[The detection and semiquantitative determination of non-esterified chloramphenicol in chloramphenicol-hydrogen succinate and chloramphenicol sodium succinate].
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Chloramphenicol↗
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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↗
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↗
Combined action of chloramphenicol and ampicillin on chloramphenicol-resistant Haemophilus influenzae.
The interaction of ampicillin and chloramphenicol on three ampicillin-susceptible, chloramphenicol-resistant strains of Haemophilus influenzae was studied by checkerboard testing with subcultures, time-kill experiments, and a disk method. In all three strains there was inhibition of the bactericidal action of ampicillin by chloramphenicol at concentrations close to the MIC (10 micrograms/ml). This chloramphenicol concentration was close to that which might be achieved in cerebrospinal fluid during treatment for meningitis and was in the bactericidal range for chloramphenicol-susceptible organisms. It is suggested however that in the initial treatment of meningitis caused by ampicillin-susceptible, chloramphenicol-resistant strains, inhibition of the action of ampicillin by chloramphenicol may represent a clinical risk.
Ampicillin↗
Kinetics of induction and purification of chloramphenicol acetyltransferase from chloramphenicol-resistant Staphylococcus aureus.
Plasmid-mediated chloramphenicol resistance in Staphylococcus aureus has been shown to involve acetylation of chloramphenicol by an enzyme induced by growth in the presence of the antibiotic and certain analogues. Analysis of the kinetics of induction has been complicated by (i) the intrinsic inhibitory effects of chloramphenicol on induced enzyme synthesis and (ii) the rapid disappearance of inducer after synthesis of the acetylating enzyme. The compound related to d-threo chloramphenicol which lacks a C(3) hydroxyl substituent (3-deoxychloramphenicol) is a potent inducer of chloramphenicol acetyltransferase but is ineffective as an antibiotic and is not a substrate for the enzyme. The availability of such a "gratuitous" inducer has simplified an analysis of the kinetics of induction of chloramphenicol acetyltransferase. The enzyme from induced bacteria has been purified to homogeneity and has been compared with the analogous enzyme present in E. coli which harbors a resistance transfer factor with the chloramphenicol resistance determinant.
Acyltransferases↗
Distribution of chloramphenicol acetyltransferase and chloramphenicol-3-acetate esterase among Streptomyces and Corynebacterium.
Chloramphenicol-3-acetate esterase activity was detected in cell-free extracts of strains of Streptomyces venezuela, Streptomyces sp. and Streptosporangium viridogriseum var. kofuense which produced chloramphenicol and also Corynebacterium hydrocarboclastus which produced chloramphenicol analogs (corynecins). None of the cell-free extracts of chloramphenicol- or corynecin-producing strains possessed chloramphenicol acetyltransferase activity under conditions which avoided the influenced of the esterase activity. Among 20 strains examined that did not produce chloramphenicol, chloramphenicol acetyltransferase was detected in cell-free extracts of one strain of Streptomyces coelicolor Müller and one strain of S. fradiae ISP5063.
Acetyltransferases↗
Occurrence of chloramphenicol acetyltransferase and Tn9 among chloramphenicol-resistant enteric bacteria from humans and animals.
The occurrence of chloramphenicol acetyltransferase (CAT) among chloramphenicol resistant enteric bacteria from humans, animals (cats, dogs) and sewage was examined. The enzyme appears to be the basis of resistance in 83 and 84 per cent of bacteria of humans and sewage origin, and in 50 per cent of bacteria from animals. In order to identify type I CAT among chloramphenicol resistant isolates, total cellular DNA was probed with a 32P-labelled fragment of the CAT structural gene from the transposable element Tn9. Nineteen per cent of chloramphenicol resistant enteric bacteria of clinical origin, 11% of sewage isolates, and 11% of veterinary isolates gave positive hybridization results. The difference between bacteria of clinical and veterinary origin in respect of both parameters tested is significant and is interpreted as indicating genetic dis similarity between the two pools in regard to chloramphenicol resistance. This may reflect a lack of contact between the two pools, or host bacterial factors with select against CAT-mediated (and type I CAT more specifically) resistance to chloramphenicol.
Acetyltransferases↗
Rosanilins: indicator dyes for chloramphenicol-resistant enterobacteria containing chloramphenicol acetyltransferase.
