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Twenty-four general practitioners completed a questionnaire on behalf of their partners in the practices before attending the symposium. The main points that emerged were that trimethoprim was the most popular antibiotic for treatment of acute urinary infection and that the most common duration of treatment was 5 to 7 days. A panel discussion, with audience participation, covered duration of treatment, antibiotic resistance, specimen collection, management of different patient groups and availability of information concerning resistance patterns. Nineteen of the original 24 general practitioners returned the post-meeting questionnaire, and stated that, as a result of what they had heard at the symposium, they were contemplating changing the way in which they managed urinary infections. Information concerning bacteriuria in pregnancy and changing patterns of bacterial resistance to antibiotics were of particular interest.

The effect of alkalinisation and increased fluid intake on bacterial phagocytosis and killing in urine was studied. Phagocytosis of Escherichia coli and Staphylococcus saprophyticus by polymorphonuclear neutrophils (PMN) took place in only one of three first voided early morning urine samples from volunteers, and no bacterial killing occurred. This was attributed to the high osmolality (690 to 720 mOsm) and low pH of the early morning urine; two samples were pH 5.8 and the third, in which phagocytosis occurred, was pH 6.4. Afternoon urine samples from the same volunteers had lower osmolality and a higher pH, with a high rate of phagocytosis (or = 88%) and 55-69% killing. PMN remained viable (mean 94%) after exposure for 1 h to both early morning and afternoon urine. Volunteers taking 4 g sodium citrate showed a mean rise of urinary pH of 1 unit. Water loading in patients with urinary tract infections produced a bacteria to neutrophil ratio conducive to bacterial killing, bacterial counts being reduced by a mean of 2.5 logs after 1-3 h without a corresponding reduction in neutrophils. Thus, raising the pH and reducing the osmolality of urine increases the ability of neutrophils to eliminate infecting organisms.

All episodes of recurrent infection in a CAPD unit over a 26-month period have been analysed to discover whether relapse and reinfection have different prognostic importance. Relapse and reinfection were distinguished by detailed microbiological investigation. Prognosis was expressed in terms of outcome of treatment and the fate of the Tenckhoff catheter. Twenty-nine patients suffered recurrent infections (i.e. more than one infection during a 12-month period). Nine (6 male, 3 female, age range 42-73 years) had relapses, and 20 (16 male, 4 female, age range 42-74 years) reinfections. The characteristics of the two groups of patients were indistinguishable. Relapse was of graver prognostic consequence: patients who relapsed were significantly less likely to respond to antibiotic treatment (78% versus 20%) and have to have their catheters removed (78% versus 10%) than those with reinfections. Thus it is important to differentiate relapse from reinfection in CAPD peritonitis. In addition to being helpful for the management of individual patients, this is essential if results of therapeutic trials are to be interpreted correctly.

A study of the in-vitro activity of RP 59500, a semisynthetic derivative of pristinamycin, against a range of Gram-positive bacteria including erythromycin-resistant strains was undertaken. MICs were determined by plate dilution in IsoSensitest agar and MBCs by velvet pad replication. RP 59500 was found to have in-vitro activity almost identical to that of its parent compound, pristinamycin. Sixty methicillin-resistant Staphylococcus aureus (MRSA) and 60 methicillin-sensitive S. aureus (MSSA) were found to be sensitive to RP 59500, with MICs of 0.13-1 mg/L. All the MSSA and most MRSA showed an MBC less than 2 mg/L. Erythromycin-resistant S. aureus (62) were as sensitive to RP 59500 as were erythromycin-sensitive strains (58). RP 59500 was more active against MRSA than fusidate, vancomycin, amikacin, ciprofloxacin, imipenem or erythromycin. Forty strains of coagulase-negative staphylococci (11 were erythromycin-resistant) showed MICs of 0.25-1 mg/L, and RP 59500 was more active than methicillin, erythromycin, imipenem, cefotaxime or vancomycin. Sixty strains of streptococci (20 pneumococci and 40 of groups A, B, C, or G) and 20 enterococci were inhibited by 0.13-1 mg/L and 0.25-4 mg/L, respectively. Gram-positive bacilli (five each of diphtheroids, lactobacilli, Listeria monocytogenes and Bacillus spp., and 19 Clostridium spp.) were also sensitive, with MICs of between 0.06 and 4 mg/L. All 279 strains tested were judged to be sensitive to RP 59500, which was bactericidal and showed a small inoculum effect. The activity against MRSA, and against erythromycin-resistant strains of all species was particularly interesting.

