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The biliary excretion and pharmacokinetics of mezlocillin have been studied in jaundiced patients with total external bile drainage through a percutaneous transhepatic catheter. In 10 of 11 studies, 2 g mezlocillin intravenously resulted in biliary concentrations sufficient to exceed the minimum inhibitory concentrations of most common biliary pathogenic organisms. In 6 h, 0.2-6.2% of the dose given was recovered in bile. The biliary clearance was 0.21-7.82 ml/min and increased with the duration of biliary decompression. The serum half-life of mezlocillin was prolonged (1.81 +/- 0.23 h, mean +/- SD), and was due to reduced biliary and renal clearance.

We review the discovery and development of the cephalosporins and subsequently cefaclor. Cefaclor is active against a wide range of commonly encountered bacterial pathogens, acting by inhibiting cell wall synthesis. Its in vitro activity compares favourably with other beta-lactam antibiotics. Its pharmacokinetic properties indicate that an 8-hourly dosing schedule is appropriate. In addition a delayed release formulation allowing twice daily dosage has been developed. The efficacy of both formulations of cefaclor has been verified by many clinical trials. Cefaclor has been widely used in infections of the respiratory tract (including otitis media), urinary tract and soft tissues. The results of therapy are summarized. The low incidence of adverse events is highlighted and the beneficial influence of this on compliance is described. Finally, the pharmaco-economics of cefaclor are considered.

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.

Trimethoprim is the best known inhibitor of bacterial dihydrofolate reductase. Initially, this was always combined with sulphamethoxazole. It was later combined with other sulphonamides (eg. sulphamoxole, sulphadiazine or sulfametopyrazine), but the sulphonamide moiety as a contributor to clinical efficacy was increasingly questioned. Thus, in 1979 (in UK) trimethoprim alone was introduced. Justification for the combination was based on: (a) synergy occurs in vitro (b) bactericidal activity, while the two components are bacteriostatic (c) the emergence of resistance was claimed to be lower. However, these claims were not substantiated by studying the microbiological and pharmacokinetic properties of trimethoprim and the sulphonamides, but most importantly by the results of clinical trials. These show that in most indications, trimethoprim alone is as good, cheaper and causes considerably fewer adverse events than use with a sulphonamide. For urinary infections most agree that monotherapy is best. In respiratory infections diaminopyrimidines have relatively poor activity against important pathogens, eg pneumococci and especially Moraxella catarrhalis. It could be argued in these case that the addition of a sulphonamide may increase therapeutic efficacy. This can only be resolved by large clinical trials. In brucellosis and gonorrhoea, where sulphonamides are more microbiologically active than diaminopyrimidines, it is likely that combination with another antibiotic is needed. However, too much reliance must not be placed on extrapolating from trimethoprim to other diaminopyrimidines; conclusions should be drawn from work using the other compounds.

Experiments were performed to determine the effects of products of bacterial growth (including endotoxin) on phagocytosis and intracellular killing by polymorphonuclear leucocytes (PMNL) in urine. Bacteriologically filtered supernates of two strains of Escherichia coli grown in urine were added in varying amounts to mixtures of PMNL and E. coli, also in urine. Phagocytosis of the two strains was reduced from > 90% in controls to 66% and 48%, respectively, in the presence of undiluted culture filtrate (containing endotoxin 2-2.5 micrograms/ml). Intracellular killing was also decreased and was abolished by dilutions corresponding to endotoxin concentrations of 0.6 and 0.75 micrograms/ml. When PMNL exposed to these inhibitory dilutions were resuspended in fresh urine, their phagocytic ability was fully restored and 13-24% of their killing activity was regained. A minimum concentration of commercially purified E. coli endotoxin of 200 micrograms/ml was required to abolished PMNL killing, with phagocytosis uninhibited. The results strongly suggest that bacterial growth metabolites, not endotoxin, are responsible for the depression of phagocytosis and intracellular killing in infected urine. A moderate dilution of the bacterial products in urine permits good PMNL function. Extrapolating this to the clinical situation, diluting the urine by water loading (as recommended for patients with urinary infections) should ensure efficient activity of PMNL under in-vivo conditions providing urinary pH and osmolality are not adversely affected.

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.

