Failure to detect multiresistant Escherichia coli in Bristol.
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Disease Outbreaks↗
Biomedical subjects
D S Reeves
Publications and source records attributed to D S Reeves.
Activity in vitro of CGP 31608, a new penem antibacterial agent.
The in-vitro activity of CGP 31608 (hereinafter termed CGP), a new penem, was tested by an agar dilution technique in comparison with imipenem, Sch 34343, cefotaxime, ceftazidime, aztreonam, ampicillin, gentamicin and ciprofloxacin. 480 clinical isolated were tested, some of which were selected because of their multiple resistance. CGP showed consistent activity against a wide range of species, having MIC90 values of 2-8 mg/l for almost all Enterobacteriaceae, Pseudomonas spp., Haemophilus spp., Corynebacterium spp. and Bacteroides spp. It was the most active agent tested against staphylococci having an MIC90 of 0.25 mg/l, showing no reduction in activity against methicillin-resistant strains. Lesser activity was observed against some streptococci, Proteus spp. and clostridia. Tests carried out in broth demonstrated that CGP activity was constant over a pH range of 6-8 and was unaffected by the presence of 50% serum or 50% urine. The rate of killing of CGP, gentamicin, cefotaxime and ciprofloxacin was investigated in broth against log and stationary-phase cultures of Staphylococcus aureus and Escherichia coli. The most rapid rate of kill was seen with ciprofloxacin, while CGP exhibited a more rapid bactericidal effect than cefotaxime against Staph. aureus. The stability of CGP was studied at two concentrations in serum, broth and phosphate buffer at 4 degrees C, room temperature and 37 degrees C. In serum the half-life was 112 h at 4 degrees C, 35 h at room temperature and 11.4 h at 37 degrees C. Protein binding tested at concentrations of 5-100 mg/l was 2-6.3%.
Anti-Bacterial Agents↗
The pharmacokinetics of fusidic acid.
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Administration, Oral↗
AAC(1): a new aminoglycoside-acetylating enzyme modifying the Cl aminogroup of apramycin.
An aminoglycoside-acetylating enzyme produced by a strain of Escherichia coli with an unusual resistance phenotype was characterized. This enzyme was found to mono-acetylate apramycin, butirosin, lividomycin and paromomycin and diacetylate ribostamycin and neomycin to give reaction products which were distinguishable by HPLC analysis from those of AAC(2'), AAC(3) and AAC(6') enzymes. The enzyme, however, was not found to acetylate amikacin, fortimicin, geneticin, gentamicin, kanamycin A, netilmicin or tobramycin. The reaction product from the action of this enzyme on apramycin was purified and identified by nuclear magnetic resonance studies as 1-N-acetyl apramycin. The second site at which ribostamycin and neomycin B were modified by this enzyme was not determined but is postulated as the 6'-amino group. It is proposed that this enzyme be named AAC(1).
Acetyltransferases↗
A preliminary report on the pharmacokinetics of ofloxacin, desmethyl ofloxacin and ofloxacin N-oxide in patients with chronic renal failure.
The in vitro activities of ofloxacin, desmethyl ofloxacin and ofloxacin N-oxide were determined and a specific high performance liquid chromatography (HPLC) assay for these 3 compounds was devised as part of a study of the pharmacokinetics of ofloxacin and its metabolites in patients with impaired renal function. Desmethyl ofloxacin had significant antimicrobial activity but less than that of the parent drug. In 2 patients with chronic renal failure, specific HPLC assay indicated an extended half-life for ofloxacin (approximately 13 hours) and the appearance in serum of low concentrations of both metabolites after 10 hours, persisting until the last blood sample was taken (32 hours). Further studies using specific assays are needed, particularly in patients undergoing haemodialysis and after administration of multiple doses.
Anti-Infective Agents↗
Effect of oral ciprofloxacin on the faecal flora of healthy volunteers.