Rosanilin dyes such as crystal violet and basic fuchsin have been used as indicator dyes in solid growth medium for chloramphenicol-resistant enterobacterial colonies containing the enterobacterial resistance enzyme chloramphenicol acetyltransferase (CAT). On certain media containing rosanilins, cells containing CAT formed darker colonies than cells not containing CAT. Contrast was affected by the types and concentrations of complex nutrients, sugars salts, and rosanilin dyes present. When crystal violet was used as the indicator dye, contrast could not be obtained for strains whose growth was partially inhibited by crystal violet. Contrast could not be obtained between yeast colonies with and without the enterobacterial resistance enzyme, between Bacillus subtilis colonies with and without the staphylococcal resistance enzyme, or between enterobacterial colonies with and without the staphylococcal resistance enzyme. The darker coloration of enterobacterial colonies with the enterobacterial enzyme was due to the binding of dye to enzyme. Rosanilin dues have been used to score resistance phenotypes by colony color, to detect chloramphenicol-sensitive sectors in chloramphenicol-resistant colonies, and to screen for occasional chloramphenicol-sensitive cells in a resistant population during cloning by insertional inactivation of the chloramphenicol resistance gene.
Acetyltransferases↗
Relationship between in vitro susceptibility test results for chloramphenicol and production of chloramphenicol acetyltransferase by Haemophilus influenzae, Streptococcus pneumoniae, and Aerococcus species.
Haemophilus influenzae, Streptococcus pneumoniae, and Aerococcus species were tested for susceptibility to chloramphenicol by standard broth microdilution and disk-diffusion methods. MICs and zone diameter breakpoints were correlated with production of chloramphenicol acetyltransferase (CAT). A comparison of MICs and zone diameters indicated that the interpretative criteria for H. influenzae and S. pneumoniae should be an MIC of less than or equal to 4 micrograms/ml or a zone diameter greater than or equal to 25 mm for susceptible strains and an MIC of greater than or equal to 8 micrograms/ml or a zone diameter of less than or equal to 20 mm for resistant strains; for Aerococcus species, interpretative criteria should be an MIC of less than or equal to 8 micrograms/ml or a zone diameter of greater than or equal to 20 mm for susceptible strains and an MIC of greater than or equal to 32 micrograms/ml or a zone diameter of less than or equal to 12 mm for resistant strains. All but four strains of H. influenzae and one strain of S. pneumoniae that were resistant to chloramphenicol by these criteria produced CAT. For Aerococcus species, however, chloramphenicol-resistant strains were negative for CAT as determined by a commercially available disk test. When comparing susceptibility results with CAT production, thiamphenicol was a better indicator of the presence of the enzyme than chloramphenicol and may be useful in assaying resistance to chloramphenicol.
Chloramphenicol↗
Chloramphenicol alone versus chloramphenicol plus penicillin for bacterial meningitis in children.
367 children with cerebrospinal-fluid findings suggestive of bacterial meningitis were randomised to receive either chloramphenicol alone by intramuscular injection, or chloramphenicol plus penicillin by intravenous injection. Sequential analysis showed no difference in mortality between the two treatments. 48 (26%) of the 183 children in the chloramphenicol alone group died, and 49 (27%) of the 184 children in the chloramphenicol plus penicillin group died. In children with bacterial meningitis chloramphenicol alone given by intramuscular injection is as effective as chloramphenicol plus penicillin given intravenously.
Bacterial Infections↗
Chloramphenicol alone versus chloramphenicol plus penicillin for severe pneumonia in children.
748 children with severe pneumonia in three hospitals in Papua New Guinea were randomised to receive intramuscular injections of either chloramphenicol alone or chloramphenicol plus penicillin. Sequential analysis showed no difference between the two treatments. 48 (13%) of the 377 children in the chloramphenicol alone group died, and 3 (0.8%) were changed to different treatment. 62 (17%) of the 371 children in the chloramphenicol-plus-penicillin group died, and 6 (1.6%) were changed to different treatment. The difference in failure rates (death or withdrawal for change of treatment) was 4.8% +/- 5.2% (+/- 95% confidence limits). In children with severe pneumonia, treatment with chloramphenicol alone is as effective as treatment with chloramphenicol plus penicillin.
Child↗
The safety and efficacy of topical norfloxacin compared with chloramphenicol for the treatment of external ocular bacterial infections. The Norfloxacin-Chloramphenicol Ophthalmic Study Group.
