Hepatitis C virus infection.

Hepatitis C virus (HCV) infection is a major public health problem. Up to 3% of the world's population is infected with HCV, and at least 200 000 adults in the UK carry the virus. Of those exposed to HCV, 80% become chronically infected, and at least 30% of carriers develop chronic liver disease, including cirrhosis and hepatocellular carcinoma. This review provides an overview of selected features of the molecular biology and pathogenesis of HCV infection, and thereafter discusses in detail the epidemiology of HCV, the hepatic and extra-hepatic diseases caused by the virus, and the current treatment options for both acute and chronic virus infection. The special cases of healthcare workers, prison inmates and individuals coinfected with human immunodeficiency virus and HCV are considered in detail.

Third-generation cephalosporins in the treatment of rare infections.

This article reviews the published clinical experience of the use of the third-generation cephalosporins in the treatment of rare infections. Rare infections are defined as those caused by unusual pathogens or multi-resistant organisms as well as those occurring in unusual or pharmacologically protected body sites. Examples of such infections are uncommon causes of meningitis and ventriculitis, brain abscess, rare causes of bacterial endocarditis, metastatic Salmonella infections, spontaneous bacterial peritonitis and liver abscess, late complications of Lyme borreliosis, uncommon Pseudomonas infections, and post-reconstructive surgery Aeromonas cellulitis. Although these data are largely anecdotal, they form a useful body of information, providing guidance on the management of similar problems encountered by other doctors, while suggesting areas of further investigation for the management of a variety of unusual infections with the third-generation cephalosporins.

Antibacterial activity of quinupristin/dalfopristin. Rationale for clinical use.

Most Gram-positive organisms are highly susceptible to the streptogramin, quinupristin/dalfopristin (RP 59500; Synercid). Minimum inhibitory concentrations for 90% of isolates (MIC90) were < or = 1 mg/L for Staphylococcus aureus, S. epidermidis, S. haemolyticus, Streptococcus pneumoniae, S. pyogenes and Listeria monocytogenes. Importantly, quinupristin/dalfopristin shows similar activity against methicillin-susceptible and -resistant strains of S. aureus, and streptococci with benzylpenicillin (penicillin G)- or erythromycin-acquired resistance. Enterococci have varying susceptibility to quinupristin /dalfopristin, although most isolates tested are susceptible to the drug, including vancomycin-resistant and multiresistant Enterococcus faecium. E. faecalis are generally the least susceptible. Among the Gram-negative respiratory pathogens Moraxella catarrhalis is susceptible and Haemophilus influenzae is moderately susceptible to quinupristin/ dalfopristin; however, Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter spp. are resistant. The drug is active against anaerobic organisms tested, including Clostridium perfringens, Lactobacillus spp., Bacteroides fragilis and Peptostreptococcus. Synergy has been demonstrated in vancomycin-resistant and multiresistant E. faecium, and methicillin-sensitive and -resistant S. aureus with the combination of vancomycin and quinupristin/ dalfopristin. Quinupristin/dalfopristin shows antibacterial activity in vivo in animal models of infection, including methicillin-sensitive and -resistant S. aureus infection in rabbits, S. aureus and S. pneumoniae in mice, and erythromycin-sensitive and -resistant viridans group streptococci infections in rats. The drug is rapidly bactericidal against Gram-positive organisms (with the exception of enterococci) at concentrations similar to or within 4-fold of the MIC, and it has a long postantibiotic effect both in vitro and in vivo.

The role of new quinolones in the treatment of respiratory tract infections.

Infections of the respiratory tract are the leading cause of antibacterial prescribing in both hospital and community practice. The microbial aetiology is diverse in both of these settings and differs in the distribution and virulence of the pathogens. Furthermore, in recent years the antibacterial susceptibility of many of the common pathogens has changed significantly. In particular, penicillin resistance has emerged among pneumococci, while beta-lactamase production among Haemophilus influenzae and many Gram-negative bacilli has led to alterations in first-line therapy options. The fluoroquinolone antibacterials have been used in selected respiratory tract infections, but concerns have remained with regard to their efficacy in infections caused by marginally susceptible organisms, and in particular pneumococcal infections. The availability of a number of quinolones with enhanced Gram-positive activity, which includes Streptococcus pneumoniae, is of considerable interest. In vitro data and preliminary clinical experience with sparfloxacin suggest that managing pneumococcal lung disease with this and future agents is a distinct possibility. One caveat must be considered, and that is the potential for more resistant strains of pneumococci emerging, against which even these new quinolones could prove less effective.

Practical considerations and guidelines for the management of community-acquired pneumonia.