The effect of oral ciprofloxacin on the intestinal flora was investigated in six male volunteers aged between 21 and 54 years. Faecal specimens were cultured quantitatively for aerobic and anaerobic micro-organisms before, during and after a five day course of ciprofloxacin. Ciprofloxacin resulted in a significant reduction in aerobic flora in all volunteers and colonisation with resistant coagulase-negative staphylococci or corynebacteria in two volunteers. The total anaerobic flora counts were significantly reduced in only one volunteer. Neither Clostridium difficile nor its toxin was detected and there was no significant colonisation with Pseudomonas spp. or yeasts; no ciprofloxacin-resistant gram-negative bacilli were detected. Peak serum levels on days 1 and 5 of 1.6-4.3 mg/l (mean 2.7) were achieved after 30-90 min and urine recovery over the five days was 27.1-44.6%.
Administration, Oral↗
The identification of the aminoglycoside-phosphorylating enzymes APH(2'') and APH(3') from the characterization of their reaction products by high performance liquid chromatography.
A method is described for the identification of the aminoglycoside-phosphorylating (APH) enzymes APH(2'') and APH(3') by the high performance liquid chromatographic (HPLC) identification of their products of reaction with kanamycin and ATP. Twelve reference strains which produce either APH(2'') or APH(3') were examined by both this method and the radioenzymatic profile method; correct enzyme identification was made with 12/12 of the strains by the HPLC method and 11/12 of the strains by the radioenzymatic profile method. Reaction products of APH(2'') or APH(3') with ATP and butirosin, geneticin, lividomycin, ribostamycin, sissomicin or tobramycin were also characterized by HPLC. Conditions for their chromatography are given.
Aminoglycosides↗
The assay of chloramphenicol acetyltransferase activity by high performance liquid chromatography.
A high performance liquid chromatographic method is described for the assay of chloramphenicol acetyltransferase activity which detects the formation of both 3-acetoxy chloramphenicol and 1,3-diacetoxy chloramphenicol. In experiments performed at pH 6.8 only 3-acetoxy chloramphenicol was detected while in experiments performed at pH 7.8 both 3-acetoxy and 1,3-diacetoxy chloramphenicol were detected.
Acetylation↗
Pharmacokinetics of cefotetan in patients with end-stage renal failure on maintenance dialysis.
The pharmacokinetics of a single intravenous dose of cefotetan were studied in 17 volunteer patients with end-stage renal failure, requiring intermittent haemodialysis in 12 cases or undergoing continuous ambulatory peritoneal dialysis in 5 cases. Between haemodialysis the mean plasma elimination half life was 20.4 h (S.E.M. +/- 2.1). This decreased to 7.5 h (S.E.M. +/- 0.6) during haemodialysis. In patients treated by continuous ambulatory peritoneal dialysis the mean plasma elimination half life was 15.5 h (S.E.M. +/- 1.9). Small amounts of cefotetan (5-9% of the administered dose) were recovered in the peritoneal dialysates removed over the 24 h following the dose.
Cefotetan↗
Identification of individual aminoglycoside-inactivating enzymes in a mixture by HPLC determination of reaction products.
A method is described for the detection and identification of two aminoglycoside-acetylating (AAC(2') or AAC(3) or AAC(6')) or -phosphorylating (APH(2'') or APH(3')) enzymes when these are present in the same crude enzyme extract. Crude enzyme extracts were prepared from reference strains of bacteria producing AAC(2'), AAC(3), AAC(6'), APH(2'') or APH(3') enzymes and mixed to give the following paired enzyme combinations: AAC(2') + AAC(3), AAC(2') + AAC(6'), AAC(3) + AAC(6') and APH(2") + APH(3'). These enzyme mixtures were examined by the radioenzymatic profile method for the identification of aminoglycoside-modifying enzymes and their reaction products with butirosin, lividomycin and kanamycin (AAC) or lividomycin and kanamycin (APH) characterized by high performance liquid chromatography (HPLC). Only two of the eight enzymes present were identified by the radioenzymatic method, but all eight were correctly identified by the HPLC method.
Acetylation↗
The effect of quinolone antibacterials on the gastrointestinal flora compared with that of other antibacterials.
