J Antimicrob Chemother

Acute pancreatitis as a model of sepsis.

Year 1998
Wilson PG. Manji M. Neoptolemos JP.
University Department of Medicine, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK.
Severe acute pancreatitis has many similarities to sepsis syndrome and septic shock. The haemodynamic features of cardiovascular instability, reduced ejection fraction and decreased systemic vascular resistance are indistinguishable in each of these conditions. In addition there are many striking similarities in the cytokine and inflammatory mediator profiles, suggesting that the haemodynamic abnormalities may result from the same pathogenic mechanisms, albeit as a result of different inflammatory stimuli. Although septic complications of severe acute pancreatitis do arise these are usually late features and in the early phase of a severe attack there is sterile pancreatic necrosis. Evidence suggests that the important cytokines in the development of complications and multiple organ failure in severe acute pancreatitis are tumour necrosis factor-alpha, interleukin-1, interleukin-6 and interleukin-8. In addition, endotoxin and other important inflammatory mediators including platelet activating factor and phospholipase A2 are implicated in the development of complications in both severe acute pancreatitis and sepsis. Patients with severe acute pancreatitis are not an entirely homogeneous group but in terms of pathogenesis and complications of their disease they have much more in common with each other than the patients who are collected under the unifying diagnosis of 'sepsis'. The similar clinical and biochemical features between severe acute pancreatitis and sepsis make the former an excellent model for studying the pathogenesis of the sepsis syndrome.

Antibiotic accumulation and membrane trafficking in cystic fibrosis cells.

Year 1998
Quesnel LB. Jaran AS. Braganza JM.
School of Biological Sciences, University of Manchester, UK.
Cystic fibrosis (CF) results from mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) which is a regulated chloride channel. The deltaF508 mutation prevents the post-translational glycosylation and membrane insertion of the protein. Severe disease follows, with the formation of a viscous mucus and subsequent chronic bacterial infection of the lungs, necessitating frequent, and often long, periods of antibiotic treatment. The pharmacokinetics of antibiotics in CF patients are abnormal, with lower blood serum levels and higher clearance rates which have never been satisfactorily explained. We found that accumulation of gentamicin in nasal polyp tissue non-CF cells was subject to regulation by the effectors and inhibitors of CFTR function; regulation was lost in deltaF508 CF cells and accumulation was more than doubled because of the inhibition of exocytosis.

Clinical impact and associated costs of Clostridium difficile-associated disease.

Year 1998
Spencer RC.
Bristol Public Health Laboratory, Bristol Royal Infirmary, UK.
Toxin-producing Clostridium difficile is the commonest cause of nosocomial diarrhoea and, as such, poses a major problem in our hospitals. The main population susceptible to disease is the elderly, for reasons that remain unclear. By contrast, carriage rates in neonates are high, but disease is low. The organism also has a major clinical impact in the immunosuppressed host, patients undergoing surgery (especially gastrointestinal) and those with severe underlying disease and longer hospital stay. Other interventions with high-risk associations are enemas, nasogastric and gastrostomy tubes and anti-peristaltic drugs. Data on the associated costs of C. difficile diarrhoea are not freely available, but one estimate is that in an average-sized district general hospital, 100 cases of C. difficile infection can be expected each year with an extra annual cost of 400,000 pound sterling and 2100 lost bed days.

Pathogenesis of Clostridium difficile infection.

Year 1998
Borriello SP.
Central Public Health Laboratory, London, UK. PBorriello@phls.co.uk
Clostridium difficile produces two major toxins referred to as toxins A and B. These are thought to be primarily responsible for the virulence of the bacterium and the major contributors to the pathogenesis of antibiotic-associated gastrointestinal disease. The molecular organization and control of expression of toxins A and B is now starting to be understood, and the cellular mechanism of action of both toxins, glucosylation of Rho family proteins, has been discovered. Other factors, such as production of proteolytic and hydrolytic enzymes, expression of fimbriae and flagella, chemotaxis and adhesion to gut receptors, and production of capsule, may all play a part in pathogenesis by facilitating colonization or by directly contributing to tissue damage, or both. Differential expression between strains of various combinations of these colonization and virulence factors may explain the apparent variability in virulence of C. difficile strains.

The role of antimicrobial agents in the aetiology of Clostridium difficile-associated disease.

