Biomedical subjects
Publications and source records attributed to J M Hamilton-Miller.
A lady with recurrent urinary infection associated with sexual intercourse with her husband is described. The source of the infection was from the husband's chronically infected prostate.
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DuP 105 and 721, synthetic antibiotics belonging to a totally novel chemical class (oxazolidinones), have been found to be active in vitro against a wide range of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. DuP 721 had geometric mean MICs ranging from 1.1 to 16 mg/l against 167 strains of Staph. aureus, Staph. epidermidis, Staph. saprophyticus, streptococci of Groups A, B and D and diphtheroids. DuP 105 was between 1.5 and eight-fold less active. Bacteroides fragilis strains were also susceptible to the DuP compounds (mean MICs being 8.3 and 14.9 mg/l for DuP 721 and 105, respectively), but other Gram-negative species and yeasts were not inhibited by concentrations in excess of 100 mg/l. Both compounds had a predominantly bacteriostatic action. No primary resistance was found, and the incidence of resistant variants in 105 strains tested was less than 1 per 10(8) bacteria.
Twelve cases of peritonitis caused by Gram-positive bacteria in 11 dialysis patients were treated with teicoplanin. Treatment, which was continued for three weeks, consisted of the addition of teicoplanin to the dialysis fluid. Six patients who were febrile on admission were also given a single intravenous dose of 400 mg teicoplanin. For patients on continuous ambulatory peritoneal dialysis 20 mg teicoplanin per litre was added to each dialysis bag during the first week of treatment, to alternate bags during the second week, and only to the overnight dwell bag in the third week. For patients on intermittent peritoneal dialysis, 20 mg/l teicoplanin was added at each dialysis session. Resolution of peritonitis occurred in all patients within one to five days (mean 2.2); nine were discharged within this period and the patients continued to treat themselves at home. The other two patients were kept in hospital for reasons unconnected with the peritonitis. Nine patients have remained well at follow-up 2-13 months (mean 6.3) later. Two patients, both of whom had Staphylococcus aureus peritonitis, relapsed three months after the end of treatment. Mean serum teicoplanin concentrations were less than 10 mg/l, except in one patient who was re-treated when he relapsed. No adverse effects were recorded; one patient who developed a conductive hearing loss was found to have otitis media and obstruction due to wax. We conclude that teicoplanin is safe and effective in treating peritonitis in patients on peritoneal dialysis.
The reversal of the antibacterial activity of trimethoprim against different species of Gram-positive cocci (Staphylococcus aureus, Staph. epidermidis, Staph. saprophyticus, group B streptococci, Streptococcus faecalis and Str. faecium) by thymine, thymidine and various 'folates' (folate, folinate, dihydrofolate and tetrahydrofolate) was tested. Against group B streptococci and staphylococci only thymidine antagonized trimethoprim. However, for enterococci, thymine, thymidine, dihydrofolate, tetrahydrofolate and folinate all reversed the activity of trimethoprim, although by different amounts. Dihydrofolate was significantly more effective as a trimethoprim antagonist for Str. faecium than for Str. faecalis. While thymine and thymidine caused the MIC of trimethoprim against enterococci to increase more than 100-fold--thereby rendering them resistant--the 'folates' brought about much smaller increases in trimethoprim MIC, in the order of ten-fold only. Thus, even in the presence of 'folates' enterococci remain sensitive in vitro to trimethoprim.
The historical development of antibiotics has been summarized. Three distinct phases are discernible. The first (from historical times to about 1900) involved mostly folk remedies. The second (1900-c. 1940) was ushered in by Paul Ehrlich's development of the concept of 'selective toxicity' and saw the establishment of arsenicals and sulphonamides. The third, lasting to the present day, started with the exploitation of the pioneering studies of Fleming, Dubos and Waksman on antibiotic production by soil fungi. This latest phase has continued with the improvement of natural products by the skills of the medicinal chemist. The properties and evolution of three major groups of antibiotics, penicillins, cephalosporins and aminoglycosides are fully described. Finally, pathways of possible future evolution of antibiotics are outlined.