Growing points and problem areas in the field of urinary tract infections are critically surveyed. It is concluded that there is a particular need for advances in rapid tests for bacteriuria (to distinguish between symptomatic patients who are infected and those who are not) and for the determination of antibiotic sensitivity of infecting organisms. The aetiology of the "urethral syndrome" (dysuria and/or frequency without a significant bacteriuria) is still obscure although it is becoming clear what suggested possible causes are not responsible for it. Another unresolved problem is whether or not to treat asymptomatic bacteriuria in all groups of patients especially the elderly, and in the absence of pyuria. Similarly it is still not decided what are the optimal lengths of time and dosages of antibiotics to treat various types of urinary infections. Finally, difficulties involved in preventing infections of in-dwelling catheters, and the possibility of obtaining a protective vaccine are discussed.

A five day course of clavulanate-potentiated amoxicillin (Augmentin) has been compared with a single oral dose of fosfomycin trometamol in the treatment of patients complaining of symptoms suggesting urinary tract infection. The study took place in a single urban general practice of 15,000 patients in Cheshire. The microbiology was performed at a London Teaching Hospital. 141 patients entered the trial. 65 had a significant bacteriuria, 62 of which were assessable for the ability of the trial drugs to eradicate bacteriuria: 29 patients received clavulanate-potentiated amoxicillin and 33 fosfomycin trometamol. The cure rates, assessed at five to ten days and at four to six weeks post treatment, were 72% and 65%, respectively for clavulanate-potentiated amoxicillin and 85% and 81%, respectively for fosfomycin trometamol. Side effects, assessed in all 141 patients, occurred in 11.6% receiving clavulanate-potentiated amoxicillin and in 8.3% receiving fosfomycin. Statistically there is no difference between any of these findings and the effect of sample size is discussed. 69 patients were symptomatic but did not have a significant bacteriuria ("urethral syndrome"). These patients were assessed for the effect of treatment in relieving symptoms: 33 received fosfomycin trometamol and 36 clavulanate-potentiated amoxicillin. The success and speed of relieving the symptoms were very similar in the two groups. The finding that both groups responded equally well appears to refute an aetiological role for lactobacilli and diphtheroids in the "urethral syndrome", since these organisms are resistant to fosfomycin but sensitive to clavulanate-potentiated amoxicillin.

Sera from patients with primary biliary cirrhosis exhibit variable autoantibody reactivity against mitochondria, the commonest antigen (designated M2) including three structures of approximate M.W. 70, 50 and 40 kD. The nature of these antigens has only recently been established; the 70 and 50 kD are the transacetylase E2 and component X, respectively, of the pyruvate dehydrogenase complex and are distinct polypeptides. We have demonstrated, by immunoblotting, elution and rebinding of antibodies, unequivocal cross-reactivity between the major bands of the M2 antigen. In addition, cross-reactivity has been shown between antibodies binding to each of the three M2 bands of mitochondria and two major antigenic bands of both Gram-negative and Gram-positive bacteria. Conversely, antibodies eluted from these two bands of Escherichia coli were found to bind all three M2 bands of mitochondria. These results suggest that the antibodies of primary biliary cirrhosis contain both peptide-specific and cross-reacting antibodies, the latter recognizing a common "M2 epitope" that might include nonprotein components of the peptides. However, direct and competitive enzyme-linked immunosorbent assays failed to implicate the coenzyme of the pyruvate dehydrogenase complex, lipoic acid or its amide, as the common antigenic moiety.