Primary biliary cirrhosis (PBC) patients have a higher incidence of recurrent urinary tract infection and an increased prevalence of rough forms (mutants) of E. coli in their stool samples than other chronic liver disease patients. PBC patients exhibit autoantibody reactivity against mitochondria, the most common antigen (M2) being a family of antigens with the major components having approximate molecular weights of 74, 56, 52 and 48 kD. Cross-reactivity between M2 antigen components and corresponding antigenic bands of bacteria has been demonstrated with PBC sera. Patients with recurrent urinary tract infections, all of whom had normal liver function and were taking prophylactic antibiotic treatment, had weak anti-mitochondrial antibody (AMA) reactivity (69%), with reactivity against the 74-kD antigen alone being the most common. When antibody to the 74-kD band was eluted, it was found to cross-react with bacterial membrane fractions. In the controls, 12/77 chronic liver disease patients and 2/24 normals possessed AMA. Rough forms of bacteria were found in the urine of patients with significant bacteriuria: 39% PBC, 5.3% chronic liver disease and 41% of the recurrent urinary tract infection group. M2 antibodies may be induced by urinary organisms in 'normal' women with recurrent bacteriuria and in females with PBC.

The oxazolidinone compound E3709, which contains a 4-pyridyl group, was found to be more active in vitro than other members of this series, such as DuP 721. MIC 90 for staphylococci (including methicillin-resistant isolates), streptococci (including Enterococcus faecalis), Clostridia , and diphtheroids was μ g/ml. Haemophilus influenzae, Moraxella catarrhalis and Bacteroides fragilis were less susceptible, with an MIC 90 between 2 and 8 μg/ml. E3709 MICs of Gram-negative species ranged from 100 to >100 μg/ml. At a concentration of 10 μg/ml, E3709 was bactericidal for selected Grampositive species. A postantibiotic effect of 3 hr was observed against staphylococci. Resistance to E3709 was not detected.

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.

The in-vitro activities of the topical agents azelaic acid, nitrofurazone, silver sulphadiazine and mupirocin have been determined against 80 strains of MRSA collected from worldwide sources. MICs were determined by agar dilution (with an inoculum of approximately 5.0 x 10(5) cfu) in Iso-Sensitest agar, and MBCs were measured by replica-plating from MIC plates using velvet pads. The agents tested were uniformly active against MRSA, mupirocin being the most active (MIC50 0.15 mg/L) followed by nitrofurazone (MIC50 19 mg/L), silver sulphadiazine (MIC50 85 mg/L) and azelaic acid (MIC50 850 mg/L). Concentrations of azelaic acid, nitrofurazone and silver sulphadiazine close to the MIC were bactericidal, but mupirocin was only bactericidal at concentrations substantially greater than the MIC. In time-kill experiments, azelaic acid and nitrofurazone were gradually bactericidal, silver sulphadiazine was rapidly bactericidal and mupirocin was not bactericidal. Silver sulphadiazine killed sulphonamide-sensitive and sulphonamide-resistant strains equally rapidly. No resistant mutants were found to azelaic acid, nitrofurazone or silver sulphadiazine in an inoculum of 10(9) cfu, but two strains yielded (frequency: 1.0 x 10(-9)) mutants resistant to mupirocin. Our in-vitro results suggest azelaic acid, nitrofurazone and silver sulphadiazine could be of use for clearing staphylococcal carriage.

The activities in vitro of ceftazidime and of cefuroxime have been compared against 201 strains of bacteria which had been isolated either from outbreaks of nosocomial infection or were typical of strains causing such outbreaks. Ceftazidime was found to be about 1000 times more active against Pseudomonas spp. and Proteus vulgaris, and between 10 and 100 times more active against Klebsiella pneumoniae, Enterobacter spp., Citrobacter freundii, Serratia marcescens, Proteus rettgeri, Proteus morganii, Providencia stuartii, Alcaligenes faecalis and Acinetobacter spp. On the other hand, cefuroxime was more active against Staphylococcus epidermidis. An increase in inoculum size to 106 had little effect on the activity of ceftazidime, except in the case of Pr. vulgaris strains, which grew, although only to a very limited extent, even in the presence of high concentrations of ceftazidime. Anaerobic and hypercapnic conditions did not adversely affect the activity of ceftazidime. Our in-vitro results thus indicate that ceftazidime had as broad a spectrum as gentamicin, and is more intrinsically active.