Although there is limited information on some of the newer quinolones it is likely that all such agents have a similar effect on the faecal flora. Ciprofloxacin seems to be best studied, and typical changes include regular and complete suppression of the enterobacteria and a slight diminution of enterococci. Total counts of anaerobic flora remain virtually unchanged, although small reductions have been noted in some studies for bacteroids, anaerobic cocci, fusobacteria and anaerobic non-sporing Gram-positive bacilli. Overgrowth of yeasts was not seen except when administration was prolonged. The results so far suggest that the newer quinolones will have a useful role in selective gut decontamination, the prevention of reinfection of the urinary tract, and the treatment of intestinal infection. Such early clinical results as have been published confirm this view. Of the other antibacterial agents discussed only some recent cephalosporins (cefotaxime, ceftazidime), aztreonam, cotrimoxazole and aminoglycosides have effects on the faecal flora similar to those of the newer quinolones. The remaining agents either have little or no effect or produce changes, such as a marked reduction in anaerobic flora, which are generally considered to be undesirable.
Anti-Bacterial Agents↗
Resistance to ciprofloxacin.
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Anti-Bacterial Agents↗
The human pharmacokinetics of cefotaxime and its metabolites and the role of renal tubular secretion on their elimination.
The pharmacokinetics of cefotaxime were investigated in human volunteers given constant intravenous infusions, intravenous bolus, and intramuscular doses of the drug. After intravenous dosing, the plasma levels of cefotaxime declined in a biphasic manner with a terminal half-life varying between 0.92 and 1.65 hr. Moreover, the pharmacokinetics were linear up to at least a 2.0 g dose for volume of distribution based on area (23.3-31.3 l), plasma clearance (249-2.88 ml/min), and renal clearance (151-177 ml/min). Renal tubular secretion of intact cefotaxime and each of its metabolites was demonstrated by its interaction with probenecid, although the ratio of drug to metabolites ultimately excreted in urine after probenecid was similar to that seen normally (54 +/- 6, 19 +/- 4, 6.5 +/- 0.7 and 5.5 +/- 0.7% for cefotaxime, DACM, M2, and M3, respectively, when calculated as a percentage of the dose). The observed half-lives of DACM, M2, and M3 were 2.3 +/- 0.4, 2.2 +/- 0.1 and 2.2 hr, respectively. However, when the true half-life of DACM was calculated (0.83 +/- 0.23 hr) it was not only significantly shorter than that observed but also shorter than that for intact cefotaxime. The plasma clearance of DACM (744 +/- 226 ml/min) was much higher than that of cefotaxime while the volume of distribution was of a similar order (56 +/- 24 l). When administered intramuscularly, there was good absorption of cefotaxime from the site of injection (92-94%) giving maximum plasma levels of the drug of between 30 and 35 mg/l at approximately 40 min after dosing. Thereafter, the plasma levels of cefotaxime declined in a monophasic manner with a half-life (1.0-1.2 hr) similar to that of the terminal half-life seen after intravenous administration. Lidocaine had no significant effect on either its absorption or elimination kinetics.
Adult↗
Ceftriaxone: a three centre comparative in vitro susceptibility study.
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Bacteria↗
Advantages and disadvantages of an in-vitro model with two compartments connected by a dialyser: results of experiments with ciprofloxacin.
A two-compartment in-vitro model is described in which the compartments are separated by a hollow-fibre dialyser. It was used successfully to simulate the 2-compartment kinetics of intravenously administered ciprofloxacin and to observe the activity of ciprofloxacin against a strain of Serratia marcescens growing in the peripheral compartment. Because of the complexity of the apparatus, however, the experiments were labour-intensive, prone to break-down, and gave results only slowly. There was a possibility that drug-resistant variants were carried over from one experiment to the next by re-use of the dialyser. While the model could give very flexible kinetics and retained all of the culture, there were constraints on the variations in kinetics from the physical sizes of the compartments and practicable flow rates. An ever-present problem was the possibility of fluid diafiltering rapidly into either compartment. Such a model should perhaps only be used when a very short drug half-life is to be simulated or very flexible kinetics required. Simpler, multi-channel equipment could be more productive.
