscular injection with the drug at a dose of 25 mg/kg body weight (b.w.). The assay can be used as a screening tool for chloramphenicol use in animals.
Animals↗
Chloramphenicol resistance in Myxococcus xanthus.
Derivatives of Myxococcus xanthus FB(t) resistant to chloramphenicol (25 mug/ml) arose spontaneously with a frequency of approximately 10(-7). One of these organisms (FB(t)Cam(1) (r)) was characterized. FB(t)Cam(1) (r) showed a unique type of phenotypic instability. After transfer from medium containing chloramphenicol to medium lacking the drug, resistance was lost after approximately one generation. The loss resulted in a sharp drop in the total number of chloramphenicol-resistant organisms and was not due to segregation of chloramphenicol-susceptible organisms during growth. Cell-free extracts of strain FB(t)Cam(1) (r) converted chloramphenicol to acetyl chloramphenicols in a fashion implicating activity of chloramphenicol acetyltransferase. This activity was lost simultaneously with the loss of chloramphenicol resistance after removal of the drug from cultures. Organisms with a similar phenotype to FB(t)Cam(1) (r) could be produced at high frequencies when strain FB(t) was exposed to low concentrations of chloramphenicol (2 to 5 mug/ml), to 3-acetylchloramphenicol (25 mug/ml), or to 1,3-diacetylchloramphenicol (25 mug/ml). Since strain FB(t) is capable of deacetylating acetyl chloramphenicols, these effects are probably all due to low concentrations of chloramphenicol. In the presence of chloramphenicol, FB(t)Cam(1) (r) produced fruiting bodies and myxospores on fruiting agar; however, glycerol-induced myxospore formation was inhibited. In the absence of the antibiotic, chloramphenicol resistance was maintained by glycerol-induced myxospores.
Chloramphenicol↗
Occurrence of chloramphenicol-acetylating enzymes in various gram-negative bacilli.
The occurrence of a chloramphenicol-acetylating enzyme, similar to that found in Escherichia coli, carrying an R factor was investigated in various gram-negative bacilli. The acetylated products of chloramphenicol were identified by chromatography and quantitatively assayed after benzene extraction. The investigated strains were of the Salmonella-Arizona group, the Klebsiella-Aerobacter group, Serratia marcescens, the Proteus group, and Pseudomonas aeruginosa, most of which were isolated from 1947 to 1957. Both chloramphenicol-sensitive and -resistant strains were included, but none of them was able to transfer chloramphenicol resistance by conjugation. In the Proteus group, a significant level of a chloramphenicol-acetylating enzyme was found in most strains, whether they were sensitive or resistant to chloramphenicol; the resistant strains showed higher levels of the enzyme. Some chloramphenicol-sensitive strains lacked this enzyme. Only the sensitive strains containing the enzyme could easily produce chloramphenicol-resistant mutants with higher enzyme activity. Thus, the chloramphenicol resistance of this group can be reasonably explained on the basis of the chloramphenicol-acetylating enzyme. All of the Pseudomonas aeruginosa strains were resistant to chloramphenicol, and most strains showed low levels of the enzyme (which, however, did not appear sufficient to explain their resistance). All of the strains of the other groups (except one strain of Enterobacter cloacae) lacked the enzyme, although most strains of the Klebsiella-Aerobacter group and of S. marcescens were resistant to chloramphenicol. With respect to the origin of the resistance gene of the R factor, it is noteworthy that the strains of Proteus mirabilis isolated in 1947 possessed this enzyme before the discovery of chloramphenicol.
Acetates↗
Effect of Chloramphenicol on Denitrification in Flexibacter canadensis and "Pseudomonas denitrificans".
It was recently reported that chloramphenicol inhibits existing denitrification enzyme activity in sediments and carbon-starved cultures of "Pseudomonas denitrificans." Therefore, we studied the effect of chloramphenicol on denitrification by Flexibacter canadensis and "P. denitrificans." Production of N(inf2)O from nitrate by F. canadensis cells decreased as the concentration of chloramphenicol was increased, and 10.0 mM chloramphenicol completely inhibited N(inf2)O production. "P. denitrificans" was less sensitive to chloramphenicol, and production of N(inf2)O from nitrate was inhibited by only about 50% even in the presence of 10.0 mM chloramphenicol. These results suggested that inhibition of denitrification enzyme activity depended on the concentration of chloramphenicol. Increasing the concentration of chloramphenicol decreased the rate of production of nitrite from nitrate by F. canadensis cells, and the concentration of chloramphenicol which resulted in 50% inhibition of production of nitrite from nitrate was 2.5 mM. In contrast, the rates of production of nitrite from nitrate by intact cells and cell extracts of "P. denitrificans" were inhibited by only 58 and 54%, respectively, at a chloramphenicol concentration of 10.0 mM. Chloramphenicol caused accumulation of NO from nitrite but not from nitrate and inhibited NO consumption in F. canadensis; however, it had neither effect in "P. denitrificans." Chloramphenicol did not affect N(inf2)O consumption by these organisms. We concluded that chloramphenicol inhibits denitrification at the level of nitrate reduction and, in F. canadensis, also at the level of NO reduction.