Sixty-two strains of Staphylococcus aureus and coagulase-negative staphylococci, 21 Streptococcus faecalis and 17 other strains of streptococci isolated from cases of endocarditis were tested for sensitivity against rifampicin, teicoplanin, vancomycin, fusidic acid, erythromycin and novobiocin. Only rifampicin, novobiocin and teicoplanin were found to be active against the great majority of these strains. The microbial properties of these antibiotics suggest the necessity of combinations for effective therapy. The combinations rifampicin + novobiocin and rifampicin + teicoplanin were additive and suppressed the emergence of resistant mutants. Thus according to in vitro tests, either of these two combinations would be suitable for prophylactic use in high-risk patients, especially those scheduled to receive prosthetic implants.

A combination of nitrofurantoin (100 mg) and sulphadiazine (300 mg) given 12-hourly for 7 days was used to treat 51 patients with recurrent urinary infections who were attending an out-patient clinic. Either nitrofurantoin or sulphadiazine was active in vitro against all the organisms isolated. The cure rate 1 week after the end of treatment was 82%; 10 patients relapsed during the following month, giving a cure rate 5 weeks after the end of treatment of 57%. Side effects, although relatively common (37%), were mild. The outcome of treatment with these two long-established drugs is thus as good as that obtained with some newer and more expensive preparations.

of Pseudomonas aeruginosa. Overall, 81% of the strains were sensitive to amikacin and 33% of the strains were sensitive to butirosin, the next most active compound. Results indicated that 54% of the P. aeruginosa strains were sensitive to amikacin and 33% were sensitive to tobramycin. From resistance patterns, enzymes responsible for inactivation of the antibiotics were deduced. The most common enzyme was aminoglycoside nucleotidyltransferase(2"), either alone or combined with either aminoglycoside phosphotransferase(3')-I or aminoglycoside phosphotransferase(3')-II. Aminoglycoside acetyltransferase(2) was identified exclusively in strains of Providencia stuartii. Specific enzymes could not be identified for 30 strains, 21 of which were P. aeruginosa. Several laboratory studies have shown that amikacin, a semisynthetic derivative of kanamycin, not only has a broad spectrum of antibacterial activity but also is active against a significant proportion of bacteria that are resistant to one or more of the aminoglycoside antibiotics. The major reason for this finding seems to be that amikacin is a substrate for only one of the eight known aminoglycoside-inactivating enzymes, namely, aminoglycoside acetyltransferase (6')

Amikacin (250 or 500 mg) was administered intramuscularly twice daily at 12-hr intervals to 34 patients with infections due to various gram-negative bacteria. Usually one or more aggravating factors were present, such as serious underlying pathology or therapy with steroids or immunosuppressants. Clinical isolates from most patients were resistant to gentamicin and other aminoglycosides. The overall response to therapy was excellent in 20 patients; in eight patients clinical response was good, but the organism persisted. Six patients showed some improvement without complete resolution of the infection or eradication of the causative organism. There were no complete clinical or bacteriologic failures. Ototoxicity was not observed in any patient. Levels of blood urea nitrogen and serum creatinine increased in two patients but returned to pretreatment levels within two weeks after therapy. No other adverse reactions were noted. Amikacin may replace gentamicin as initial therapy in serious gram-negative bacillary infections, particularly when resistance to gentamicin is a problem.

Techniques for the microbiological assay of nitrofurans are described. In one the indicator strain is Bacteroides fragilis; use of this system enables concentrations of nifuratel and furazolidone of down to 0.7 micrograms/ml to be estimated. The other system uses a recombination-deficient (recA-uvrA-) mutant of Escherichia coli; with this indicator, concentrations of 0.2 micrograms/ml, or less, of five nitrofurans can be assayed.