Community-acquired pneumonia (CAP) is a common condition which has a significant mortality. The management of a patient with CAP is centred around assessment and correction of gas exchange and fluid balance together with administration of appropriate antibiotics. Up to 10 different pathogens regularly cause CAP, of which Streptococcus pneumoniae is the most important. These different pathogens cannot be distinguished by clinical features or simple laboratory tests. Microbiological tests are slow and insensitive, so empirical therapy is necessary, at least initially. Accurate assessment of illness severity is the most important factor determining initial management, since this assists the decision of whether to admit the patient to hospital in addition to guiding antibiotic choice and route of administration. Two different approaches to severity assessment are outlined. Our antibiotic recommendation for empirical therapy for the patient managed at home and the previously fit patient admitted to hospital is amoxicillin. Amoxicillin/clavulanate plus a macrolide is our choice for the severely ill previously fit patient and a third-generation cephalosporin plus a macrolide is recommended for the severely ill patient with comorbidity. Alternative pathogens and specific treatment regimens are also described. There may be several causes of treatment failure, and in patients who fail to respond to therapy, it is essential to review all the initial clinical and laboratory information, which if necessary must be repeated.

MHC haplotype influences primary Giardia muris infections in H-2 congenic strains of mice.

The course of primary Giarda muris infections was studied in H-2 congenic strains of mice on the BALB and C57BL/10 (B10) genetic backgrounds. Infection was curtailed more rapidly in B10 strains, compared with BALB strains, and unaffected by H-2 haplotype. On the other hand the duration of infection in BALB strains did vary with H-2 haplotype with BALB/B(H-2b) mice taking significantly longer to clear infection than BALB/c(H-2d) and BALB/K(H-2k) mice. These experiments demonstrate that both MHC and non-MHC genes influence the outcome of primary G.muris infections.

Serological grouping of streptococci by a slide coagglutination method.

A new method for the serological grouping of streptococci by coagglutination with specific antibodies absorbed to protein A-containing staphylococci has been assessed. A total of 242 strains of streptococci, including beta-haemolytic streptococci of groups A, B, C, F, and G, Streptococcus pneumoniae and Strep. faecalis were studied. All streptococci of groups A, B, C, and G, groupable by standard methods, were correctly grouped by coagglutination, although 7-3% showed varying degrees of cross-agglutination. Two beta-haemolytic strains of Strep. faecalis produced coagglutination with group C streptococcal reagent. The method appears to be quick, accurate, reproducible, and simple to perform.

Stimulation of growth on a deficient medium of a Klebsiella aerogenes species by sulphonamide, para-amino benzoic acid, nitrofurantoin, and some other substances.

A strain of Klebsiella aerogenes is described which was unable to grow from light inocula on 5% lysed horse blood diagnostic sensitivity test (DST) agar. It was able to grow on DST agar without added horse cells and MacConkey and nutrient agar. Growth on a deficient medium was promoted by sulphonamides and nitrofurantoin as well as by para-amino benzoic acid, para-amino salicylic acid, procaine hydrochloride, thymine, and uracil.

Pneumonia: the impact of antibiotic resistance on its management.

Pneumonia in the community affects between 1 and 5 per 1000 per year. The microbial aetiology is diverse and influenced by preexisting disease, seasonality, as well as animate and inanimate environmental sources; pneumococci, Legionella spp., Mycoplasma pneumoniae, and more recently Chlamydia pneumoniae are the predominant bacterial pathogens. Gram-negative enteric bacteria although less common are particularly virulent. Antibiotic resistance is well established for Haemophilus influenzae and Gram-negative bacillary infections, but has been a recent phenomenon in the case of Streptococcus pneumoniae, which is numerically the leading pathogen. Despite the concerns raised by this reduced susceptibility to penicillin, evidence that this has been translated into increased clinical failures is currently difficult to establish. Macrolide and tetracycline resistance among pneumococci is more common. beta-Lactamase production by H. influenzae has now reached levels where, in those with severe pneumonia, beta-lactamase stable agents are preferred. Consensus Guidelines on the treatment of community acquired pneumonia have been published by the British Thoracic Society, the American Thoracic Society, and from Expert Panels in Canada and France. These emphasize severity assessment and differentiate management in the community or hospital setting. The recommended regimens are compared and contrasted. In conclusion, mild/moderate pneumonia, when pneumococcal in nature, is likely to still respond to amoxycillin or penicillin G, but in higher dosages where pneumococcal resistance is documented. However, in severe infection where pneumococcal resistance, other beta-lactamase-producing pathogens, or an atypical infection could be operating, it is important that initial empirical therapy be broad spectrum and promptly administered. Treating multiresistant pneumococcal disease in those allergic to beta-lactams presents a particular dilemma. Glycopeptides are currently preferred.

Characterisation and antibiotic susceptibilities of Streptobacillus moniliformis.