Year 1998
Spencer RC.
Bristol Public Health Laboratory, Bristol Royal Infirmary, UK.
High Clostridium difficile disease rates were originally associated with clindamycin use, but this association has declined in recent years following the decline in the clinical use of clindamycin, and disease is now particularly associated with the use of broad-spectrum antibiotics, especially the cephalosporins. There are now sufficient reports in the literature to merit the discontinuation of the widespread use of cephalosporins, especially in the elderly, by the substitution, wherever possible, with antibiotics not associated with the promotion of C. difficile-associated disease. Such agents include benzylpenicillin, gentamicin, trimethoprim, ciprofloxacin and the ureido-penicillins. Widespread education about the proper use of antibiotics in clinical practice remains essential.

The diagnosis of Clostridium difficile-associated disease.

Year 1998
Brazier JS.
Anaerobe Reference Unit, Public Health Laboratory, University Hospital of Wales, Heath Park, Cardiff, UK.
There are well-documented risk factors associated with the development of antibiotic-associated diarrhoea; knowledge of these and of the typical signs and symptoms should alert the clinician to the possibility of Clostridium difficile-associated diarrhoea (CDAD). It is therefore common practice in large general hospitals for clinicians to request, and for laboratories to include, investigations for C. difficile on in-patient stool specimens to confirm a diagnosis of CDAD. The laboratory methods used to investigate for CDAD are divided into two main categories: those that are aimed at detecting the presence of C. difficile or its products, and those that detect either of its two major toxins, A (enterotoxin) and B (cytotoxin). Within each of these broad strategies there are various rationales which are reviewed here.

Treatment of Clostridium difficile infection.

Year 1998
Wilcox MH.
Department of Microbiology, University of Leeds and The General Infirmary, UK. markwi@pathology.leeds.ac.uk
The treatment options for Clostridium difficile infection remain limited, although promising agents are currently being assessed. Metronidazole is the first-line drug of choice for those patients requiring specific anti-C. difficile treatment. Much of the interest in alternative therapies has centred on the difficult management issues posed by patients with multiple symptomatic recurrences of C. difficile infection. However, it is now clear that the majority of these episodes are due to reinfections with new C. difficile strains and not relapses caused by the original bacterium. Hence, the true efficacy of the alternative regimens remains unclear. Individuals susceptible to C. difficile reinfections need to be protected from exposure to C. difficile until their bowel flora recovers. While several biotherapeutic approaches to the treatment and prevention of C. difficile infection have been described, few controlled data are available. Preliminary studies with anti-C. difficile bovine immunoglobulin concentrates for treatment and prevention have produced promising results. Vaccination to prevent C. difficile infection, particularly in high-risk elderly patients managed within institutions where C. difficile is endemic, is a worthwhile therapeutic goal.

The epidemiology and typing of Clostridium difficile.

Year 1998
Brazier JS.
Anaerobe Reference Unit, Public Health Laboratory, University Hospital of Wales, Heath Park, Cardiff, UK.
Clostridium difficile is normally a harmless environmental bacterium but, under certain circumstances, it can cause hospital outbreaks of disease. To understand the disease epidemiology, outbreaks have been investigated by many different methods. The phenotypic and genotypic approaches to typing are reviewed here and the epidemiology of C. difficile-associated disease is elucidated in light of recent information.

Infection control and prevention of Clostridium difficile infection.

Year 1998
Worsley MA.
North Manchester Healthcare Trust, Trust Headquarters, Crumpsall, Manchester, UK.
Clostridium difficile has become a major problem as a nosocomial pathogen that is associated with the use of antibiotics. In the prevention and control of C. difficile disease it is important that programmes are directed at primary and secondary prevention. The three main elements of prevention are: (i) restricted use of antibiotics; (ii) strict enteric precautions when looking after patients with diarrhoea; and (iii) meticulous cleaning of clinical areas. Although poor handwashing is known to play a key role in the spread of infection, there is evidence that compliance with handwashing protocols is low in many hospitals. Infection control teams need to continue to develop creative education programmes to improve compliance with simple infection control procedures. Consideration needs to be given to ensure that patients have access to handwashing and are well informed about infection prevention. Further work needs to be carried out to establish the efficacy of disinfectants in the environment and the identification of a user-friendly, effective sporicide. The importance of both thorough cleaning with detergents to reduce the number of spores in the environment, and clean equipment for each patient should continue to be emphasized.

Treatment of Pseudomonas aeruginosa lung infection in cystic fibrosis with high or conventional doses of ceftazidime.