The properties of trimethoprim (TM), reviewed here, show it to be an excellent antimicrobial agent in its own right. However, with very few exceptions, TM has been made available clinically only in combination with a sulphonamide, usually sulphamethoxazole (SMX). We present evidence to suggest that the decision so to restrict the availability of TM was mistaken. Synergy between TM and SMX can be shown clearly in vitro, but there is no evidence from clinical trials that it plays a significant therapeutic role in urinary infections. Also, there is no evidence that combining the two antibiotics suppresses the emergence of resistance. Recently, sulphonamides other than SMX have been proposed as partners for TM, mainly on pharmacokinetic grounds. Compounds other than sulphonamides may also be logical partners for TM: we have made extensive studies on TM + rifampicin, for instance, and have obtained excellent results in certain clearly-defined patient groups. Only clinical trials of these new combinations will reveal whether they are superior to TM/SMX. There is already sufficient evidence to suggest that TM alone will be as effective as, and more acceptable than, TM/SMX. We propose that further large-scale clinical trials with TM alone be carried out, both to treat acute urinary infections and in prophylaxis.

Mecillinam (MC) was found to be inhibitory at low concentrations to a wide range of Gram-negative bacteria; the sensitivity of such strains could be predicted by using a 10 microgram disk. Resistance to MC did not appear to be associated with beta-lactamase-mediated destruction of the antibiotic. Ampicillin-resistant strains tended to be less sensitive to MC. MC and cephradine acted synergistically against Proteus mirabilis, Pr. vulgaris, Prov. stuartii and Serratia marcescens, and the combination was additive against most Klebsiella aerogenes, Enterobacter spp. and Escherichia coli.

Twenty clinical isolates of Staphylococcus aureus, resistant to both gentamicin and methicillin, were tested in vitro for sensitivity to rifampicin, novobiocin, fusidic acid, vancomycin, teicoplanin and an extended range of aminoglycosides. Rifampicin was the most active compound tested, having an MIC of less than 0.02 mg/l. All the strains were inhibited by 1 mg/l of novobiocin, vancomycin and teicoplanin, and only one strain was resistant to fusidic acid. 50% of the strains were inhibited by less than 1 mg/l of amikacin and netilmicin, but other aminoglycosides were of poor activity. Resistant mutants were selected when strains were grown in the presence of rifampicin, novobiocin or fusidic acid alone, but this did not occur when rifampicin was combined with either novobiocin or vancomycin. Pharmacokinetic and other considerations suggest that a combination of rifampicin and novobiocin deserves further assessment for the treatment of infections caused by this type of organism.

Experimental data, pharmacokinetic results, and clinical trials suggest that trimethoprim (TMP) is effective when used alone and is not associated with the toxicity and adverse effects caused by sulfonamides. Because an analysis of in vitro, pharmacokinetic, and clinical data suggested that the combination of rifampicin and TMP (Rifaprim) would be safe and highly active, an eight-year study of this combination for the treatment of urinary tract infection was done. The results were encouraging. Furthermore, a large multicenter trial of Rifaprim in 800 patients showed Rifaprim to be superior to trimethoprim-sulfamethoxazole for the treatment of chronic infections of the upper urinary tract. In another controlled trial, Rifaprim proved valuable for the treatment of urinary tract infections that resisted eradication and recurred frequently. Evidence suggests that Rifaprim may be useful in the treatment of other disease, such as staphylococcal osteitis (especially that caused by highly resistant organisms). Unlike antibiotics such as gentamicin, the use of which requires hospitalization of the patient and careful monitoring of levels in blood, Rifaprim can be used at home. Thus the danger of nosocomial infection is avoided.

Although rifampicin is active against virtually all pathogenic bacteria, acquisition of resistance means that it cannot be used alone for treating infections. We have shown that, in combination with trimethoprim, this handicap can be overcome. Not only is the emergence of resistance prevented by the presence of trimethoprim, but antibacterial synergy is often observed. By applying certain logical guidelines, we have been able to suggest an appropriate combination of rifampicin and trimethoprim, which is now being tried in the treatment of various injections. There is no evidence that the emergence of resistant tubercle bacilli will be encouraged by the use of rifampicin in this way: on the contrary, this risk seems extremely remote.