The characteristics of seven strains of Streptobacillus moniliformis, including four isolates from a recent outbreak of Haverhill fever, are reported. Acid production from carbohydrates was uniform apart from variable reactions with mannose and salicin. Enzymatic reactions determined by the API ZYM system and fatty-acid profiles were generally consistent and may be of value in the rapid identification of S. moniliformis. Penicillin was the most active of the antibiotics tested in vitro, which supports its use as the drug of choice in the treatment of Haverhill fever.

A morphological study of bacterial colonisation of intravenous cannulae.

In an investigation of bacterial colonisation of intravascular cannulae, 16 peripheral venous cannulae of the Venflon variety and 24 chronic haemodialysis cannulae were studied after removal from patients. Studies of colonisation included semi-quantitative microbiological culture and scanning electronmicrographic (SEM) observations. The microbiological findings indicated colonisation of the intravascular portion of the catheter in 4 of 16 Venflon cannulae and 18 of 26 haemodialysis cannulae, largely with skin commensal organisms. The results of the SEM studies were in broad agreement with the microbiological observations. Surface defects on the cannulae were shown to be associated with microbial colonisation which occurred either as isolated colonies or in association with a cellular fibrinous matrix. These observations are illustrated and discussed.

Peritonitis complicating continuous ambulatory peritoneal dialysis in Nottingham 1983-1988.

During the period 1983-1988 the incidence of peritonitis in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) in Nottingham fell from 2.0 to 1.2 episodes/patient/year. Cefuroxime, given intraperitoneally for 10 days, as recommended in published guidelines, failed to cure 35% of episodes of peritonitis, although only 7% of the pathogens responsible for these episodes were resistant in vitro. Cefuroxime is probably no longer appropriate as first line treatment of CAPD peritonitis.

Experimental infection of human nasal mucosal explants with Neisseria meningitidis.

The interaction of Neisseria meningitidis with rhinopharyngeal epithelium was studied by experimental infection of explants of human nasal turbinate mucosa with two wild strains: a fully capsulate case isolate, and an epidemiologically related non-capsulate nasopharyngeal isolate. After incubation for 4 h, epithelial cells of infected explants changed conformation from tall columnar morphology towards cuboidal, and there was increased discharge of mucus globules from goblet cells. By 24 h there was significant damage to infected epithelia, including projection of cells out of the surface, cytoplasmic blebbing and mitochondrial abnormalities. Meningococci were associated with surface non-ciliated cells by 4 h after infection. By 24 h after infection they were associated extensively with all cell types exhibiting damage. There was little association with secreted mucus. In areas of cell damage, penetration between surface cells was observed. Endocytosis into non-ciliated cells was observed in only a minority of explants studied and only in those infected for 24 h. From this intracellular site there was apparent migration to adjacent cells and to intercellular locations. No organisms were observed within or beneath basement membrane collagen in any explants but internalisation into mononuclear phagocytes was observed occasionally.

Introduction: standards of antibacterial performance.

The development and clinical use of antimicrobial agents continue to evolve in line with new science, understanding and needs. While antimicrobial resistance remains an important determinant for drug development and therapeutic choice, pharmacokinetic and pharmacodynamic parameters are having an ever-increasing importance in defining performance targets for new and established agents. Recently licensed new therapies are largely directed at serious hospital-associated Gram-positive infections, whereas in the community, therapeutic choice remains dependent on well-established agents from limited classes of antimicrobials. In order to maximise the benefits from such agents, it is appropriate that dosage regimens and antibacterial choices be reviewed in the light of new knowledge, particularly in the area of pharmacokinetics and pharmacodynamics. Antimicrobial resistance continues to evolve, notably within respiratory pathogens, therefore steps must be taken to maintain optimum therapeutic outcomes and also limit the development and spread of resistant strains. Whilst changes in patient and physician attitudes and behaviour towards better quality prescribing are important, new agents must also be developed to provide adequate coverage for resistant pathogens. Development times for novel agents and classes of antimicrobials are long, with uncertain safety profiles and chances of success. Thus, the development of new formulations of existing agents, designed to overcome current resistance patterns, constitutes a potentially important additional strategy towards appropriate prescribing.

Sales of over-the-counter remedies as an early warning system for winter bed crises.

