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The current document bestows an expert synopsis of key new information presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting in 2003. Data is presented on the socio-political aspects of and policies on antimicrobial prescribing, novel mechanisms of resistance in Streptococcus pneumoniae, and current epidemiological trends in global resistance. Novel information on new (and existing) antimicrobial agents--new penicillins, cephalosporins, monobactams and oxipenem inhibitors, ketolides, glycopeptides, fluoroquinolones (and hybrids), peptides, daptomycin, aminomethylcyclines, glycylcyclines, and newer formulations of agents such as amoxycillin-clavulanate--provides renewed hope that resistant pathogens can be controlled through use of more potent agents. Improved strategies for the use of existing antimicrobial agents, such as the use of high-dose regimens, short-course therapy, also may delay or reduce the development of resistance and preserve the value of our antibiotic armamentarium.

Lower respiratory tract infections account for a large proportion of prescribed antibiotics and, with emerging resistance to standard agents, the introduction of the fluoroquinolones, in particular ciprofloxacin, has provided a further component in the armamentarium. This review encompasses 37 published clinical trials which featured ciprofloxacin; 3274 patients with lower respiratory tract infections were treated with this agent; in 94.1% of patients treatment was clinically successful and 90.9% of cases showed eradication of the causative pathogen. When these data were supplemented with previously unpublished information from the clinical trial database, specific organism eradication rates of 86.1%, 96.2% and 94.6% for Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis, respectively, were observed. These findings suggest that the high respiratory tissue penetration of ciprofloxacin and the achievable minimum inhibitory concentrations lead to acceptable clinical outcomes in lower respiratory tract infections.

Azithromycin, a novel azalide antibiotic structurally related to erythromycin, has been shown by in vitro studies to have similar activity to erythromycin against Gram-positive pathogens but additionally to have increased activity against some Gram-negative bacteria, notably Haemophilus influenzae. Azithromycin achieves excellent concentrations in tissues, polymorphonuclear leucocytes and alveolar macrophages, and has a prolonged tissue elimination half-life. These properties suggest that short-course, once-daily treatment regimens will be appropriate for a variety of bacterial infections, including those of the respiratory tract, skin and soft tissues. The results of a series of clinical trials using such a regimen are reviewed. It is concluded that azithromycin is clinically and bacteriologically effective in these indications and is well tolerated when compared with regimens using standard antibiotics.

The features of 70 cases of bacterial endocarditis are reported. Streptococcus viridans was the cause in 45 per cent, staphylococci in 27 per cent, and enterococci in 7 per cent. Rheumatic heart disease was the predisposing factor in less than one quarter of patients and in almost half there was no obvious pre-existing cardiac disease. Apart from cardiac murmurs and pyrexia, the classical features of infective endocarditis were uncommon, haematuria being observed in less than one-third. Most patients were over the age of 30, one-third more than 60 years of age and the peak incidence occurred in the seventh decade. The mortality was 34 per cent, being highest in infection caused by Staphylococcus aureus. Adverse prognostic features included cardiac failure, advanced age and peripheral embolization. One-third of infections were caused by bacteria resistant to penicillin.

We have studied cefuroxime, a new beta-lactamase resistant cephalosporin, and cefoxitin, the first cephamycin antibiotic, which is also resistant to many beta-lactamases. Both of these antibiotics have been shown to be microbiologically superior to the "first generation" cephalosporins, cefuroxime having notable activity against Haemophilus influenzae, and cefoxitin against Bacteroides fragilis. Neither antibiotic is absorbed from the gut but, following parenteral administration, serum, urine and bile concentrations are high. Clinical trials have been conducted on both cefoxitin and cefuroxime. The results of these have been satisfactory and untoward side-effects minimal. We suggest that cefoxitin will be particularly valuable in the management of abdominal sepsis and cefuroxime in infections caused by H. influenzae.