Year 1998
De Boeck K. Breysem L.
Department of Pediatrics, University Hospital of Leuven, Belgium. christiane.deboeck@uz.kuleuven.ac.be
In cystic fibrosis patients with Pseudomonas aeruginosa colonization and increasing pulmonary infection, ceftazidime 150 mg/kg/day was compared with 320 mg/kg/day. Changes in clinical findings, laboratory tests, pulmonary function and chest radiographs were evaluated after 14 days of treatment in hospital. Both treatments were associated with a significant improvement, but the higher dose did not offer an additional benefit. An increase in alanine aminotransferase (ALT) occurred after both treatments; with a significantly greater increase after the high-dose therapy (mean increase +/- S.E.M. 8% +/- 2% vs 2% +/- 1 %; P < 0.01). All but one of the ALT values after treatment were within normal limits.

Synergic interactions of macrolides and proton-pump inhibitors against Helicobacter pylori: a comparative in-vitro study.

Year 1998
Malizia T. Tejada M. Marchetti F. Favini P. Pizzarelli G. Campa M. Senesi S.
Dipartimento di Biomedicina Sperimentale, Infettiva e Pubblica, Universita degli Studi di Pisa, Italy.
Thirty-eight clinical strains of Helicobacter pylori were isolated from patients with chronic gastritis and gastroduodenal ulceration, and their susceptibility to macrolide antibiotics (roxithromycin, flurithromycin, azithromycin, erythromycin) in combination with proton-pump inhibitors (lansoprazole and omeprazole) and bismuth subcitrate was assayed. Chequerboard titration was used to analyse the results of antimicrobial interactions and showed that the activity of macrolides was enhanced by combining them with lansoprazole, omeprazole or, to a lesser extent, bismuth subcitrate. While the interactions between erythromycin and the proton-pump inhibitors or bismuth subcitrate were always additive, the combinations of roxithromycin-lansoprazole, flurithromycin-omeprazole and azithromycin-lansoprazole acted synergically on 82%, 60% and 60% of H. pylori strains, respectively. These results may, in part, account for the enhanced clinical efficacy of macrolides administered with proton-pump inhibitors in the treatment of H. pylori-associated diseases.

AIDS-related cryptosporidial diarrhoea: an open study with roxithromycin.

Year 1998
Sprinz E. Mallman R. Barcellos S. Silbert S. Schestatsky G. Bem David D.
Department of Internal Medicine, Hospital de Clinicas de Porto Alegre, Universidade Federal Do Rio Grande do Sul, Brazil.
In immunocompromised patients, cryptosporidial diarrhoea is a debilitating and potentially life-threatening infection for which no effective specific therapy exists. In an uncontrolled study of 24 AIDS patients with diarrhoea exclusively due to Cryptosporidium spp., treatment with roxithromycin, 300 mg bd for 4 weeks, produced symptomatic improvement of diarrhoea in 79% of cases, with 50% of patients achieving complete response. The response rate was 100% in a subgroup of five patients with no previous or concomitant opportunistic infections. In complete responders, improvement was rapid, occurring within 3-5 days, and the duration of response was at least 6 months. Response did not appear to be correlated with the degree of immunodeficiency. The most limiting adverse effects were abdominal pain (two patients), elevated hepatic enzymes (two patients) and abdominal pain with elevated hepatic enzymes (one patient). Minor symptoms, such as gastrointestinal upset, occurred in nine patients. We conclude that roxithromycin is relatively well tolerated and effective against cryptosporidial diarrhoea in AIDS patients. Further studies to optimize dosing regimens are required.

Roxithromycin treatment for diarrhoea caused by Cryptosporidium spp. in patients with AIDS.

Year 1998
Uip DE. Lima AL. Amato VS. Boulos M. Neto VA. Bem David D.
Department of Infectious and Parasitic Diseases, Clinics Hospital of Sao Paulo University, Brazil.
In view of the action of newer macrolide antibiotics on intracellular protozoa, we have investigated the efficacy of roxithromycin in the treatment of cryptosporidiosis in 26 patients with AIDS. Cryptosporidiosis was confirmed either by faecal examination for parasites (modified Kinyoun method) or by detection of the parasite in biopsy material obtained by colonoscopy. Patients received oral roxithromycin (300 mg bd) for 4 weeks. Twenty-two patients completed the study. At the end of the study, 15 patients (68%) were considered to be cured and six patients (27%) improved, and treatment failed in one patient (5%). We conclude that roxithromycin is a useful treatment for diarrhoea caused by Cryptosporidium spp. associated with AIDS.