Summary A total of 120 patients, including 53 pregnant women with significant bacteriuria, received 163 7-day courses of oral antimicrobial agents allocated in a randomised manner. The cure rates after 6 weeks' follow-up ranged from 73% to 86%, and there was no statistical difference between preparations of ampicillin, carbenicillin indanyl ester, and 2 different formulations of nifuratel. Side-effects occurred in 30% to 40% of the courses of penicillin drugs, but in under 15% of the course of nifuratel. It is concluded that the new oral preparation of carbenicillin is a useful addition to the list of antimicrobial agents which are effective in the treatment of urinary infections in domiciliary patients. Furthermore, nifuratel has been confirmed as a highly active non-toxic drug which is valuable in the treatment of urinary infections.

Five nitrofurans – nitrofurantoin, nifuratel, nitrofurazone, furazolidone and SQ 18,506 – have been tested against 201 microbial strains. Escherichia coli , Streptococcus fa

STAPHYLOCOCCUS AUREUS is one of the most versatile human pathogens. In the late 1930s, sulfonamides offered the first challenge to S. aureus, but they failed because of their poor clinical performa...

Patients with primary biliary cirrhosis have an abnormally high incidence of urinary tract infection (35%). Susceptibility to urinary infection and other infectious diseases has been linked with certain blood group antigens and secretor status. We have therefore studied these characteristics in patients with primary biliary cirrhosis. We were unable to show any abnormal distribution in blood groups or secretor status in patients with primary biliary cirrhosis (compared with a normal population) which might reflect their predisposition to urinary infection. The distribution of blood groups and secretor status in patients with primary biliary cirrhosis with a history of urinary infections was not significantly different from patients without such a history. Escherichia coli strains isolated from patients with primary biliary cirrhosis did not bind in any greater numbers to the uroepithelial cells of primary biliary cirrhosis patients than to the cells of a normal healthy control. We therefore conclude that blood group distribution, abnormal secretor status, and epithelial cell type are not important factors in the predisposition of primary biliary cirrhosis patients to urinary infections.

Over an 18-month period (October 1973 to April 1975), 133 strains of gram-negative bacteria with acquired resistance to trimethoprim (TM) were isolated from infected urines cultured at the Royal Free Hospital. The overall frequency of resistance was 3.2%. A disproportionately high number of resistant strains (63.1%) were Kebsiella aerogenes. Resistance to TM mediated by R plasmids occurs infrequently (9% of all resistant strains); the majority of TMR plasmids isolated belonged to one incompatability group (W). Chromosomally mediated resistance to TM in most Escherichia coli and K. aerogenes strains appears to be due mainly to production of a dihydrofolate reductase with a reduced susceptibility to TM. In some strains, increased activity of the DHFR was also a contributing factor. Increase in enzyme level alone was only great enough to account for the level of resistance to TM in a small number of cases.

The cephamycins are a group with great potential. The first member of the group intended for therapeutic use offers the following advantages over existing cephalosporins: 1. Stability to various beta-lactamases; in an environment increasingly threatened by R-factors, this property may be of increasing value as time passes. 2. Possible lack of cross-allergenicity with other beta-lactam antibiotics. 3. Activity against anaerobic strains. Cefoxitin is only the first semi-synthetic derivative; presumably there are other compounds awaiting assessment which have even more favourable properties.

The incidence of resistance to trimethoprim among urinary isolates between October 1978 and November 1979 was 11.5%, more than double the figure found April 1973 and October 1975. Of the resistant strains, 60% had a minimum inhibitory concentration in excess of 1 mg/ml. Escherichia coli and Proteus mirabilis showed the greatest increase in resistance since the previous study. Rather wide fluctuations occurred in the incidence of resistance for various species when the figures were analysed over two-month periods, hence studies of short duration must be interpreted with caution. There are not yet enough data from this or other studies for the cause of the increased incidence of resistance to trimethoprim to be determined.

Rifampicin (rif) and trimethoprim (tm) are familiar broad-spectrum oral antimicrobial agents. Both drugs owe their antibacterial activity primarily to their effect on the biosynthesis of nucleic acids. Their target sites may thus be regarded as occurring on the same metabolic pathway; sequential blockade of a metabolic pathway has been shown to result in a potentially synergistic situation. Consequently, we tested rif and tm in combination, to investigate possible antibacterial interactions.