Journal Article↗
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.
Adolescent↗
The monitoring of serum chloramphenicol levels in children with severe infections.
Serum chloramphenicol levels were evaluated in 52 children with severe infection treated intravenously with chloramphenicol succinate and orally with chloramphenicol palmitate, chloramphenicol monostearoylglycolate or chloramphenicol in capsules. Effective serum levels were recorded with all chloramphenicol preparations. The variability was largest with chloramphenicol monostearoylglycolate. In a case of neonatal Escherichia coli meningitis good serum levels of chloramphenicol were achieved with chloramphenicol palmitate orally, supporting the view that oral chloramphenicol palmitate can be used to treat serious infections in this age group. Our data and those in the literature show that monitoring of serum chloramphenicol levels in neonates is necessary. After the neonatal period monitoring of serum chloramphenicol levels is useful in avoiding too high concentrations. On the other hand, toxic effects of high concentrations can be recognized from reticulocyte and haemoglobin, neutrophil and platelet counts, which should be performed every three to four days.
Adolescent↗
Temperature-sensitive chloramphenicol acetyltransferase from Escherichia coli carrying mutant R factors.
Bacteria carrying temperature-sensitive mutant R factors for chloramphenicol resistance were isolated. In the presence of chloramphenicol, these bacteria grew at 34 C but not at 43 C. The mutations in the chloramphenicol resistance gene of the R factors affected neither the resistance of the bacteria to dihydrostreptomycin and tetracycline nor the stability of the R factors at 43 C. The chloramphenicol acetyltransferase obtained from Escherichia coli K-12 carrying the mutant R factors was heat-labile as compared with that from a strain carrying the wild-type R factor. We could not find chloramphenicol acetyltransferase activity in 17 chloramphenicol-sensitive and 5 -resistant strains (selected in vitro) of E. coli examined. The results strongly suggest that the chloramphenicol resistance gene of the R factors is the structural gene of the chloramphenicol acetyltransferase rather than the genome controlling the expression of a chromosomal determinant for the enzyme. Furthermore, the studies confirm that the existence of the chloramphenicol acetyltransferase is the primary cause of chloramphenicol resistance of bacteria carrying the R factor. Both the enzyme activity producing the monoacetyl derivative from chloramphenicol and the subsequent formation of the diacetate from the monoacetyl product were heat-labile to the same degree. The results suggest that only one enzyme participates in two steps of chloramphenicol acetylation.
Acyltransferases↗
Genetics and biochemical studies of chloramphenicol-nonproducing mutants of Streptomyces venezuelae carrying plasmid.
Chloramphenicol-nonproducing and plasmid-less mutants obtained previously by treatment with acriflavine still produced a small amount of chloramphenicol in a medium. To study the role of plasmid in chloramphenicol production, 70 chloramphenicol-nonproducing mutants were isolated by acriflavine treatment, high-temperature incubation, UV-irradiation or nitrosoguanidine treatment, starting from a producer (SVM2). Most of them did not produce any amount of chloramphenicol. One mutant, SVM2-2A7 was found to produce 1-deoxychloramphenicol instead of chloramphenicol. The mutations (cpp) affecting chloramphenicol production were analyzed by crosses with a producing strain carrying the complementing auxotrophic markers. Except for the plasmid-less strains, all Cpp mutations including the 1-deoxychloramphenicol-producing mutation were mapped between met and ilv on the chromosome. Additional crosses indicated that these chromosomal cpp mutants still carried the plasmids which had a role in increasing chloramphenicol production. Therefore, it can be concluded that the structural genes for all or most steps of chloramphenicol biosynthesis including the 3-hydroxylation of p-aminophenylalanine are located between met and ilv on the chromosome of S. venezuelae and that the plasmid plays an important role in increasing the chloramphenicol production. The activity of arylamine synthetase involved in the initial step of the chloramphenicol biosynthesis was unrelated to the presence or absence of plasmid. Moreover, the presence of plasmids was not required for host resistance to chloramphenicol.
Chemical Phenomena↗