Anti-Bacterial Agents↗
Comparative in-vitro activity of Sch 34343, a new penem antibiotic.
Using an agar dilution technique we examined the in-vitro activity of Sch 34343 against 485 clinical bacterial isolates. Ampicillin, mezlocillin, cefuroxime, cefotaxime, cefotetan, ceftazidime, ceftriaxone, imipenem (N-formimidoyl thienamycin) and gentamicin were used for comparison. Sch 34343 exhibited activity against all species tested, excepting Pseudomonas aeruginosa and Pseudomonas species. Unlike many newer beta-lactams, Sch 34343 was highly active against Gram-positive species. It was consistently active against the Enterobacteriaceae, with MIC50 and MIC90 being usually closely similar, as were results with two inoculum sizes (104 and 106 cfu). This, together with its activity against strains resistant to many other beta-lactam agents, suggested high stability to beta-lactamases. Sch 34343 was the most active compound tested against Bacteroides fragilis. In tests of combined bacteriostatic action with gentamicin no synergy was seen. It had bactericidal action in broth culture, against sensitive strains of E. coli, Klebsiella pneumoniae, Staphylococcus aureus and Streptococcus faecalis. It showed good stability in aqueous solution and serum at low temperatures at pH values in the physiological range, and was moderately stable at 37 degrees C. Binding in human plasma was 72%. We concluded that Sch 34343 is a highly promising agent with a broad spectrum of activity making it potentially suitable as monotherapy for patients with infection of undetermined bacterial aetiology, particularly if Bact. fragilis is a possible pathogen.
Anti-Bacterial Agents↗
The in vitro antibacterial activity of ceftriaxone in comparison with nine other antibiotics.
The results of a large three centre co-ordinated study into the in vitro susceptibility of bacterial clinical pathogens showed no significant evidence of regional variation within the U.K. towards the 10 antibiotics examined. The newer cephalosporins were highly potent and superior to other antibiotics against the Enterobacteriaceae, with ceftriaxone and cefotaxime the most potent. Against Pseudomonas aeruginosa, gentamicin was the most active, followed by ceftazidime, piperacillin and ceftriaxone; cefotetan was the least active. Staphylococcus aureus and Staphylococcus albus were most susceptible to cefuroxime and gentamicin, though most were also susceptible to ceftriaxone, cefotaxime and cefoxitin. Streptococcus (Groups A and B), Streptococcus pneumoniae and Neisseria spp. were susceptible to most agents other than gentamicin, but ceftriaxone and cefotaxime were overall the most potent. Ceftriaxone was the most active agent against Haemophilus influenzae. The newer agents were variable and relatively poor against anaerobes and only amoxycillin and piperacillin were significantly active against Streptococcus faecalis. The overall resistance level to the third generation cephalosporins was low.
Anti-Bacterial Agents↗
Is coagulase-negative staphylococcal bacteraemia in neonates a consequence of mechanical ventilation?
The clinical symptoms associated with coagulase-negative staphylococcal bacteraemia in infants on a Special Care Baby Unit were investigated. They were compared with those of blood culture-negative controls matched for age and weight. Infants with positive cultures were further sub-divided by judging the isolate to be a contaminant or a pathogen. There was a high incidence of respiratory symptoms in the latter patients, particularly in infants of less than 37 weeks gestation. These symptoms often responded to antimicrobial chemotherapy, particularly in infants given correct antibiotics, as demonstrated by laboratory sensitivity testing. Bacteraemia was usually detected shortly after starting mechanical ventilation, and may be its consequence in premature infants. Gentamicin-resistance occurred in over 50 per cent of blood culture isolates of coagulase-negative staphylococci. We postulate that coagulase-negative staphylococci can be a neonatal pathogen requiring appropriate antimicrobial chemotherapy.
Coagulase↗