Summary Tests of phagocytosis and killing by polymorphonuclear neutrophil leucocytes (PMNL) are usually done with pre-opsonised organisms. Phagocytosis of 11 strains of Escherichia coli, pre-opsonised, and in the stationary phase, resulted in the killing of only one strain although all the organisms were phagocytosed. However, when the same strains were added unopsonised to a PMNL-serum mixture, eight were killed after phagocytosis. With two of these strains, the amount of killing was inversely proportional to the time of preopsonisation. E. coli incubated for 30 min in dilute peptone water in Hanks's Balanced Salts Solution before phagocytosis also became resistant to killing; bacterial division did not occur during this period. Experiments with bacteria in urine confirmed these findings and showed that E. coli exposed to serum or urine before phagocytosis became resistant to killing by PMNL. E. coli rapidly changes its sensitivity to phagolysosome killing during transition from stationary to lag phase in a nutrient medium. This resistance is retained through the exponential phase but is lost during the stationary phase. The killing of Pseudomonas, Enterobacter, and Acinetobacter by PMNL was unaffected by varying the method of opsonisation or the phase of growth. If this phenomenon occurs in vivo it may affect the outcome of infections caused by strains of E. coli that survive killing by PMNL.

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.

Objective: We have sought ways to circumvent resistance, by combining nisin with other antibiotics known to target bacterial cell wall biosynthesis. Methods: Twenty strains each of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) were tested in vitro by standardized methods against nisin alone and combined with bacitracin, ramoplanin and chloramphenicol. Results: Ramoplanin was the most potent compound, and bacitracin had the least activity. Two-way synergy was observed with nisin and ramoplanin. However, chloramphenicol was clearly antagonistic to the activity of nisin. Conclusions: Observations of synergy between nisin and ramoplanin against MRSA and VRE offer a promising approach to the concept of combining nisin with inhibitors of cell wall peptidoglycan. Further investigations are needed in order to develop this approach as a clinical possibility.

Summary The pH of urine samples from patients suffering symptoms suggesting urinary infection (e.g. dysuria, frequency, urgency) was measured while the patients were symptomatic and again when they had become asymptomatic. There was no correlation between the urine pH and the incidence or number of symptoms. No differences were observed between either the distribution or means of urine pH values in symptomatic and asymptomatic patients. There were also no significant differences in either symptomatology or urine pH between patients with significant bacteriuria and those without significant bacteriuria. These results cast doubt upon the traditional (but unproved) belief that alkalinizing the urine helps to reduce symptoms of dysuria and/or frequency, whether or not associated with urinary infection.

Metal compounds have been used as antibacterial agents for centuries. The in-vitro activity of two metal containing complexes, one gold, the other osmium, was investigated using a panel of clinically isolated bacteria and Candida albicans. Twenty strains of each organism were used and MIC and MBC values determined using the agar plate dilution method. Protein binding effects on the activity of the compounds were also investigated using media supplemented with 5% human blood. In-vivo activity of the two compounds was subsequently determined in a hairless-obese mouse skin-surface activity model. Both compounds were highly active against the Gram-positive organisms and Candida albicans in vitro. The gold compound had some Gram-negative activity but the osmium complex was inactive against these organisms. Both were extensively protein bound. In the in-vivo experiment the gold compound achieved a 2-3 log reduction for all the test organisms and was at least as good as or superior to mupirocin in its eradication rate. The osmium compound was inactive.

Co-trimoxazole is still widely used for indications where trimethoprim alone is equally effective. The pharmacological rationale of the combination of trimethoprim and sulphamethoxazole involves synergistic action of the two drugs. This is true only from a laboratory point of view; several considerations have led to the conclusion that the synergism between the two components is of only in vivo marginal importance in determining the clinical efficacy of co-trimoxazole. This is due to a greater tissue affinity of trimethoprim compared to that of sulphamethoxazole and, therefore, to the different tissue concentration ratios obtained in vitro and in vivo. Another claim sustaining the combination is the prevention of developing resistance to trimethoprim; however, there is no substantial clinical evidence to support this claim. It does seem likely that trimethoprim has protected against the emergence of that sulphonamide resistance. This slight benefit is outweighed by the disadvantages of the combination, mainly consisting of the occurrence of adverse events due to the sulphonamide moiety. Consequently, the incidence and severity of the adverse events seen with co-trimoxazole should be reduced by using trimethoprim alone. There are only a few cases where co-trimoxazole is better than trimethoprim: toxoplasmosis, brucellosis, nocardiosis, chancroid and pneumonia due to Pneumocystis carinii. For the other and many common infections, scientific rationale, economic and clinical reasons dictate that trimethoprim is superior to co-trimoxazole.