Since the development of the sulphonamides in the 1930s and the subsequent development of antibiotics from the 1940s onwards, there have now been many drugs developed which are capable of chemotherapeutic activity in a patient infected by a susceptible micro-organism. This review is concerned with precise descriptions of important groups of antimicrobial drugs, with emphasis being placed on the more recently developed drugs. With each group of drugs the pharmacology, major therapeutic indications, dosages and adverse reactions are discussed. Part II of the review discusses the cephalosporins, polymyxins and aminoglycosides. The place of each in therapy is defined.

In this paper infections associated with immunological and white blood cell deficiencies are discussed, together with certain aspects of infection in patients suffering from chronic renal failure and other non-malignant disease states. Reference is made to experience of opportunistic infections at East Birmingham Hospital, and certain aspects of the prevention and management of these conditions are outlined.

Ciprofloxacin is a new 4-quinolone antibacterial agent with an extended antibacterial spectrum, enhanced potency and the ability to produce therapeutic serum, tissue and urine concentrations after oral administration. Unlike earlier 4-quinolones, it is active against gram-positive cocci and opportunistic organisms such as Pseudomonas aeruginosa. This overview demonstrates that the oral formulation has been shown to be clinically effective in a broad range of urinary and respiratory infections, gonorrhoea, gastro-intestinal infections including typhoid fever, surgical infections, skin and soft tissue sepsis and in a variety of infections caused by Pseudomonas aeruginosa, notably cystic fibrosis. Adverse reactions are infrequent and in almost every case have proved mild and transient. Ciprofloxacin has great potential for the oral therapy of infections which have traditionally required parenteral chemotherapy.

Fourteen patients with infections caused by Serratia marcescens were seen over an eight-month period in a large general hospital. Predisposing factors suggested an 'opportunistic' pattern similar to that previously described in the United States. S. marcescens is an important pathogen which may be increasing in significance in the United Kingdom. Multiple resistance of the organism to antibiotics other than gentamicin makes the finding of apparent sensitivity to co-trimoxazole of potential therapeutic value.

An intravenous formulation of Augmentin was used as sole chemotherapy in the treatment of patients with severe infections. Fourteen of 17 assessable patients (82%) responded satisfactorily including six with bacteraemia. Adverse reactions occurred in 38% of patients but in all but one, withdrawn due to diarrhoea, were trivial. There was no significant intolerance.

We treated 193 patients either intravenously (94) or subcutaneously (99) for at least 5 days with porcine intestinal mucosal heparin and followed them up prospectively with frequent platelet counts to determine the incidence of heparin-related thrombocytopenia and arterial thrombosis. None of the patients in the study developed severe thrombocytopenia (platelet count, less than 100 x 10(9)/L) or arterial thrombosis. Eight patients had a platelet count of 100 to 140 X 10(9)/L on one occasion, with a count of greater than 140 x 10(9)/L on the subsequent measurement. The mean (+/- SD) values of the initial and lowest platelet counts during therapy in all patients were 288 +/- 100 x 10(9)/L and 253 +/- 88 x 10(9)/L, respectively, with the lowest counts occurring on day 4.1 +/- 4.2. A least-squares line was computed for each patient to fit the day and counts; the slopes were significantly different from zero and negative in 7.8% of patients and positive in 14.5%. This multicenter study confirms the reports that the incidence of heparin-related severe thrombocytopenia and arterial thrombosis is distinctly low in patients treated with porcine-mucosal heparin.

Cefoxitin is a new cephamycin antibiotic that has recently become available for clinical trial. We report here the results of an uncontrolled trial of cefoxitin treatment in 31 hospital patients with various acute infections, 20 of whom were cured. Serum, urine, and bile concentrations of cefoxitin greatly exceeded the minimum inhibitory concentration (MIC) required for clinically important Gram-negative organisms. We conclude that cefoxitin will have a place in the management of serious infections, particularly in the abdominal cavity and renal tracts.

In the summer of 1975 an extensive epidemic of disease due to echovirus type 19 occurred in the West Midlands. The features of this outbreak, and their relationship to the syndrome referred to as 'epidemic neuromyasthenia', are discussed. The two diseases are considered to be separate entities.