Two hundred and forty-six patients with signs of acute bacterial conjunctivitis and/or blepharitis were randomised to receive either norfloxacin or chloramphenicol for one week in this double-masked parallel group study. Ninety-two per cent of the norfloxacin-treated patients and 93% of the chloramphenicol-treated patients were rated as either clinically improved or cured at the end of the treatment period. Based upon pre-treatment bacteriological cultures, 31.3% of the patients had significant bacterial infection of the lids and/or conjunctiva. All of these culture-positive patients were rated as either clinically improved or cured. Based upon post-treatment cultures, 72 of 82 strains of Gram-positive and Gram-negative bacteria were eradicated or suppressed following treatment with either norfloxacin or chloramphenicol. However six of 41 strains persisted for norfloxacin and four of 41 for chloramphenicol. Two norfloxacin-treated patients and three chloramphenicol-treated patients had adverse experiences, predominantly ocular discomfort, which required cessation of drug therapy. Norfloxacin appears to be an effective and relatively safe agent for the treatment of bacterial infections of the lids and/or conjunctiva. In this study, norfloxacin was clinically and microbiologically similar in activity to chloramphenicol.
Acute Disease↗
Response of typhoid fever caused by chloramphenicol-susceptible and chloramphenicol-resistant strains of Salmonella typhi to treatment with trimethoprim-sulfamethoxazole.
Chloramphenicol remains the drug of choice for the treatment of typhoid fever in most areas despite the risks of relapses and toxicity. In a comparison of the efficacy of trimethoprim-sulfamethoxazole (TMP-SMZ) and chloramphenicol against typhoid fever, 60 patients in Indonesia were randomly assigned to receive either TMP-SMZ (320 mg of TMP and 1,600 mg of SMZ daily) or chloramphenicol (2 g daily) for 14 days. TMP-SMZ was significantly more effective in sterilizing the blood, but the two drugs were equally effective with regard to relapse rate, frequency of prolonged fever, and mortality. Use of TMP-SMZ in Vietnam for the treatment of typhoid fever caused by chloramphenicol-resistant Salmonella typhi showed that TMP-SMZ is as effective as ampicillin. Likewise, a review of other published reports suggests that TMP-SMZ has an overall record in the treatment of typhoid fever that is equal to or better than the records of other available drugs. TMP-SMZ has emerged as a satisfactory alternative to chloramphenicol for the treatment of typhoid fever and should be especially useful in areas where chloramphenicol-resistant S. typhi has been isolated.
Adolescent↗
Comparison of trimethoprim-sulfamethoxazole and amoxicillin in therapy of chloramphenicol-resistant and chloramphenicol-sensitive typhoid fever.
The efficacy of orally administered trimethoprim-sulfamethoxazole was compared with that of oral amoxicillin in therapy of typhoid fever due to both epidemic chloramphenicol-resistant and endemic chloramphenicol-sensitive Salmonella typhi. Both drug regimens were effective and of comparable value in treatment of chloramphenicol-resistant infections, as measured by duration of fever (124 hr and 115 hr, respectively) and duration of bacteremia (1.0 and 0.4 days, respectively). Trimethoprim-sulfamethoxazole therapy of infections due to chloramphenicol-sensitive S. typhi resulted in more rapid lysis of fever than did amoxicillin therapy. Trimethoprim and sulfamethoxazole were not synergistic in vitro against the chloramphenicol-resistant strain of S. typhi, and the role of sulfamethoxazole in treatment of such infections appears to be minimal. Oral administration of trimethoprim-sulfamethoxazole is effective therapy of chloramphenicol-resistant, and probably of ampicillin-amoxicillin-resistant, typhoid fever.
Adolescent↗
[Need for the determination of chloramphenicol levels in the treatment of bacterial-purulent meningitis with chloramphenicol succinate in infants and small children].