Synergy was found between sulphonamide and trimethoprim in ratios 1:1 and 20:1 against both trimethoprim-sensitive enterococci (17 strains) and trimethoprim-resistant enterococci (23 strains). Many of these strains were resistant to kanamycin, tetracycline, streptomycin and/or erythromycin. Resistance to kanamycin, but not to trimethoprim, was clearly associated with the presence of a plasmid of molecular weight 35-45 Md. Elimination of this plasmid in three out of four highly trimethoprim resistant strains brought about loss of resistance to both kanamycin and trimethoprim. Furthermore, it was possible to transfer trimethoprim resistance from three of five highly resistant strains, but not from three strains with low-grade resistance. It is concluded that resistance to trimethoprim in enterococci can be encoded on a plasmid, and that the gene responsible may be on a transposon. No significant differences were found between the specific activities of dihydrofolate reductase from trimethoprim-sensitive and -resistant strains. The enzyme from resistant strains was several orders of magnitude less susceptible to inhibition by trimethoprim than was the enzyme from sensitive strains.
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The periurethral enterobacterial flora was identified before infective episodes in 56 patients with recurrent urinary infection. There were 91 episodes of infection, with colonisation by aerobic gram-negative bacilli in 60. In only 31 (34%) episodes were patients colonised with the infective strain. In 31 episodes there was no colonisation of the perineum and in 29 there was heterologous colonisation. In another group of 54 women investigated during an enterobacterial infection of the urine there was colonisation with the infecting organism in 55 (86%) of 64 episodes; in 2 there was no colonisation; and 7 (11%) were associated with a heterologous strain. Women who have recurrent urinary infections are susceptible to perineal and periurethral colonisation with gram-negative bacteria but the infection need not be with the colonising enterobacteria.
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Cephradine 250 mg at night for 12 months was given as a prophylactic measure to 33 female patients of mean age 41.6 years, who had a history in the preceding 12 months of between three and 24 (median = 7) episodes of frequency and/or dysuria. When on such treatment the mean period between symptomatic attacks was 300 days, while before treatment attacks occurred at a mean frequency of 60.3 days. Thus, prophylactic cephradine increased the interval between attacks five-fold. In a total of 9002 patient-days of treatment, only five bacteriuric breakthrough infections occurred. 27% of the patients reported adverse effects "probably" or "possibly" related to treatment. Hence, cephradine appears to be as effective and better tolerated than macrocrystalline nitrofurantoin, presently the drug of choice for the prophylaxis of recurrent urinary infections.
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Women with recurrent urinary tract infections treated with cefuroxime axetil (500 or 250 mg twice daily) for 7 days had a higher relapse rate when tested 6 weeks after the start of treatment than those given amoxycillin (250 mg three times daily). The poor performance of cefuroxime axetil is explained by variable bioavailability.
The most important role of the clinical microbiology laboratory is to advise clinicians in their choice of antimicrobial therapy. While the application of modern laboratory techniques is enabling sensitivity testing to cephalosporins to be performed with increasing precision, the ability to predict accurately clinical efficacy has not improved in parallel. For the cephem group in particular, the present confusion as to the numerical value of breakpoints and their interpretation, and the overuse of 'class testing' are making the task of the clinical microbiologist more difficult. For most purposes, simple disc sensitivity testing of cephems gives sufficient information, and it is simple to carry out, as no special media or growth conditions are required. Further studies are required to answer an outstanding question of great importance, namely, what the clinical prognostic significance is of results of sensitivity testing of 'methicillin-resistant' Staphylococcus aureus and coagulase-negative staphylococci, as these organisms often appear sensitive to cephems in vitro. For the research worker, the cephems provide tools of almost unrivalled power in the investigation of such microbiologically important topics as cell wall synthesis, bacteriolysis, membrane function and various aspects of enzyme regulation and inhibition. Relatively minor changes in the structure of cephem molecules can markedly affect their binding to bacteria, thus allowing probing of the functions of the individual penicillin-binding proteins. In Gram-negative bacteria, membrane function can be selectively changed by the action of subinhibitory concentrations of cephems, as it is intimately connected to the integrity of the peptidoglycan moiety. Induction and derepression of beta-lactamases may be responsible for a new type of bacterial resistance.