Cefuroxime axetil, an orally absorbed pro-drug of cefuroxime was used to treat a mainly elderly group of patients with symptomatic urinary tract infections. The drug was clinically effective and the bacteriological short term and long term cure rates (55% and 48% respectively) comparable to those of other antibiotics. The study had to be terminated however after the development of three cases of antibiotic associated colitis. Studies of the pharmacokinetics of the drug in volunteers gave inconsistent results suggesting that there may be variable bioavailability of the compound.

The pharmacokinetics of ciprofloxacin following a single 100 mg oral dose were evaluated in elderly patients (mean age 74 years), laboratory staff (30-40 years) and students (less than 20 years). There were no significant differences in serum Tmax (1.2-1.3 h) or in overall serum elimination half-life (3.7-4.0 h) but Cmax in elderly patients was more than double that in young volunteers (P less than 0.005). The serum AUC value was greater both in fasting students (1.4 mg/h/l) compared with the same subjects after food (1.09: P less than 0.01) and, after food, in elderly patients (1.95) compared with students (0.81: P less than 0.005). Urinary recoveries were greater in fasting subjects and in all categories of volunteers compared with elderly patients. However, in the elderly, urinary ciprofloxacin concentrations (0-6 h mean 66 mg/l: range 17.4-200 mg/l) were more than adequate for the eradication of urinary pathogens.

Factors affecting fibrin formation and dissolution were compared for 15 women taking combined oral contraceptives and 15 women using nonpharmacological methods of birth control. The two groups were matched for age, body weight, time of blood collection, and day in menstrual cycle; none of the women was receiving other drugs known to affect the blood coagulation or fibrinolytic parameters measured in this study. Fibrinogen concentrations tended to be higher in the experimental group; the degree of fibrinogen degradation, number of fibrin cross-links, and levels of factor XIII and plasminogen were the same for both group. There were significant reductions in antithrombin activity, the euglobulin lysis time, and fibrinolytic inhibitor level in women using oral contraceptives. An estrogen dose effect was suggested for fibrinogen concentration and the degree of antithrombin activity. The increased fibrinolytic activity and decreased fibrinolytic inhibitor levels are consistent with in vitro observations that antithrombin also inhibits plasmin activity. Thus while oral contraceptive-induced depression of antithrombin III could possibly predispose to thrombosis by diminishing the inhibition of the serine protease clotting factors, the concomitant decreased level of plasmin inhibition might balance the system by favoring thrombolysis as well as the digestion and inactivation of certain clotting factors by plasmin.

We have investigated the pathway of prothrombin activation in blood and plasma. By means of a rapid purification procedure involving chromatography on DEAE-cellulose and hydroxyapatite, we demonstrated that the major prothrombin fragment in serum is that representing the amino-terminal half of prothrombin (i.e. F1-2). The F1-2 isolated was characterized by its size, amino acid and antigenic compositions, amino-terminal residue, and the peptides (designated F1 and F2, respectively) it yielded upon hydrolysis by thrombin. Measurements by the isotope dilution technique showed that F1-2 could account for the fate of at least 90% of the prothrombin originally present in plasma. By contrast, the serum concentration of the fragment representing the amino-terminal third of prothrombin (viz. F1) was less than 10% that of F1-2. These results demonstrated that the major route of prothrombin conversion in blood or plasma involves the removal of the combined activation fragment (F1-2) as a single peptide.

Isolated genetic deficiencies of complement components in man are rare. We describe two kindreds with inborn deficiencies of either C5 or C6 in which both propositi presented with recurrent bacterial meningitis. Neisseria meningitidis was isolated from the cerebrospinal fluid of the C5-deficient patient and bactericidal activity against his autologous meningococcus was absent from whole fresh patients' serum despite a rising titre of complement-fixing antibody. The stimulated movement of normal leucocytes was impaired in the presence of C5-deficient serum but not in the presence of C6-deficient serum; neither deficiency reduced significantly the complement-dependent opsonization of Saccharomyces cerevisiae. HLA typing and complement component phenotyping showed no segregation with the complement defect in either the C5- or C6-deficient families. Normal individuals and apparent heterozygotes with approximately half the normal levels of the relevant component were found in both families, in keeping with an autosomal codominant inheritance of the defects.