17 cases of purulent meningitis in 15 children, aged 1 day to 5 years (median 8 months) were treated with continuous i.v. infusion of chloramphenicol succinate. Free chloramphenicol in serum and cerebrospinal fluid (C.F.) was assayed by high performance liquid chromatography (HPLC). CF chloramphenicol levels averaged 45 +/- 14% of the serum level. Out of 16 patients only five received the usually recommended dosage. In three others because of initially or progressively high serum levels the dose had to be diminished. In eight others because of subtherapeutic levels the dose had to be raised. The highest dose (390 mg/kg body weight/d) was required in a 2 month old boy. He was shown to have a clearance rate for free chloramphenicol considerably higher than has been reported so far. Maturation of the metabolism could be observed in a small-for-date newborn who acquired a grey baby syndrome during the treatment of his first meningitis. Several weeks later he required exactly the recommended dose to reach therapeutic chloramphenicol levels. As a consequence of these observations we strongly recommend meticulous drug monitoring of chloramphenicol in order to meet the large biological variations seen particularly in neonates and young infants in their capacity to reach and maintain therapeutic serum levels.
Bacterial Infections↗
3-(Bromoacetyl)chloramphenicol, an active site directed inhibitor for chloramphenicol acetyltransferase.
Bacterial resistance to the antibiotic chloramphenicol is normally mediated by chloramphenicol acetyltransferase (CAT), which utilizes acetyl coenzyme A as the acyl donor in the inactivation reaction. 3-(Bromoacetyl)chloramphenicol, an analogue of the acetylated product of the forward reaction catalyzed by CAT, was synthesized as a probe for accessible and reactive nucleophilic groups within the active site. Extremely potent covalent inhibition was observed. Affinity labeling was demonstrated by the protection afforded by chloramphenicol at concentrations approaching Km for the substrate. Inactivation was stoichiometric, 1 mol of the inhibitor covalently bound per mole of enzyme monomer, with complete loss of both the acetylation and hydrolytic activities associated with CAT. N3-(Carboxymethyl)histidine was identified as the only alkylated amino acid, implicating the presence of a unique tautomeric form of a reactive imidazole group at the catalytic center. The proteolytic digestion of CAT modified with 3-(bromo[14C]-acetyl)chloramphenicol yielded three labeled peptide fractions separable by reverse-phase high-pressure liquid chromatography. Each peptide fraction was sequenced by fast atom bombardment mass spectrometry; the labeled peptide in each case was found to span the highly conserved region in the primary structure of CAT, which had been tentatively assigned as the active site. The rapid, stoichiometric, and specific alkylation of His-189, taken together with the high degree of conservation of the adjacent amino acid residues, strongly suggests a central role for His-189 in the catalytic mechanism of CAT.
Acetyltransferases↗
Chloramphenicol induces translation of the mRNA for a chloramphenicol-resistance gene in Bacillus subtilis.
cat-86 is a plasmid gene specifying chloramphenicol-inducible chloramphenicol acetyltransferase activity in Bacillus subtilis. Inducibility has been suggested to result primarily from activation of the translation of cat-86 mRNA by subinhibitory levels of chloramphenicol. To directly test the involvement of transcription in cat-86 induction, the gene was transcriptionally activated with a strong promoter, resulting in the synthesis of relatively high levels of cat-86 mRNA in uninduced cells. When RNA synthesis was blocked with rifampin (100 micrograms/ml), de novo inducibility of cat-86 by chloramphenicol could be demonstrated for more than 30 min. These results indicate that concurrent transcription is not essential for cat-86 induction. Accordingly, cat-86 is one of only a few inducible bacterial genes in which the primary form of regulation is at the translational level. This form of regulation may apply to other cat genes of Gram-positive origin whose expression is also inducible by chloramphenicol.
Acetyltransferases↗
Chloramphenicol resistance that does not involve chloramphenicol acetyltransferase encoded by plasmids from gram-negative bacteria.
Chloramphenicol resistance-specifying plasmids from incompatibility groups P-1 and C did not encode chloramphenicol acetyltransferase (CAT). Expression of resistance was inducible by subinhibitory concentrations of the drug. The mechanism of resistance was thought to be a cytoplasmic membrane-located barrier to the permeability of the drug into the cell. No evidence for the inactivation of the drug was obtained. In vitro polypeptide synthesis directed by ribosomes isolated from resistant and sensitive cells was equally sensitive to inhibition by chloramphenicol suggesting that a ribosomal mechanism was not involved. Spheroplasts expressed the same level of resistance as whole cells. Strains specifying intracellular CAT did not degrade chloramphenicol in the culture medium if they also carried a chloramphenicol resistance plasmid not specifying CAT.
Acetyltransferases↗