A prospective, randomised study of 56 patients comparing teicoplanin with vancomycin for suspected or proven severe Grampositive infection was conducted. The majority of infections were soft tissue infections (8 teicoplanin; 16 vancomycin) and by chance a significantly higher number of Hickman catheter-related infections occurred in the vancomycin arm (4 vs. 14, P < 0.01). Teicoplanin was administered as a single daily dose of 400 mg iv or im; 5 patients received 200 mg following the initial dose of 400 mg. Vancomycin was given 1 g every 12 h. Fifty-four patients were evaluable for efficacy (26 teicoplanin, 28 vancomycin). Of these, 18 episodes in 17 patients (teicoplanin) and 19 episodes in 18 patients (vancomycin) gave an evaluable clinical response, the success rates being similar (76% teicoplanin; 68% vancomycin). Staphylococcus aureus was the most common pathogen isolated; all pathogens were susceptible to both glycopeptides with MICs < 4 mg/l. Bacteriological elimination rates were similar in both groups (71% teicoplanin; 78% vancomycin). Significantly more patients given vancomycin experienced adverse events (7 teicoplanin; 16 vancomycin; P = 0.03). This caused treatment to be discontinued in 4 cases, compared with only one receiving teicoplanin. The most common vancomycin-related events were histamine-associated reactions (15 patients), including 2 cases of Red Man Syndrome, and nephrotoxicity (5 patients). There were no histamine-mediated events and only one case of nephrotoxicity with teicoplanin. Teicoplanin and vancomycin show similar clinical and bacteriological efficacy and teicoplanin is significantly less toxic and easier to use in patients with severe infection.

Co-trimoxazole is still widely used for indications where trimethoprim alone is equally effective. Microbiological and pharmacokinetic considerations reveal that trimethoprim alone provides adequate anti-microbial activity for treatment of conditions for which co-trimoxazole is often given. Synergy may be shown in vitro, but in clinical practice is an unusual occurrence. There is no evidence from clinical studies that the sulphonamide moiety fo co-trimoxazole prevents the development of resistance to trimethoprim. The adverse event profile of co-trimoxazole is a summation of that of sulphonamide and of trimethoprim. Thus, using trimethoprim alone should reduce both the incidence and potential severity of adverse events seen when co-trimoxazole is used. Clinical trials have shown trimethoprim to be as effective as co-trimoxazole in many of the common bacterial infections of the urinary and respiratory tracts. However, there are a few specific varieties of infection for which co-trimoxazole can be shown to be superior to trimethoprim: these include toxoplasmosis, brucellosis, nocardiosis, chancroid and pneumonia caused by Pneumocystis carinii. For many common infections, scientific, rational, economic and clinical reasons dictate that trimethoprim is preferable to co-trimoxazole.

Staphylococcus aureus strains resistant both to methicillin and aminoglycosides emerged during the late 1970s. These have become endemic in hospitals all over the world. Outbreaks of infection and colonization may cause severe clinical and managerial problems, as therapeutic options are limited and it may be difficult to clear the carrier state. The genetics and biochemistry of these organisms are well studied, but additional antibiotics active against these strains are needed. The most urgent requirement is for rational and effective policies for control of their spread.