28 patients suffering from a variety of bacterial infections have been treated with cefuroxime. 18 were cured and 6 improved during treatment. Side effects were minimal and intramuscular injection was well tolerated. Serum and urine levels well in excess of the MICs of sensitive organisms were obtained using dosages of 750 mg 8 hourly. Biliary excretion was impaired in the presence of obstruction, but adequate bile levels of cefuroxime were observed following relief of the obstruction. Cefuroxime was widely active against gram-negative bacilli and against Streptococcus faecalis, but less active against Bacteroides spp.

Twenty-six patients with enteric fever treated with amdinocillin and/or its pivaloyloxymethyl ester in 1975 to 1978 were compared with 21 patients with enteric fever treated with trimethoprim-sulfamethoxazole in 1972 to 1974. Diagnosis was based on clinical illness and isolation of Salmonella typhi or S. paratyphi A/B from blood cultures or stool cultures. The dosage of pivamdinocillin in adults was 400 to 800 mg, every 6 hours, for 10 to 16 days; dosage in children was half this amount for 11 to 15 days. Of the 21 patients treated with trimethoprim-sulfamethoxazole, 18 (86 percent) showed a satisfactory clinical response; 13 of these 18 had negative stools immediately after therapy, and two more were negative at the time of discharge (total: 83 percent). Mean hospital stay of these patients was 34.5 days. Of the 26 patients treated with amdinocillin, 23 showed a satisfactory clinical response; 20 of those responding clinically were still excreting the causative organism at the end of therapy; seven of the group remained as convalescent patients who continued to excrete the causative organism in feces at the time of discharge. Mean hospital stay was 43 days. The results of initial trials of amdinocillin and ampicillin in combination suggest that such therapy may be preferable to use of amdinocillin alone, although the excretion of the causative organism during convalescence has not been adequately assessed.

Members of the viridans group of streptococci are the commonest causes of bacterial endocarditis. However, Streptococcus mutans, a member of this group associated with dental caries which might be expected to be commonly associated with endocarditis, has only rarely been reported. This is possibly because of difficulties in isolation and identification. Differing blood culture media may affect the chances of isolation of these organisms, and, though brain-heart infusion, thiol, tryptic soy, and glucose-brain infusion broths have all proved satisfactory, subcultures may require increased CO2 concentrations for growth. Plemorphism in the resultant colonies and in the individual organisms may give rise to a hazardous misinterpretation of this appearance as contamination. Strep. mutans and the similarly penicillin sensitive Strep. bovis may be differentiated from the penicillin resistant enterococci by their lincomycin sensitivity and intolerance of 6-3 per cent sodium chloride. Precise differentiation of streptococci in bacterial endocarditis is of value both epidemiologically and in the management of the disease.

Clavulanic acid is an inhibitor of certain beta-lactamases, notably those enzymes which inactivate the penicillins and cause resistance of important bacteria to these antibiotics. Microbiological, pharmacological, and clinical studies show that clavulanic acid in combination with amoxycillin is effective and safe in the treatment of urinary-tract infection caused by amoxycillin-resistant bacteria.

The results of a clinical trial of sultamicillin, a novel mutual pro-drug combination of ampicillin and the beta-lactamase inhibitor sulbactam, in ampicillin-resistant urinary tract infections are reported. The majority of infections treated occurred in elderly geriatric in-patients. Two dosage schedules were investigated, both resulting in the same total daily dosage (1500 mg sultamicillin). These were 750 mg sultamicillin, 12-hourly (series I) and 500 mg sultamicillin, 8-hourly (series II), each administered orally for seven days. Short term cure rates (after exclusion of superinfections and reinfections) of 79.5% (series I) and 82% (series II) were obtained one week after therapy, falling to 69% and 50%, respectively, at three to six week follow up. Sultamicillin was well tolerated. Pharmacokinetic studies confirmed intestinal absorption of both constituents in young volunteers and in the elderly.