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.

Virtually all the agents now available for the treatment of infections were discovered by chance, or at best developed without a specific plan rather than on the basis of a sequence of logical experiments. An element of reason went into the original decision to screen samples of soil for the presence of microorganisms (usually molds) capable of producing antibiotic substances, but thereafter the procedures used were, of necessity, entirely empirical. Although there are notable exceptions, such as hexamine, mandelic acid, nalidixic acid, the nitrofurans, sulfonamides, p-aminosalicylate, and isoniazid, nearly all the clinically useful antibacterial compounds such as the (3-lactam compounds, aminoglycosides, tetracyclines, and macrolides were developed by observation and experiment without any background theory. Admittedly, some of the more sophisticated refinements have been planned by chemical methods, and the introduction of the semisynthetic penicillins and cephalosporins was a major advance in antimicrobial therapy. Nevertheless, empiricism was inevitable, and history has shown that the mode of action of an antibacterial compound is rarely known until some time after its introduction into clinical practice. The best example is penicillin. The explanation for selective toxicity of penicillin was not known until more than 20 years after its discovery, and the method of transport of wall components by lipid intermediates in the membrane remains to be elucidated.

In order to test their value in urinary infection a double-blind trial was carried out using ampicillin, cephalexin, trimethoprim-sulphamethoxazole (co-trimoxazole), and trimethoprim. Eighty-three courses of treatment were given to hospital patients, 149 to pregnant women, and 107 to patients with dysuria and frequency seen in domiciliary practice. Thus infections of varying severity in defined groups of patients caused by organisms with different antibiotic sensitivities were treated.Analysis of the overall results (339 courses) was compared with those from the individual groups and considerable variation in response was found. In domiciliary infections and bacteriuria in pregnancy trimethoprim alone proved to be at least as effective as the other three compounds and caused fewer than half the number of side effects. In the hospital patients co-trimoxazole was superior to trimethoprim.The overall results for ampicillin and cephalexin were similar although cephalexin proved to be inferior in treating symptomatic domiciliary infections.

Pivampicillin hydrochloride (the only form at present widely available) is not suitable for administration to infants. Pivampicillin free base, however, can be used in syrup form and is therefore suitable for paediatric use. We have carried out a preliminary pharmacokinetic study in adult volunteers with the pivampicillin free base. The mean peak blood level following a dose equivalent to 250 mg. anhydrous ampicillin, attained after one hour, was 5.2 µg/ml.; mean urinary recovery was 72.2%. Thus, the free base is as well absorbed as is the hydrochloride.

The activity of cefoxitin was compared with that of cephalothin against 229 bacterial strains. Cefoxitin was more active against most Gram-negative strains, notably against indole-producing Proteus spp., which are usually resistant to the cephalosporins. Cefoxitin was not susceptible to any significant extent to degradation by beta-lactamases produced by Gram-negative organisms. Against Gram-positive organisms, however, cefoxitin was considerably less active than cephalothin, but minimum inhibitory concentrations for Staphylococcus aureus were well within therapeutically attainable blood levels.Pharmacokinetic studies in 18 volunteers showed a higher and longer sustained antibiotic activity in serum and urine after injections of cefoxitin than after equal doses of cephalothin. Urinary recovery of cefoxitin activity was also much higher than that of cephalothin. No evidence of toxicity due to cefoxitin was found. Cefoxitin was slightly less painful after intramuscular injection than cephalothin.

We have compared the antibacterial activities of cephalexin and cephradine against Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus (Micrococcus spp. type III), and group B streptococci (35 strains in total), using the Biophotometer. Analysis of growth curves obtained in the presence of various concentrations of the antibiotics revealed little difference between the activities of the two cephalosporins. However, both antibiotics showed maximal activity at 8-16 microgram/ml, and increasing the concentration past this point resulted in a reduced antibacterial effect. Unlike the other species tested, streptococci were not lysed by cephalexin or cephradine.