Phagocytosis and intracellular killing of two strains of Escherichia coli and a Staphylococcus saprophyticus by polymorphonuclear neutrophils (PMN) in pooled sterile urine at three osmolalities (800, 485, and 200 mosM/kg of H2O) between pHs 5 and 8 was investigated. Urine at 800 mosM virtually abolished phagocytosis of both E. coli strains, regardless of pH, and reduced the phagocytosis of S. saprophyticus to 30%; no killing of any organisms took place at this osmolality. On the other hand, phagocytosis was a good in urine as in Hanks balanced salt solution at both 485 and 200 mosM between pHs 6 and 8. Phagocytosis of all three strains was virtually abolished at pH 5. Killing of the strains by PMN was optimal between pHs 6.5 and 7.5 in urine at 485 mosM (being at least 90% of the control values in Hanks balanced salt solution), whereas at 200 mosM killing was reduced to 50 to 70% of these values. Reduced killing of all three strains occurred at pH 8, whereas at pH 6 only S. saprophyticus was killed. Thus, the bactericidal activity of PMN in urine was more sensitive than phagocytic function to alterations in pH. The dominant modulating factor affecting PMN function in urine of 500 mosM or less was pH, but osmolality had a greater influence at 800 mosM. Thus, raising the pH of urine and reducing the osmolality may increase the ability of natural defense mechanisms to eliminate infecting organisms.

The oxazolidinone compound E3709, which contains a 4-pyridyl group, was found to be more active in vitro than other members of this series, such as DuP 721. MIC90 for staphylococci(including methicillin-resistant isolates), streptococci (including Enterococcus faecalis), Clostridia, and diphtheroids was less than 0.5 micrograms/ml. Haemophilus influenzae, Moraxella catarrhalis, and Bacteroides fragilis were less susceptible, with an MIC90 between 2 and 8 micrograms/ml. E3709 MICs of Gram-negative species ranged from 100 to greater than 1000 micrograms/ml. At a concentration of 10 micrograms/ml, E3709 was bactericidal for selected Gram-positive species. A postantibiotic effect of 3 hr was observed against staphylococci. Resistance to E3709 was not detected.

Two different doses of cefaclor advanced formulation (AF), a new sustained-release formulation of cefaclor, were compared with the regular formulation of cefaclor for efficacy and safety in the treatment of uncomplicated cystitis and asymptomatic bacteriuria. A 7-day course of treatment was used, and the trials were double-dummy and double-blind. In one trial, cefaclor AF 500 mg once daily (at night) was compared with cefaclor 250 mg three times a day. Satisfactory clinical and bacteriological responses were found in 179/189 (94.7%) and 160/191 (83.8%) patients, respectively, given cefaclor AF and in 82/87 (94.3%) and 74/90 (82.2%) patients given cefaclor, 5-9 days after the end of treatment. In the other trial, cefaclor AF 375 mg twice daily was compared with cefaclor 250 mg three times a day. Satisfactory clinical and bacteriological responses were obtained in 164/180 (91.1%) and 156/184 (84.8%) patients, respectively, given cefaclor AF, and in 86/92 (93.5%) and 81/93 (87.1%) patients taking cefaclor, 5-9 days after the end of treatment. Very similar results were found in both studies in those patients who were assessable 3-5 weeks later. Only 4.3% and 2.4% of patients treated with cefaclor AF (375 mg and 500 mg, respectively) and 2.2% of cefaclor patients discontinued therapy due to adverse events. The three most commonly reported events were vaginal moniliasis or vaginitis (8.6%), headache (5.0%) and nausea (4.8%). No significant differences were found between clinical efficacy and safety parameters in the different study groups, and it was concluded that cefaclor AF in a twice-daily or once-daily dosage is as effective and as safe as the currently recommened three-times-a-day dosage of cefaclor.

Minimum inhibitory and minimum bactericidal concentrations (MIC and MBC) of daptomycin and of vancomycin have been compared against 80 strains of methicillin-resistant Staphylococcus aureus isolated from many parts of the world. In the presence of 30 mg/l of Ca++, daptomycin at 4 mg/l killed all the strains tested, and was only slightly less active than vancomycin.