OBJECTIVES: To evaluate the pattern of emergency adult medical admissions during the winter period and the usefulness of sales of over-the-counter cough/cold remedies as a predictor of these. METHODS: The databases of a single NHS trust acute unit and pharmacy outlets in its catchment area were analyzed retrospectively, comparing numbers of emergency admissions, ICD-10 discharge codes, local electronic point-of-sale (EPOS) and national sales data. RESULTS: Over nine consecutive winter periods from 1992/3, peak admissions always occurred within a defined ten-day period from 29th December to 9th January. Emergency admissions increased significantly during this period (P = 0.0002). Pharmaceutical/retail data were available for three consecutive winters 1998/99, 1999/2000 and 2000/2001, none of which coincided with increased influenza activity nationally. Acute respiratory illness as defined by International Classification of Diseases, 10th edition (ICD-10) discharge coding did not appear to contribute to the increase in admissions at the peak. However, National and Local EPOS sales were positively correlated with admissions and the rate of EPOS sales exceeded an empiric threshold of 1000 units per week two weeks prior to the admissions peak in each year. CONCLUSIONS: Emergency admissions over the winter period are increasing and can be expected within a period of only ten days each year. No firm relationship between acute respiratory illness and admissions could be defined but local EPOS data may give up to two weeks warning of the peak in admissions and merits further prospective evaluation.

Limitations of presently available glycopeptides in the treatment of Gram-positive infection.

The glycopeptide antibacterial drugs vancomycin and teicoplanin are widely used in hospitals for therapy of severe or multiresistant Gram-positive infections, notably staphylococcal, enterococcal and rarely pneumococcal. Vancomycin has also been used in the management of Clostridium difficile enteropathy. The incidence and potential for resistance differ between agents. The in vitro activity, pharmacokinetics and clinical use of glycopeptide, as well as epidemiology of glycopeptide resistance are discussed. There are limited comparative studies indicating the need for further investigation. Therapeutic drug monitoring has been widely used for vancomycin and less commonly for teicoplanin, but remains controversial. Advances in our understanding of their pharmacodynamics and clinical studies are helping clarify the situation. This paper reviews the current literature and highlights limitations of glycopeptides in treating Gram-positive infection.

A review of worldwide experience with sparfloxacin in the treatment of community-acquired pneumonia and acute bacterial exacerbations of chronic bronchitis.

The worldwide occurrence of community-acquired pneumonia (CAP) shows an undiminished prevalence of this serious illness and hospitalisation is common in those patients with severe illness. The diversity of bacterial pathogens that can act as aetiologic agents presents a challenge to initial empiric antimicrobial management. In recent years, treatment has been further complicated by an increased incidence of antibiotic resistance in pathogens such as Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. The newly available fluoroquinolones including sparfloxacin offer an alternative approach to empiric management. Sparfloxacin is active against many typical and atypical pathogens, as well as strains resistant to conventional agents. In comparative studies, the in vitro potency of sparfloxacin and its pharmacokinetic profile have been confirmed. The clinical trial efficacy and safety data suggest it might be a useful empiric therapy for both CAP and acute bacterial exacerbation of chronic bronchitis.

Studies on the microbiological safety of the valved side-port of the 'Venflon' cannula.

A randomized prospective study was conducted to assess the effect of inserting a bacteria-retaining filter into the side-port of 'Venflon' cannulae. Observations were made on 109 cannulae with filters and 100 without. Although there was a trend towards a reduced rate of side-port colonization in the cannulae with filters this was not paralleled by any reduction in the incidence of local inflammation or colonization of the intravascular segment (IVS) of the cannula. Of the 37 cannulae with positive cultures from the skin at the cannula insertion site 22 yielded indistinguishable bacteria from the IVS, while only three of the 25 positive side-port cultures were similarly associated. It is concluded that in the majority of cases, organisms isolated from the IVS originate on the skin and that organisms introduced via the side-port rarely lead to IVS colonization.

Community-acquired pneumonia.

The aetiology of community-acquired pneumonia is reviewed, and the identification of the most likely pathogens, based on clinical presentation, is discussed. By far the major pathogen in community-acquired pneumonia is Streptococcus pneumoniae; the relative frequency of other pathogens, and particularly the atypical pneumonias caused by Mycoplasma and Legionella spp., will depend on local epidemiological factors. The diagnostic tests to confirm diagnosis and subsequent treatment of these infections are reviewed.

Pseudomonas peritonitis in continuous ambulatory peritoneal dialysis: laboratory predictors of treatment failure.

Five episodes of pseudomonas peritonitis complicating continuous ambulatory peritoneal dialysis (CAPD) which were not cured by intraperitoneal antibiotics were studied to assess causes for treatment failure. The activity of gentamicin and ceftazidime against these strains was decreased in the presence of sterile used dialysate compared with nutrient broth. Likewise, kinetic studies showed that in dialysate therapeutically used concentrations of antibiotics failed to kill the isolates over 24 h. All five pseudomonas strains were adherent to silicone rubber Tenckoff catheter segments. An in vitro model of CAPD peritonitis demonstrated that persistence of viable adherent bacteria, after exposure to therapeutic concentrations of gentamicin and ceftazidime, contributes to the failure of antibiotics to cure pseudomonas CAPD peritonitis.