Eighty women with recurrent urinary infections (a median of seven episodes per year) were randomized to twelve months prophylaxis with cefaclor 250 mg or macrocrystalline nitrofurantoin 50 mg, at night. Seventy-three patients (37 given cefaclor and 36 given macrocrystalline nitrofurantoin) were assessable for efficacy. The incidence of radiological abnormalities in the two treatment groups was 23% and 30% respectively. Ninety-five percent of the patients taking cefaclor were symptomatically improved during the twelve months of prophylaxis and 86% remained abacteriuric; corresponding figures in the group taking macrocrystalline nitrofurantoin were 86% and 85% respectively. There were 88 breakthrough infections in patients taking cefaclor (6 resistant strains), and 9 in those patients taking macrocrystalline nitrofurantoin (6 by resistant strains). The mean interval between symptomatic episodes on prophylactic therapy increased by 5.6-fold in patients taking cefaclor, and 4.3-fold in those taking macrocrystalline nitrofurantoin. Resistant coliforms were found in only 3 out of 37 patients studied after twelve months prophylaxis; these organisms did not proceed to cause infections. All 80 patients were assessable for adverse events: 5 out of 39 taking cefaclor (12.8%) reported an event "probably" associated with the antibiotic, and 3 (7.7%) stopped taking the drug for various reasons; corresponding figures for macrocrystalline nitrofurantoin were 17.1% and 9.8% respectively. Patients with a radiological abnormality responded well to long-term low-dose prophylaxis with either agent. Cefaclor seems to offer an alternative to macrocrystalline nitrofurantoin for the prophylaxis of recurrent urinary infections in women.

One hundred and thirteen patients with dysuria and/or frequency were treated randomly with either 500 mg cephradine 12-hourly or 125 mg cefuroxime axetil 12-hourly, for seven days. A total of 71 patients were found to have urinary infection: bacteriological cure rates were 97% one week post-treatment, and 96% five weeks post-treatment, for both antibiotics. On direct questioning, adverse events were reported by eight patients out of 59 taking cephradine and by three of 54 who had received cefuroxime axetil. However, only three and one respectively stopped taking the antibiotic due to the adverse event. Analysis of diary cards, completed by 109 patients, showed a significantly higher incidence of increased frequency of bowel movements in those taking cefuroxime axetil. It is concluded that both antibiotics are of equal value in the treatment of simple acute urinary infections in general practice.

Eighty-eight women with a history of recurrent urinary tract infection (at least four attacks in the preceding 12 months) were randomized to take either norfloxacin 200 mg at night (45 patients) or macrocrystalline nitrofurantoin 100 mg at night (43 patients) for 12 months. A decrease in the number of symptomatic attacks while taking this prophylaxis was observed in 94 per cent of the patients and this improvement was maintained during the 6 months following the end of prophylaxis in 69 per cent. The mean interval between symptomatic episodes while taking prophylaxis was 7.2-fold and 6.9-fold greater, respectively, than in the 12 months before starting prophylaxis. There were only nine breakthrough infections during 74 patient-years of prophylaxis, four in patients taking norfloxacin (two enterococci, one Staphylococcus epidermidis, one Escherichia coli), and five in those taking macrocrystalline nitrofurantoin (four E. coli, one Klebsiella pneumoniae). Adverse events caused four patients taking norfloxacin (8 per cent) and seven taking macrocrystalline nitrofurantoin (14 per cent) to stop prophylaxis. Norfloxacin had a marked suppressive effect on the coliform part of the faecal flora, with no emergence of resistance. Thus, norfloxacin appears to be an excellent alternative agent to macrocrystalline nitrofurantoin for the prevention of recurrent urinary infections.

SUMMARY Eighty-eight women with a history of recurrent urinary tract infection (at least four attacks in the preceding 12 months) were randomized to take either norfloxacin 200 mg at night (45 patients) or macrocrystalline nitrofurantoin 100 mg at night (43 patients) for 12 months. A decrease in the number of symptomatic attacks while taking this prophylaxis was observed in 94 per cent of the patients and this improvement was maintained during the 6 months following the end of prophylaxis in 69 per cent. The mean interval between symptomatic episodes while taking prophylaxis was 7.2-fold and 6.9-fold greater, respectively, than in the 12 months before starting prophylaxis. There were only nine breakthrough infections during 74 patient-years of prophylaxis, four in patients taking norfloxacin (two enterococci, one Staphylococcus epidermidis , one Escherichia coli ), and five in those taking macrocrystalline nitrofurantoin (four E. coli , one Klebsiella pneumoniae ). Adverse events caused four patients taking norfloxacin (8 per cent) and seven taking macrocrystalline nitrofurantoin (14 per cent) to stop prophylaxis. Norfloxacin had a marked suppressive effect on the coliform part of the faecal flora, with no emergence of resistance. Thus, norfloxacin appears to be an excellent alternative agent to macrocrystalline nitrofurantoin for the prevention of recurrent urinary infections.

Minimum inhibitory concentrations of cefixime, cefaclor and loracarbef have been determined against 200 strains of bacteria, representing a wide selection of species causing urinary infections. Cefixime was poorly active against Gram-positive species, but was active (MIC90 less than 2 mg/l) against almost all the Gram-negative pathogens tested (except Pseudomonas aeruginosa), and particularly so against Klebsiella pneumoniae and members of the tribe Proteae. Cefaclor and loracarbef were more active against the Gram-positive species than was cefixime, but had a less broad spectrum against the Gram-negative species. Cefixime use seems more appropriate in nosocomial than in domiciliary urinary infections.

Effective drugs are available for the short-term treatment and long-term prophylaxis of UTI in the elderly population in the absence of obstructive uropathy, just as in younger patient groups. The frequency of treatment failures and adverse reactions varies with the type and dosage of the drug in use as well as the subpopulation of elderly patients being treated.

The evolution of the fluoroquinolones is described, and structure-activity relationships outlined. The in-vitro antimicrobial activities of ciprofloxacin, enoxacin, norfloxacin, ofloxacin and pefloxacin against a wide range of organisms are critically reviewed. In-vitro factors influencing fluoroquinolone activity are discussed. Reports of the acquisition of resistance to the fluoroquinolones are evaluated. Finally, possible future directions for this group of antibiotics are discussed.

Eighty-eight female patients with a history of recurrent urinary tract infections were treated according to a randomization scheme with either 1 g of cephradine every 12 h (47 patients) or 375 mg of amoxicillin-clavulanate every 8 h (41 patients) for 7 days. The treatments were equally effective (cure rates of 89% for cephradine and 88% for amoxicillin-clavulanate) and showed similar relapse rates (cephradine, 14%; amoxicillin-clavulanate, 11%). Adverse effects were similar in both groups (cephradine, 23%; amoxicillin-clavulanate, 22%).

We report five cases of continuous ambulatory peritoneal dialysis in which the mechanisms and sources of infection were established. We show how diligent enquiry and environmental investigation can explain the pathogenesis of infection and help in prevention by motivation of the patient.

Material extracted from propolis (bee glue) by alkaline aqueous solvents or organic solvents showed weak inhibitory activity in vitro against certain species of Gram-positive bacteria. No antimicrobial activity was detected in urine from three volunteers who had taken 500 mg propolis three times a day for 3 days.

Strains of Staphylococcus aureus resistant to both methicillin and aminoglycosides (e.g. gentamicin) emerged during the late 1970s. They have now become established in hospitals throughout the world, and outbreaks of infection and colonization cause severe clinical and managerial problems. Therapeutic options are limited and clearance of the carrier state may be difficult. Much is known about the genetic and biochemical properties of the organisms but more work is necessary both to develop antibiotics active against these strains and to formulate effective measures for their control.

A clinical trial comparing 5 days' treatment with amoxycillin/clavulanate (group A) and a single dose of fosfomycin trometamol (group B) is presented. The study was done in symptomatic patients presenting to their family practitioner, with the microbiological testing being carried out in a university hospital laboratory. Of 62 patients with significant bacteriuria, 29 were given amoxycillin/clavulanate and 33 fosfomycin trometamol, in a randomized fashion. Cure rates 1 week and 5 weeks after the end of treatment were 72 and 65% in group A and 85 and 81% in group B. Adverse events assessed in 141 patients were unusual (10.1% in group A and 8.3% in group B) and were mild in nature. The results of this study suggest that single-dose treatment with fosfomycin trometamol is effective and acceptable as a conventional course of amoxycillin clavulanate for the treatment of simple acute dysuria and/or frequency with infection.

In patients with a history of recurrent infections, treatment with enoxacin (200 mg/12 h for 3 days) relieved symptoms of acute urinary infection significantly more rapidly than treatment with cefuroxime axetil (125 mg/12 h for 7 days). Other parameters, including clinical and bacteriological cure rates and patients' overall opinion of their treatment, did not differ significantly between the treatments.